Philosophy of Immunology

PRADEU
Immunology is central to contemporary biology and

medicine, but it also provides novel philosophical insights.
Its most significant contribution to philosophy concerns the
understanding of biological individuality: what a biological
individual is, what makes it unique, how its boundaries are
established and what ensures its identity through time. The Philosophy of
Immunology also offers answers to some of the most
interesting philosophical questions. What is the definition of Biology
life? How are bodily systems delineated? How do the mind and
the body interact? In this Element, Thomas Pradeu considers
the ways in which immunology can shed light on these and
other important philosophical issues. This title is also available
Philosophy of
Philosophy of Immunology
as Open Access on Cambridge Core at http://dx. doi
.org/10.1017/9781108616706
Immunology
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Cover image: Ascidiae from Kunstformen der Natur (1904)

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Elements in the Philosophy of Biology
edited by
Grant Ramsey
KU Leuven
Michael Ruse
Florida State University
PHILOSOPHY OF
IMMUNOLOGY
Thomas Pradeu
CNRS & University of Bordeaux
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Elements in the Philosophy of Biology
DOI: 10.1017/9781108616706
First published online: November 2019
Thomas Pradeu1,2
Abstract: Immunology is central to contemporary biology and

medicine, but it also provides novel philosophical insights. Its most
significant contribution to philosophy concerns the understanding of
biological individuality: what a biological individual is, what makes it
unique, how its boundaries are established, and what ensures its
identity through time. Immunology also offers answers to some of the
most interesting philosophical questions. What is the definition of life?
How are bodily systems delineated? How do the mind and the body
interact? In this Element, Thomas Pradeu considers the ways in which
immunology can shed light on these and other important philosophical
issues. This title is also available as Open Access on Cambridge Core.
Keywords: immune system, self, individuality, cancer, neuroimmunology
© Thomas Pradeu 2019

ISBNs: 9781108727501 (PB), 9781108616706 (OC)
ISSNs: 2515-1126 (online), 2515-1118 (print)
1. ImmunoConcept (UMR5164), CNRS and University of Bordeaux, France.

2. Institut d’histoire et de philosophie des sciences et des techniques (UMR8590), CNRS and
Panthéon-Sorbonne University, France.
Contents
1 Introduction: The Centrality of Immunity in Biology

and Medicine 1
2 Immunity: A Matter of Defense? 3
3 The Unity of the Individual: Self–Nonself,

Autoimmunity, Tolerance, and Symbiosis 13
4 Cancer as a Deunification of the Individual 29
5 Neuroimmunology: The Intimate Dialogue between

the Nervous System and the Immune System 43
References 64
Philosophy of Immunology 1
1 Introduction: The Centrality of Immunity in Biology

and Medicine
Immunology is one of the most central and dynamic fields of today’s biological
and biomedical sciences. It constitutes, in fact, a pivotal bridge between basic
biology and medicine. Immunology is generally defined as the domain studying
the defense of the organism against pathogens but its scope is actually much
wider. Topics as diverse as cancer, infectious diseases, vaccination, transplanta-
tion, autoimmune diseases, chronic inflammatory diseases, metabolic diseases,
development, aging, repair and regeneration, and host–microbiota interactions,
among many others, are all directly related to the field of immunology.
Furthermore, it now appears that immune systems exist almost ubiquitously
across the living world (including in animals, plants, and prokaryotes). In fact,
virtually all domains of biology and medicine are connected to immunology,
and when opening recent issues of leading science or medicine journals, one can
get the impression that immunology is omnipresent. Why has immunology
become so central in our science and daily lives – and why does this matter
philosophically?
I work as a philosopher of science embedded in an immunology lab affiliated
with the Bordeaux University hospital. Over the years I have become increas-
ingly aware of the key role played by the immune system in practically all kinds
of diseases – in their aetiology, diagnosis, and treatment. If you receive
a transplant, the biggest challenge is immunological rejection of the graft,
which explains why you will be prescribed immunosuppressive drugs. If you
have cancer, depending on the type of tumor, you might receive one of the now
hugely discussed immunotherapies, an advance that was awarded the 2018
Nobel Prize in Physiology/Medicine and which constitutes an immense hope
for medical doctors and patients worldwide (Ribas and Wolchok 2018). Even if
you do not receive immunotherapies, the number of the different populations of
your immune cells will be checked regularly to choose and adapt your treat-
ment. Immunology is also central, naturally, for our understanding of autoim-
mune diseases: in type 1 diabetes, for instance, immunologists seek to explain
why the immune system selectively destroys pancreatic β-cells (which secrete
insulin), and how this process might be controlled (Lehuen et al. 2010). If you
happen to come back from another country with a bad viral or bacterial infec-
tion, again, the main goal of medical doctors will be to make your immune
system cope with that infectious agent without severely disturbing the balance
of your immune responses to other elements. Moreover, vaccination rests on the
idea of stimulating the immune system against a particular target. The immune
system also plays a major role in pathologies as diverse as cardiovascular
2 Elements in the Philosophy of Biology
diseases (Hansson and Hermansson 2011), neurodegenerative disorders

(Heneka et al. 2014; Heppner et al. 2015), and obesity (Lumeng and Saltiel
2011) – and for all these diseases it constitutes one important point of leverage
used in the clinic.
So, immunology is pretty much unavoidable in our daily lives, both in health
and disease. One aim of this Element is to show that immunology is also of
paramount importance for philosophers. The most central contribution of immu-
nology to philosophy concerns, arguably, the understanding of biological indivi-
duality. From the end of the nineteenth century onward, it has been recognized
that immunology raises key questions about what a biological individual is, what
makes it unique, how its boundaries are established, and what ensures its identity
through time (Tauber 1994; Pradeu 2012). This Element will explore other
philosophical lessons that can be drawn from current immunology – including
the definition of life (or, more specifically, the basic requirements for all living
things), the delineation and regulation of bodily systems, part–whole relations,
the notion of biological function, and mind–body interactions.
The main claims made in this Element are summed up in Box 1.1.
The present philosophical exploration of immunology will be made through
the examination of concrete scientific and medical examples, such as host–
microbe symbioses, cancer immunotherapies, and the CRISPR-Cas systems.
BOX 1.1 MAIN CLAIMS MADE IN THE PRESENT ELEMENT

1. Most (perhaps all) living things possess an immune system.
2. Immunity is not limited to the activity of defense. The immune system
plays a central role in activities as diverse as development, tissue
repair, and clearance of debris, among others.
3. Anyone interested in biological individuality must take into account
what immunology says on this question.
4. The immune system plays a key role in delineating (and constantly
redrawing) the boundaries of a biological individual, determining
which elements can be part of that individual, and insuring its
cohesion.
5. Cancer results from a process of decohesion in a multicellular organ-
ism, and the immune system has a major influence on the control of this
process.
6. The nervous system and the immune system intimately interact.
Neuroimmunologists’ claims that the immune system can influence
behavior and even cognition are worth examining.
This Element tries to talk simultaneously to philosophers, scientists, and med-

ical doctors. To philosophers of biology, this Element says that immunology
raises many crucial conceptual and philosophical issues and can integrate
elements coming from several related biological fields, including microbiology,
developmental biology, physiology, evolution, and ecology. For philosophers
and metaphysicians, this Element argues that immunology can shed new light
on some philosophical questions that have been fundamental since at least the
time of Aristotle, such as what constitutes the identity of an individual through
time. The message to biologists is that the immune system must be rethought as
one of the most basic and indispensable aspects of any living thing. Finally, the
suggestion to medical doctors is that a constant reflection on immunological
concepts can help open up novel therapeutic avenues – for instance, about
cancer, autoimmune diseases, or the management of ecological interactions
between microbes within our bodies. Overall, the approach taken in this
Element will be an example of philosophy in science, that is, a type of philo-
sophical work that aims at interacting intimately with science and contributing
to science itself (Laplane et al. 2019).
The contents of the Element are as follows. Section 2 critiques the idea that
immunity should be defined exclusively in light of the concept of defense of the
organism against external threats and extends immunity to other key dimen-
sions, particularly development, repair, and other housekeeping activities.
Section 3 shows that immunology is central to the definition of biological
individuality and proposes that a physiological individual is a community of
heterogeneous constituents, including microbes, unified by the action of the
immune system. Section 4 examines the claim that cancer can be defined as
a breakdown of biological individuality and argues that the immune system can
both prevent and promote this breakdown. Finally, Section 5 explores the
interactions between the nervous system and the immune system and assesses
the claim that the immune system may be involved in behavior and cognition.
2 Immunity: A Matter of Defense?

If you cut yourself with unclean tools while doing some gardening, the perva-
sive bacterium Staphylococcus aureus might enter into your body via the wound
site. If your immune system works normally, you will certainly get rid of these
bacteria rapidly. An oversimplified description of this process is that tissue-
resident cells, especially macrophages, detect the bacteria, trigger a local
inflammation (which facilitates the immune response), and usually eliminate
the bacteria, sometimes with the help of other innate immune cells (like
neutrophils) that are recruited at the site of infection. If the bacteria are not
promptly eliminated, then antigen-presenting cells, typically dendritic cells,

migrate to secondary lymphoid organs such as lymph nodes and present bacter-
ial fragments to naive lymphocytes circulating in these compartments.
Lymphocytes with high specificity and affinity for these bacterial antigens are
activated, and their populations expand. Specific lymphocytes then migrate to
the infection site, and, in concert with many other cellular and molecular
components such as antibodies, they destroy the bacteria.
The highly intertwined processes that collectively constitute an immune
response suggest that our immune system is truly a system – a set of processes
that involve many interacting cells distributed throughout the body. Indeed,
although it comprises particular cells (Box 2.1) and organs, the immune system
exerts its influence everywhere in the organism, especially via its network of
lymphatic vessels and its numerous tissue-resident cells (Figure 2.1).
The system by which an organism defends itself against pathogens is pre-
cisely what has generally been called the immune system (Janeway 2001; Paul
2015). Is the activity of the immune system, though, only a matter of defense? In
this section, I show that immunity has been understood historically as an
organism’s capacity to defend itself against pathogens, and that defensive
immune mechanisms have been identified in all species. I then argue that the
immune system cannot be reduced to its defense activity and promote on this
basis an extended view of immunity. Next, I explore the complexities of
accounting for the evolution of immunological processes and attributing
a single function to the immune system. Finally, I explain why it is difficult in
today’s immunology to offer a definition of immunity.
BOX 2.1 SIMPLIFIED PRESENTATION OF THE MAIN CELLULAR AND MOLECULAR

COMPONENTS OF THE IMMUNE SYSTEM IN MAMMALS, WITH SOME OF THEIR ACTIVITIES
1 Cells
Macrophages: phagocytosis, elimination of pathogens, clearance of debris,

antigen presentation, tissue repair.
Neutrophils: phagocytosis, elimination of pathogens, chemotaxis, constitution
of neutrophil extracellular traps, tissue repair.
Mast cells: elimination of pathogens, wound healing, immune tolerance.
Dendritic cells: antigen uptake at the periphery, antigen presentation in
secondary lymphoid organs.
Natural killer cells: elimination of infected cells and cancer cells.
Innate lymphoid cells: elimination of pathogens, tumor surveillance, tissue
repair, metabolism.
Effector T lymphocytes: stimulation of other immune cells, destruction of

infected cells.
Regulatory T lymphocytes: downregulation of other immune cells, prevention
of autoimmune diseases.
B lymphocytes: neutralization, opsonization (promotion of phagocytosis),
complement activation.
2 Molecules
Complement: phagocytosis, inflammation, membrane attack.

Cytokines, including chemokines, interferons, and interleukins: cell
signaling.
Tonsils
Thymus
Lymph node
Thoracic duct
Liver
Spleen
Kidneys Peyer’s patch
(in the small intestine)
Large intestine
Lymphatic
vessels
Bone marrow
Figure 2.1 Human immune system. The human immune system, which
comprises different organs (thymus, bone marrow, spleen, lymph nodes, and so
on), different cells (both circulating and resident) and molecules, and a network
of lymphatic vessels, exerts its influence everywhere in the organism. (Figure
drawn by Wiebke Bretting).
2.1 Historically, Immunity Has Been Understood As

the Capacity of an Organism to Defend Itself
against Pathogens
Pathogens have constituted a major force shaping the evolution of human
beings throughout their history. Devastating infectious diseases are a clear
example. Plague, caused by the bacterium Yersinia pestis, killed more than
50 million people in the fourteenth century. More recently, the pandemic of
influenza virus following the First World War killed over 40 million people
worldwide.
It has long been recognized that humans can resist some infections, with
important differences between individuals and/or populations. While some
people are killed, others show disease symptoms but survive, and still others
do not seem to be affected at all. The notion of immunity is meant to capture this
idea of a specific capacity to avoid the detrimental effects of a pathogen.
Immunity is generally defined as the capacity by which an organism can defend
itself against pathogens.
Host–pathogen interactions are complex, as each partner adapts to the other.
This emphasizes the need to always understand immune defense and patho-
genicity in their ecological and evolutionary contexts (Box 2.2).
BOX 2.2 IMPORTANCE OF THE ECOLOGICAL AND EVOLUTIONARY CONTEXT WHEN

DISCUSSING IMMUNE DEFENSE AND PATHOGENICITY
Immune defense and pathogenicity are not intrinsic properties of hosts and
microbes. Rather, they are a matter of evolutionary and ecological context.
Approaches that pay attention to evolution and ecology have historically
played an important role in immunology (Burnet 1940; Méthot and Alizon
2014). They have taught three important lessons.
1 Pathogenicity Is a Gradual and Contextual Phenomenon
An infectious microorganism is not intrinsically pathogenic (Casadevall

and Pirofski 1999; Méthot and Alizon 2014): it can be harmful in one
species and benign in another, and its virulence often varies between
different individuals in a population. Even within an individual, patho-
genicity depends on pathogen localization, host physiological and immu-
nological state at the moment of the infection, the presence of other
microorganisms, and the past interactions with this pathogen or others,
among many other factors. In addition, the vast majority of microorgan-
isms are not harmful to their hosts.
2 An Ever-Going “Arms Race” Occurs between Hosts and

Pathogens
Hosts and invaders continuously adapt one to the other. This constitutes
one of the main reasons why immune systems are so intricate, with so
many different components acting at various levels. Often, a pathogen
evolves a way to evade a given recognition system of its host species, but
then the host species evolves new recognition systems, which in turn
might be circumvented by the pathogen. Such host–pathogen competition
often takes the form of manipulation of the immune system by pathogens
(Finlay and McFadden 2006). For example, various bacteria display
molecular patterns that look like those of the host (molecular mimicry).
Furthermore, some bacteria can establish residence within immune cells,
which enables them to partly escape the immune response – as
Mycobacterium tuberculosis does in macrophages, for instance.
3 Immune Defense Comes at a Cost

As emphasized by the recent field of ecological immunology (or ecoim-
munology (Schulenburg et al. 2009)), immune responses are costly
because the immune system takes up many bodily resources, and if things
go wrong, these responses can cause terrible damage to the organism.
Ecological immunology has also shown the existence of trade-offs
between the different physiological responses of a host to various envir-
onmental challenges, for example, between immunity, reproduction,
growth, and thermoregulation (Schulenburg et al. 2009).
Historically, the definition of immunity as defense against pathogens is

intimately connected with the development of the vaccination technique
(Moulin 1991; Silverstein 2009). The birth of immunology as a biomedical
field was related with the process of so-called immunization, that is, the
acquisition of protection against a specific agent. Etymologically, immunity
means an exemption (the right to legally escape specific taxes in ancient Rome).
The development of large-scale scientific vaccinations, particularly with Robert
Koch and Louis Pasteur in the nineteenth century, is often seen as one of the
main foundations of the field of immunology (Bazin 2011). Vaccination is
connected with the idea that an organism can increase its defense capacity by
“learning” how to neutralize a given pathogen. The vaccinated organism
responds quicker and more strongly if it reenters into contact with the same
pathogen. This capacity is called immunological memory, a phenomenon that
BOX 2.3 THE DISTINCTION BETWEEN INNATE AND

ADAPTIVE IMMUNITY
AND ITS
LIMITS
Immunologists often distinguish between innate and adaptive immunity:
innate immunity is supposed to correspond to a quick immune response,
without training, whereas adaptive immunity takes more time and entails
the capacity to “learn” from previous encounters with a given target. (A
more precise definition says that innate immunity is characterized by
germline-encoded receptors, while adaptive immunity is characterized
by the production of novel immune receptors via somatic recombination
and clonal expansion (e.g., Lanier and Sun 2009).) Innate and adaptive
immunity, however, intimately and dynamically interact. Furthermore,
over the last two decades the distinction between them has blurred because
many immune components can be located on a gradient from innate to
adaptive immunity (Flajnik and Du Pasquier 2004), and immunological
memory is in fact a complex, multidimensional, and gradual process found
across the living world, including in bacteria and archaea (Pradeu and Du
Pasquier 2018).
has long been used to make a distinction between two arms of immunity, namely
innate and adaptive immunity (Box 2.3).
2.2 Defensive Immune Mechanisms Have Been Identified

in Virtually All Living Things
Beyond humans, all animals, plants, unicellular eukaryotes, bacteria, and
archaea are constantly under the potential threat of pathogens and have evolved
multiple mechanisms to cope with those pathogens (Anderson and May 1982;
Stearns and Koella 2008). Contrary to the long-held view that only vertebrates
possess an immune system, in the last thirty years or so immune systems have
been found in all the species in which their presence has been thoroughly
investigated (Pradeu 2012). Importantly, one can observe that, in all these
cases, the criterion used for saying that an immune system exists in a species
has been the identification of a system of recognition, control, and elimination
of pathogens. This confirms that defense remains the intrinsic, if sometimes
implicit, definition of immunity that most biologists adopt when they talk about
the immune system.
Plants lack a circulatory system and mobile immune cells, but they are
capable of establishing immune responses that are highly specific, with limited
damage to the host, and that can even generate a form of immunological
memory (Spoel and Dong 2012). Plants deal with pathogens by diverse
modes of recognition (including nucleotide-binding domain, leucine-rich repeat

(NLR) receptors) and effector responses (Jones and Dangl 2006).
Bacteria and archaea can be infected by pathogens, including viruses called
bacteriophages, or more simply phages. They respond to these pathogens
through different immune mechanisms, including suppression of phage adsorp-
tion, restriction modification of the invading phage genome, abortive infection,
and the recently discovered CRISPR-Cas systems (CRISPR stands for
“Clustered, Regularly Interspaced, Short Palindromic Repeats”) (Hille et al.
2018). CRISPR-Cas systems provide many bacteria and archaea with protection
against phages and other mobile elements (including plasmids and transposons)
through a three-step process. The first step is adaptation: small fragments of DNA
from the invader are incorporated into the CRISPR array of the host. The second
step is expression and processing: the CRISPR array is transcribed, and the
precursor transcript is processed to generate CRISPR RNAs. The final step is
interference: the CRISPR RNA guides a complex of Cas proteins to the matching
target, which initiates the destruction of the invading nucleic acid (Jackson et al.
2017). CRISPR-Cas has generally been described as a key defense mechanism of
prokaryotes against mobile elements (including phages) (Horvath and Barrangou
2010), along with other, more recently identified antiphage defense systems
(Doron et al. 2018). Most experts even consider CRISPR-Cas as a form of
adaptive immunity in bacteria and archaea (because it displays a form of immu-
nological memory) on top of being heritable, as it can be transmitted to daughter
cells (Horvath and Barrangou 2010; Hille et al. 2018). This has led to discussions
over the potentially Lamarckian nature of the CRISPR-Cas system (see (Koonin
2019) and accompanying commentaries).
Other important examples of organisms with now well-described immune
systems include insects (Lemaitre and Hoffmann 2007), sponges, hydra, and
slime molds (Müller 2003; Chen et al. 2007; Augustin et al. 2010).
2.3 Extended Immunity: Immunity Goes Well Beyond Defense

The centrality of host defense against pathogens in the survival of all organisms
should not obscure the fact that immunity goes well beyond mere defense. Although
immunity was long conceived exclusively as a system of defense, recent research
has shown that immune processes actually play a critical role in a wide variety of
physiological phenomena such as development, tissue repair, clearance of debris or
dead cells, maintenance of local tissue functions, metabolism, thermogenesis, and
the functioning of the nervous system, among many others (Pradeu 2012; Rankin
and Artis 2018), leading to an extended view of immunity. Repair is a particularly
fundamental process, which maintains the integrity and cohesion of the organism.
When you cut yourself, in addition to the well-known action of platelets, which
initiate blood clot and vasculature closure, a horde of immune cells is required at
every stage of the repair process to insure proper wound healing (Gurtner et al.
2008; Wynn and Vannella 2016). The three key stages are inflammation, new tissue
formation, and remodeling. The main immune cells participating in tissue repair are
neutrophils and macrophages. The plasticity and adaptation to context of these cells
are crucial (Laurent et al. 2017). Immune cells are also important in processes of
regeneration, such as those found in plants, hydra, arthropods, and amphibians, and
by which entire complex structures such as limbs can regrow (Eming et al. 2014).
Another key daily activity of the immune system is the clearance of bodily debris,
coordinated by phagocytotic cells (Nagata 2018). In addition, the immune system is
essential for development, that is, the early construction of the organism. This
includes the indispensable role of immune-mediated apoptosis and phagocytosis
very early on in many developmental processes (Wynn et al. 2013; Okabe and
Medzhitov 2016), as well as the role of the complement in development (Ricklin
et al. 2010; Stephan et al. 2012) (e.g., phagocytosis mediates the indispensable
elimination of excessive tissues; the complement, a cascade of proteins in the blood,
remodels synaptic connections in the developing nervous system). Importantly,
even though the above description applies mainly to animals, the observation that
the immune system realizes various activities beyond defense holds across all living
organisms; for example, CRISPR-Cas systems in prokaryotes participate not only
in defense but also in repair.
Many of the same actors that ensure the defense of the organism against
pathogens, therefore, are equally central for processes previously considered as
nonimmune and which overlap to a significant degree (Figure 2.2). Perhaps one
could even consider that the very division of these processes into such cate-
gories as “defense,” “repair,” and “development” reflects more the way we, as
investigators, address questions about bodily systems (and divide such pro-
cesses into convenient categories) than real differences in nature. From this
point of view, there would be much to say in favor of a revised epistemology of
immunology, understood as a reflection on how the categories by which the
immune system has been conceived (in the context of the division into systems)
could be redefined and redrawn.
2.4 Accounting for the Evolution of Immunological Processes

and Attributing a Function to the Immune System
Have Become Difficult
The extension of immunity well beyond defense has consequences for two
central issues, namely the evolutionary history of immune systems and
Defence
Maintenance of Clearance
tissue homeostasis
Immune system
Development Repair
Figure 2.2 Extended immunity: overview of the various, partly

overlapping, activities of the immune system. The immune system not only
defends the organism against different potential threats but also constructs,
repairs, cleans up the organism, and maintains tissue homeostasis, among other
activities.
functional ascription in the case of the immune system. It increasingly appears

that immune systems have evolved under different selective pressures, which
include the necessity to defend the organism against pathogens but are much
more diverse than that. Natural selection has favored immune systems efficient
at simultaneously defending, constructing, repairing, cleaning up, and main-
taining the organism. Many trade-offs exist among these various selective
pressures. For example, so-called type 2 immunity (essential for repair, but
also in response to parasites) is partly at odds with type 1 immunity (which
responds to intracellular abnormalities, including viruses and intracellular bac-
teria), as the activation of one weakens the efficacy of the other. Current
immune systems function by balancing these different dimensions and reaching
a complex equilibrium between them in the context of present and past envir-
onmental pressures (Eberl 2016).
This discussion also brings up the question of the origins of the first immune
systems. The capacity to regulate the various processes of defense, development,
repair, clearance of debris, and maintenance of homeostasis is probably as ancient
as life itself. If so, then all living things that currently exist or have existed in the
past have an immune system. The key question, therefore, becomes how replicat-
ing molecules started to acquire, a few billions of years ago, the capacity to
coalesce into groups, stick together, and maintain, repair, and defend themselves
at this emerging group level. Much later, the same question was raised for the
transition from unicellular to multicellular organisms where, again, the constitution

of an immune system at the multicellular level was crucial (Michod 1999; Pradeu
2013). Obviously, this approach to the evolution of immune systems is entirely
different from the classic (and naturally important) discussion in immunology over
how adaptive immune systems evolved in vertebrates some 400 to 500 million
years ago (Pancer and Cooper 2006). Much work remains to be done on this
question of the origins of immunity, including by developing cross-species com-
parative immunology.
What has been said here about the expansion of the scope of immunity can also
be framed in terms of the long-standing debate in the philosophy of biology about
functions (Wright 1973; Cummins 1975). Bodily systems generally have been
viewed as obvious instances of a valid functional ascription: the function of the
digestive system is to digest, the function of the respiratory system is to breathe,
and so on. According to the traditional view of immunity, the function of the
immune system is to defend the organism. Following this tradition, some philoso-
phers have suggested (Matthen and Levy 1984; Melander 1993) that the function of
the immune system, in the etiological sense (that is, what it has been selected for)
(Wright 1973), is organism defense. Yet saying what the immune system has been
selected for proves, in fact, extremely difficult. Given the various activities of the
immune system and the diversity of selective pressures it has undergone, it would
be inadequate, or at least too restricted, to say that the immune system has been
selected for its capacity to defend the organism against pathogens. It is not possible
to single out one of these aspects and say that this is “the function” (or even “the
main function”) of the immune system. It seems likely that the systemic approach
to functions (Cummins 1975) is certainly better suited for immunology, but
a detailed analysis of the promises and limitations of a systemic approach to
immune functions remains to be done.
2.5 Is It Still Possible to Offer a Precise and Simple

Definition of Immunity?
The extension of the scope of immunity well beyond defense affects dramati-
cally the meaning of the term immunity and raises a thorny but central problem:
given the diversity of phenomena in which the immune system plays a crucial
role, is there still a unity of the concept of immunity, or is it just the loose and
artificial putting together of a horde of processes under a single term? In other
words, is there ultimately such a thing as immunity that unifies all of these
processes under a single concept? I see this question as one of the most
fascinating that current and future immunology must face. Defining what counts
as an immune process and delineating the field of immunology has indeed
become extremely challenging nowadays. Focusing on defense against patho-

gens would be too narrow. On the other hand, extending the definition of
immunity so far as the overall physiological regulation of the body (as some-
times suggested by recent studies on the role of the immune system in metabo-
lism, tissue repair, homeostasis, development, and so on) would be so broad that
it might cease to be scientifically fruitful, as almost everything in biology could
be said to be immunological, at least to some degree. One possibility would be
to say that any component involved in a series of activities that includes defense
against pathogens is part of immunity (in this conception, immunity would be
centered on, but not limited to defense), but this option would still leave us with
a broad conception of immunity. Uncertainties of this kind have led to
a situation in which, perhaps unsurprisingly, current immunologists do not
offer a single and consensual response to the question “What is immunity?”
I have tried in the past to put forward a definition of immunity according to
which immunological processes correspond to all the processes of biochem-
ical recognition of a target, followed by the elimination or the regulation of
the elimination of this target (Pradeu 2012). This definition is not without
difficulties (particularly concerning the level(s) at which it is supposed to
apply), but I think it does capture the diversity of phenomena currently
studied by immunologists, while remaining sufficiently specific so as not to
include all classically understood physiological processes occurring in the
organism. It also has the advantage of reflecting the diversity of immune
systems in nature, from prokaryotes to vertebrates. More research is needed,
though, to determine whether a definition of this kind could satisfy the
majority of immunologists.
A related but broader and more imprecise characterization of immunity is to
say that immunity is one of the main devices insuring the cohesion of the
organism and the delineation of its boundaries. We will explore and assess
this view in the next section, which is devoted to immunology’s contribution to
the definition of biological individuality.
In summary, this section has shown that immune defense is essential in every
living thing, but immunity cannot be reduced to defense.
3 The Unity of the Individual: Self–Nonself, Autoimmunity,

Tolerance, and Symbiosis
In 1998, Clint Hallam, a patient from New Zealand who was operated on in
Lyon, France, received the world’s first hand graft (Dubernard et al. 1999). The
operation was a technical success, and initially the recipient seemed to feel all
right. Yet he soon started to consider as “other” (foreign) the transplanted hand,
which became unbearable for him. Hallam interrupted immunosuppressive

treatment, organ rejection started, and eventually he asked that his hand be
amputated (Dubernard et al. 2001). With face transplants (36 patients under-
went face transplants from 2006 to 2016 (Siemionow 2016)), recipients and
doctors are confronted with even more difficult and pressing identity issues
(Carosella and Pradeu 2006).
These are certainly extreme cases. Nonetheless, every year in the United
States approximately 16,000 kidney and almost 6,000 liver transplantations are
done (Wolfe et al. 2010), and in the European Union around 19,000 kidney and
7,000 liver transplants (European Directorate for the Quality of Medicines &
HealthCare 2015). Despite the apparently routine nature of such transplanta-
tions, the body does not seem ready to tolerate any component coming from
another organism. First, in the case of the kidney, for example, medical doctors,
before proceeding to transplantation, carefully check compatibility between
donor and recipient, particularly in terms of the major histocompatibility com-
plex (MHC) (Kahan 2003). Second, the transplant patient receives immuno-
suppressive drugs. Thus, even if not all these transplantations prompt the kind of
identity crisis experienced by Clint Hallam, they do raise the questions of how
the boundaries of a biological individual are defined and under which conditions
some external elements can become part of that biological individual. These are
exactly the questions that led the nascent field of immunology, in the first half of
the twentieth century, to take on the problem of biological individuality via
a combination of reflections about transplantation and infectious diseases.
The aim of this section is to show why immunology makes a critical con-
tribution to the problem of biological individuality, especially from the points of
view of boundaries and parthood just mentioned. Immunology has raised this
problem mainly through the concepts of “self” and “nonself,” so much so that in
the 1980s immunology was famously named “the science of self-nonself dis-
crimination” (Klein 1982). I examine here the conceptual and experimental
limitations of the self–nonself framework, while insisting that this critique does
not undermine the essential claim that immunology plays a key role in the
definition of biological individuality.
The outline of the section is as follows. First, I describe the birth of the self–
nonself framework in immunology. I then spell out how current immunologists
conceive biological individuality, especially on the basis of recent research on
autoimmunity, immunological tolerance, and symbiosis. Third, I explore three
arguments demonstrating the central contribution of immunology to biological
individuality. Fourth, I show that the functioning of the immune system sheds
light on how a set of heterogeneous constituents can be turned into an integrated
individual. Finally, I make a claim for combining immunology’s lessons about

biological individuality with the lessons drawn from other biological fields.
3.1 From Early Reflections about Immunological

Individuality to the Concepts of “Self” and “Nonself”
The key contribution of immunology to the reflection on biological individual-
ity and identity ever since the end of the nineteenth century has been empha-
sized by historians and philosophers of this field over the last three decades
(Löwy 1991; Moulin 1991; Tauber 1994; Pradeu 2012; Anderson and Mackay
2014). Here my goal is not to go into the details of that history, but rather to
show how these early thoughts have been revisited in recent immunology.
The idea that immunological reactions had something to do with the ques-
tions of bodily individuality and identity was expressed as early as the end of the
nineteenth century by many scientists, including, for example, Charles Richet
(Richet 1894; Löwy 1991). The many attempts to transplant body parts (espe-
cially the skin, which happens to be, in fact, an extremely difficult transplanta-
tion) in the wake of the First World War, however, constituted an important
turning point, as it led many biologists and medical doctors to raise specifically
the question of the biological determinants of the uniqueness of each individual
and its capacity to recognize these unique determinants and to potentially detect
and respond to elements that differ from them (Loeb 1937; Medawar 1957).
Starting from the 1940s, Frank Macfarlane Burnet (1899–1985) (Burnet
1940; Burnet and Fenner 1949) framed the concepts of immunological “self”
and “notself” (later called “nonself”) (Löwy 1991; Moulin 1991; Tauber 1991;
Anderson and Mackay 2014). In its most basic form, the self–nonself frame-
work says that the elements originating from an organism (the “self”) do not
trigger an immune response, while elements foreign to this organism (the
“nonself”) trigger an immune response. Such a framework can account for the
rejection by the body of both infectious agents and grafts. The self–nonself
vocabulary played an important role in establishing the study of infectious
diseases as well as research on transplantation as subdomains of the science
of immunology.
Burnet saw as a major challenge the question of how an organism can learn to
preserve the constituents of the “self.” Partly inspired by Ray Owen’s work on
chimerism (Owen 1945), Burnet postulated that, if foreign material was
implanted early in the embryo, no antibodies would develop against that
particular foreign material (Burnet and Fenner 1949). This was later confirmed
by experiments made by Peter Medawar’s group, showing that a tissue
implanted early in the mouse embryo could subsequently be tolerated
(Billingham et al. 1953). For Burnet, therefore, the self is acquired, not innate:
the organism acquires at an early ontogenetic stage the capacity to recognize its
own constituents and to avoid their destruction (Burnet and Fenner 1949;
Burnet 1969). But Burnet argues that, in nature, contrary to what happens in
these experimental settings, the immunological self reflects the genetically
endogenous components of the organism because the repertoire of immune
receptors is constituted on the basis of these endogenous elements present in the
body (Burnet 1962). Burnet considers several obvious challenges to the self–
nonself framework, including autoimmune diseases and foeto-maternal toler-
ance as well as other forms of immunological tolerance (that is, the absence of
destruction of a foreign entity by the immune system). But he treats them as
exceptions to the general rule and considers that these exceptions must be
explained via specific mechanisms (pathological mechanisms in the case of
autoimmune diseases, and particular provisory mechanisms in the case of foeto-
maternal tolerance) (Burnet 1969). All these reflections constituted the founda-
tions of a fruitful theoretical and conceptual framework about the self and
nonself, which was developed by Burnet over more than three decades, and
which combined in an innovative way molecular, cellular, ecological,
and medical considerations (Burnet 1940, 1969, pp. 309–310). Burnet shared
the 1960 Nobel Prize in Physiology/Medicine with Medawar for what was
essentially a contribution of a conceptual and hypothetical nature, as acknowl-
edged by Burnet himself (Burnet 1960, p. 700).
From a theoretical viewpoint, what Burnet sees as his main contribution to
immunology is not primarily the self–nonself theory but rather the “clonal
selection theory.” The clonal selection theory goes against instructionist
approaches to antibody formation (especially that of Linus Pauling) by stating
that, when an antigen penetrates into the organism, immune cells bearing
receptors specific for this antigen undergo selection and are subsequently
responsible for the elimination of that antigen (Burnet 1959, p. 54). Burnet
therefore proposes the adoption of a Darwinian framework at the cell level
within the multicellular organism (Burnet 1959, p. 64) – an idea that had been
suggested before him but that Burnet framed in a much more precise way
(Schaffner 1992; Silverstein 2002).
Nonetheless, the clonal selection theory and the self–nonself theory are
intimately connected, so much so that Burnet generally argues for them in
parallel (e.g., (Burnet 1959, 1969)). The phenomena that the clonal selection
theory seeks to explain are immune recognition of the antigen, immune toler-
ance, and the acquisition of “self-knowledge” by the organism. To account for
these phenomena, Burnet proposes the existence of two selective processes: one
occurs in adult life, when an antigen enters into the body, as we just saw; but
another selective process occurs long before, in early life, and this other process
is the elimination of immune cells that recognize “self” components (Burnet
1959). This explains why, in 1969, Burnet writes that the clonal selection theory
provides “the simplest possible interpretation of how the body’s own constitu-
ents are shielded from immunological attack” (Burnet 1969, p. 12).
From the second half of the twentieth century to the present day, the self–
nonself framework has been adopted by a large majority of immunologists and
enriched by a host of experimental, conceptual, and theoretical contributions
(e.g., Bretscher and Cohn 1970; von Boehmer and Kisielow 1990; Janeway
1992; Langman and Cohn 2000). Today, the self–nonself remains the dominant,
if often implicit, framework in which immunologists conceive how the immune
system works (e.g., Stefanová et al. 2002; Goodnow et al. 2005; Jiang and Chess
2009; Fulton et al. 2015). This is particularly illustrated by the fact that when
a novel immune system is identified, as recently happened with the CRISPR-
Cas systems in archaea and bacteria, scientists spontaneously use the self–
nonself vocabulary to account for its functioning (Nuñez et al. 2015) (this
comes in addition to the idea of CRISPR-Cas as a system of defense, as
discussed in the previous section). Together with the persistent use of the
self–nonself vocabulary in several other domains (including, for instance,
studies on autoimmune diseases and transplantation), this confirms the long-
standing influence of this framework in immunology over the last six decades.
3.2 Autoimmunity, Tolerance, and Symbiotic

Interactions with Microbes
Despite its undeniable success as an encompassing conceptual framework for
immunology, the self–nonself theory faces many difficulties. First, far from
being always pathological, autoimmunity has been proved to be a necessary
component of everyday immunity. A degree of autoreactivity (i.e., reaction to
“self”) characterizes the lymphocytes generated and selected in primary lym-
phoid organs as well as naïve lymphocytes circulating in the periphery (Tanchot
et al. 1997; Anderton and Wraith 2002; Hogquist and Jameson 2014). Effector
T cells are selected only if they react weakly to self elements (and not if they do
not react at all). Moreover, strong autoreactivity in the thymus can lead to the
selection and differentiation of lineages specific to self elements, including
regulatory T cells (cells that dampen the activation of the immune system and
play a key role in the prevention of autoimmune diseases) (Wing and Sakaguchi
2010). In addition, many effector immune responses that occur routinely at the
periphery during the lifetime of an organism target endogenous (“self”) ele-
ments, as illustrated by the phagocytosis of dead cells, the clearance of cellular
debris, many immune-mediated repair mechanisms, and the downregulating

action of regulatory T cells, among many other phenomena. In other words, the
claim that the immune system does not respond to self components is not true.
There exists in fact a continuum from autoreactivity (interactions between
immune receptors and endogenous motifs) to autoimmunity (the triggering of
an effector response targeting endogenous motifs) and to autoimmune diseases
(only the latter situation is pathological; it consists in the destruction of endo-
genous components, in a sustained manner and on a large scale – a given organ
or even the whole organism in the case of systemic autoimmune diseases such as
lupus) (Pradeu 2012).
Second, many genetically foreign entities are not eliminated by the immune
system and are instead actively tolerated via regulatory immune responses. This
includes examples such as foeto-maternal tolerance and various forms of
chimerism, but also, and most crucially, immunological tolerance to a large
number of bacteria, archaea, viruses, and fungi at all of the body’s interfaces,
including the gut, skin, lungs, sexual organs, and so on (Hooper and Gordon
2001; Chu and Mazmanian 2013; Virgin 2014; Chen et al. 2018). These resident
entities, which are found in almost all living things in nature, are often referred
to as the “microbiota.” Contrary to what was thought for many years, these
microbes are not “invisible” to the host immune system. The immune system
interacts and develops an active dialogue with them, which leads to the trigger-
ing of a complex balance of effector and immunoregulatory mechanisms. In
many cases, the host immune system facilitates the establishment and stability
of certain components of the microbiota (Round and Mazmanian 2009;
Donaldson et al. 2018). Importantly, microbial molecular patterns that were
conceived for a long time as pathogenic signatures can also mediate tolerogenic
immune responses (Sansonetti and Medzhitov 2009). All this confirms the
centrality of the phenomenon of immunological tolerance, especially to the
microbiota, in today’s immunology (Pradeu and Carosella 2006a; Pradeu 2012).
Immunological interactions between host and microbes enable, in general,
a peaceful coexistence between these two partners. It is estimated that a human
host, for example, is made up of as many bacterial cells as its genetically self cells
(Sender et al. 2016). Yet the most central point is not so much the number of these
resident microbes as what they do in the organism. The involvement of bacteria in
digestion has been known for decades, but recent research has shown that resident
microbes play a major and sometimes even indispensable role in host activities as
diverse as development, metabolism, defense, tissue repair (McFall-Ngai 2002;
Xu and Gordon 2003; McFall-Ngai et al. 2013), as well as many other processes,
including behavior (Sharon et al. 2016; Vuong et al. 2017; Schretter et al. 2018a).
The fitness benefit for microbes consists generally in particularly favorable niches,
where they find nutrients and protection from competitors, among other things
(Donaldson et al. 2016). Microbes can also manipulate their host in many
different ways (Sansonetti and Di Santo 2007). Finally, it is crucial to understand
that the interaction between host and resident microbes is the product of
a complex equilibrium, in which the nature of the ecological relationship can
change through time depending on the circumstances and switch from mutualism
to commensalism to parasitism (microbes that switch from the status of symbionts
to pathogens have sometimes been called “pathobionts” (Chow et al. 2011)).
Recent work on immunological tolerance and the intimate dialogue between
host and microbes across the living world invalidates the claim that the immune
system eliminates foreign (nonself) entities. In the last two decades, symbiosis
in general and symbiotic interactions with microbes more specifically have been
recognized as ubiquitous and essential phenomena in nature. The specific
contribution of immunology to this literature is to ask how symbiotic entities
can be tolerated by the immune system and how they interact with this system in
several central physiological processes (see Box 3.1).
BOX 3.1 THE IMPORTANCE OF RESEARCH ON SYMBIOSIS IN RECENT BIOLOGY AND

PHILOSOPHY OF BIOLOGY AND THE ROLE OF IMMUNOLOGY IN THAT RESEARCH
Although research on symbiosis has a long history, the last two decades
have seen a burst of investigations on this topic, at the crossroads of
different domains, largely as a consequence of new technological
advances (McFall-Ngai et al. 2013), particularly high-throughput sequen-
cing and metagenomics. A key discovery was that virtually all living
things harbor myriad microorganisms, many of which are beneficial to
the host for activities as diverse as nutrition, development, and metabolism
(Xu and Gordon 2003).
Recent work on symbiosis has also been of central interest to philoso-
phers and conceptually interested biologists. Among the central issues,
one can emphasize the degree of individuality displayed by host–microbe
associations (Gilbert 2002; Pradeu and Carosella 2006b; Gilbert et al.
2012), the marriage of ecology and developmental biology (Gilbert 2002),
an enrichment of the major transitions in evolution framework (Kiers and
West 2015), the impact of symbiotic interactions on traditional views
about evolutionary processes and the “tree of life” (Bouchard 2010) as
well as debates about the concept of “holobiont” (Zilber-Rosenberg and
Rosenberg 2008), and the long-recognized challenge of the transition from
correlation to causality in microbiome studies (for example, if the micro-
biome composition in patients with inflammatory bowel disease differs
from that of healthy individuals, is this difference a cause or

a consequence of the disease?).
Not only has immunology been one of the most active fields in the
development of this recent research on symbiosis (e.g., Hooper and
Gordon 2001), but it also offers a specific perspective on this topic,
namely the question of how so many genetically foreign entities can be
tolerated rather than eliminated by the host immune system (Xu and
Gordon 2003; Pradeu and Carosella 2006b; Round and Mazmanian
2009). In most cases, the symbiotic dialogue between the host and
microbes is mediated by immune interactions (Round and Mazmanian
2009; Belkaid and Harrison 2017), which confirms the central role of the
immune system as an interface with the environment as well as between
components of the organism. One striking result is that microbes, long
seen as what the immune system must reject, can often participate in the
immunological defense of the host against pathogenic entities (Pamer
2016), thus creating a form of “co-immunity” (Chiu et al. 2017). This
phenomenon of microbiota-mediated protection often involves compo-
nents of the virome (all the viruses living in/on a host), which increasingly
appears as a major future frontier in biomedical research (Virgin 2014).
The upshot is that the self–nonself theory is inadequate or at least incomplete,

because many self components trigger immune responses and many nonself
components are actively tolerated by the immune system. Therefore, today’s
immunology calls for novel and richer theoretical frameworks (Janeway 1989;
Grossman and Paul 1992; Matzinger 2002; Pradeu et al. 2013), as well as
renewed reflections about immunological individuality. The next section
shows why, despite the critique of the self–nonself theory presented here, the
claim that the immune system is pivotal for the definition of biological indivi-
duality remains entirely valid.
3.3 Immunology’s Contribution to the Definition

of Biological Individuality
At the most general level, the issue of biological individuality consists in
asking what makes up a countable, relatively well-delineated, and cohesive
entity in the living world (Sober 1991; Hull 1992). (Being countable and
well-delineated concerns what can be called external unity, whereas cohe-
sion has to do with internal unity.) Yet the meaning of countability, delinea-
tion, and cohesion remains unclear and is therefore a matter of debate
among philosophers of biology and biologists. Accounts of these three

dimensions have generally been based either on intuition or on evolutionary
theory (Hull 1992; Godfrey-Smith 2009), leaving aside, in most cases, other
biological fields, including physiological ones. In all these accounts the idea
of “cohesion” seems particularly diverse and equivocal: a range of concepts
have been suggested to elucidate this idea, including “functional integra-
tion” (the fact that parts are interconnected and interdependent) (Sober
1991), “near-complete decomposability” (the fact that interactions between
parts of the individual are stronger than interactions between parts of the
individual and the environment) (Simon 1969; Wimsatt 1972), and “coop-
eration and absence of conflict” (Queller and Strassmann 2009), but these
concepts only partly overlap, and they are not always easy to define and to
apply.
There is nowadays a quasi-consensus that biological individuality is
question-dependent and practice-dependent, can be realized at different levels,
comes in degrees, and should not be based on intuitions or on an anthropocentric
approach (Pradeu 2016a; Lidgard and Nyhart 2017). I agree with this consen-
sus. The specific question raised here is in what sense and to what extent the
domain of immunology contributes to addressing the problem of biological
individuality, essentially from a physiological point of view. (Section 5 dis-
cusses how to combine this approach with other approaches to biological
individuality, including evolutionary ones.)
The main claim of this section is that immunology makes an important
contribution to the definition of biological individuality insofar as it sheds
light on all three dimensions discussed above, namely countability, delineation,
and cohesion. The three main activities of the immune system participating in
the individuation of biological entities can be called “filtering over entry,”
“filtering over presence,” and “promotion of cooperation” (by “filter” I mean
allowing or, on the contrary, restraining the entry or presence of something, as
explained below). As Figure 3.1 indicates, these activities map onto countabil-
ity, delineation, and cohesion.
“Filtering over entry” refers to the fact that the immune system constantly
patrols the interfaces of the organism with the environment (skin, gut, and so on)
and determines which exogenous elements can enter the organism and which
can’t. It thus plays a decisive role in the delineation of the organism’s bound-
aries and the possibility of counting it as one single entity.
But the immune system does much more than control entries into the organ-
ism at interfaces. In a process that can be called “filtering over presence,” the
immune system constantly monitors the motifs expressed by the cells present in
all tissues and body compartments as well as their intracellular content and
Immune system Biological individuality
Filtering over entry Countability
Delineation
Filtering over presence
Cohesion
Functional integration
Promotion of cooperation Near-complete
decomposability
Copperation and absence of
conflict
Figure 3.1 The three main activities by which the immune system
participates in the individuation of biological entities and how they map
onto the traditional conception of a biological individual. Filtering over
entry sheds light on the idea of the individual as a countable and relatively well-
delineated entity, while filtering over presence and promotion of cooperation
shed light on the idea of the individual as a cohesive entity.
determines which elements are tolerated, and therefore can remain part of that
living thing, and which elements are rejected, and therefore cannot remain part
of that living thing. But what exactly does the immune system detect in this
process of internal filtering? Although it has long been said that the immune
system controls the identity of the elements with which it interacts (that is, their
conformity with the self), my own view is that the immune system eliminates
elements that change too abruptly, while tolerating elements that change slowly
(Pradeu et al. 2013). Regardless of the criterion one adopts, though, it remains
that the immune system constitutes such a filter over internal elements in
addition to filtering the entry of external elements at bodily interfaces.
Lastly, the immune system plays an important role in the promotion of
cooperation between the components of the organism. It does so in two different
ways. First, the immune system can ensure long-distance communication
between remote components of the organism. In plants this is done through
the vasculature and thanks to metabolites (Shah and Zeier 2013). In metazoans
this is made possible by different processes, most prominently the unique
mobility of immune cells. For example, immune cells can inform distant organs
about the presence of a pathogen in the organism and also contribute to tissue
remodeling in remote sites (Eom and Parichy 2017). As we will see in Section 5,
other systems like the endocrine and the nervous systems are also capable of
long-distance communication in metazoans, but the immune system is unique in
its capacity to send cells to every compartment of the organism. Second, the
immune system can eliminate noncooperative elements (“cheaters”), for
instance, cancer cells (see next section) (Michod 1999; Frank 2007), via the
detection of abnormal molecular patterns, cell stress, aberrant cellular prolif-

eration, and/or damage caused to the organism (Muraille 2013).
These last two activities (filtering over presence and promotion of coopera-
tion) contribute to the cohesion of the biological individual (Figure 3.1). They
strengthen functional integration (interconnection and interdependence), inter-
nal interactions (and therefore near-complete decomposability), as well as
cooperation and absence of conflict between components.
Two important additional remarks are in order. First, the immune system is
truly systemic, which means that, contrary to many bodily systems (e.g.,
digestive or respiratory), the immune system exerts its influence throughout
the body. Therefore, filtering over entry, filtering over presence, and promotion
of cooperation occur continuously and everywhere in the organism. (Many
organs, either located at the interface with the environment or more internal,
have been called “immunoprivileged” – for instance, the central nervous system
and the eye, among many others. Yet recent research has shown that such
compartments are not without immune influences (Mellor and Munn 2008;
Louveau et al. 2015a). They are instead places where immunological processes
are regulated differently than in the rest of the organism.)
Second, one crucial characteristic of the immunological approach to biolo-
gical individuality is its broad range of application. It applies, in fact, to the
whole living world, since immune systems are found in virtually all living
things, including prokaryotes, plants, invertebrates, and vertebrates (see
Section 2).
Thus, the immune system plays a central role in the delineation of the
boundaries of a living thing and the determination of the cohesion between its
constituents (Pradeu 2012). But is this account really different from the self–
nonself framework examined above? It is actually essential to understand how
the two accounts differ. For Burnet, the self–nonself framework is scientifically
testable and useful if and only if self and nonself are defined in terms of origins:
the self is what originates from the organism once it has acquired the capacity to
recognize its own constituents, while the nonself is everything that does not
originate from the organism. In stark contrast, the discrimination proposed
above between what is part of the living thing and what isn’t is not based on
a question of origin, since in this view many genetically foreign entities can be
accepted by the immune system while many endogenous entities are routinely
destroyed. For example, in the account developed here, microbiota components
that are immunologically tolerated belong to the organism, while they are
considered nonself and therefore not part of the organism in the self–nonself
theory. In other words, I propose that the immune system contributes to the
continuously re-delineated distinction between the “inside” and the “outside”
but this distinction is not to be confused with the opposition between the
“endogenous” (what comes from the inside) and the “exogenous” (what
comes from the outside). The resulting living thing does not coincide with the
traditional self and cannot be accounted for by Burnet’s self–nonself theory.
A related idea is that the process of dual filtering presented here is dynamic
and never-ending. There is, therefore, a constant re-delineation, through the
action of the immune system, of the constituents and boundaries of a living
thing. This sheds a crucial light on the diachronic identity of biological indivi-
duals (Wiggins 2016). An entity that is part of a living thing at a given moment
(for example, an immunologically tolerated virus) can cease to be part of that
living thing later in time (for example, if this virus is eventually eliminated by
the immune system). The resulting individuality is relative and changes con-
tinuously, but the criterion used to establish what is part and what is not part of
a living thing remains constant and offers a precise delineation.
3.4 The Role of the Immune System in Turning a Set of

Heterogeneous Constituents into an Integrated Individual
Immunology helps us better understand what makes a living thing a highly
integrated individual despite the diversity of its constituents. (Like many other
aspects of biological individuality, integration – which we defined as one way of
conceiving cohesion – is a matter of degree.) According to the immunological
account proposed here, every living thing is a chimera, a heterogeneous and
mixed entity composed of genetically diverse components (Pradeu 2010; Dupré
2010). On the one hand, it is a composite entity, comprising biotic elements that
originate both from the organism and from outside the organism (bacteria,
viruses, fungi, and so on). On the other hand, it is a very special composite entity,
exhibiting a high degree of integration, with well-delineated boundaries, tight
interactions, and strong cooperation between its components. Because of its three
key activities of filtering over entry, filtering over presence, and promotion of
cooperation, the immune system is essential in determining the constituents and
boundaries of the living thing and therefore in turning a set of heterogeneous
components into an integrated individual. In other words, the immune system
exerts a major “e pluribus unum” activity: it constantly turns a plurality of
elements that are diverse and of various origins into a cohesive unit. From this
point of view, the immune system, along with other (and closely connected)
“policing” mechanisms (such as apoptosis) and systems pertaining to adhesion
and intercellular communication, participates in the “glue” of life, the sticking
together of diverse elements that eventually constitute a physiological unit. (For
a similar claim centered on the specific example of sponges, see (Müller 2003).)
This reasoning allows us to propose an immunological definition of the

organism, understood as a physiological individual (i.e., a cohesive whole,
functioning collectively as a regulated unit that persists through time).
According to this definition, an organism is a continuously changing, function-
ally integrated whole made up of heterogeneous constituents (including many
microbes) that are locally interconnected by strong biochemical interactions
and controlled at a systemic level by immunological interactions (Pradeu 2010).
Everything that is actively interacting locally and tolerated by the immune
system is part of the physiological individual.
This means that immunological processes can help us identify and delineate
physiological individuals not via intuition and common sense (as has often been
a concern with physiological definitions) but on the basis of a clearly formulated
and scientifically grounded criterion (following the argument of (Hull 1992)).
The boundaries of the immunologically delineated living thing may be a matter
of degree and vary depending on the context, but the criterion itself is precise
and clear. For example, there are uncertainties and debates over what counts as
a biological individual in the case of a colonial entity such as the ascidian
Botryllus schlosseri (Figure 3.2): each cell, each zoid, the whole colony, or
perhaps all of them together (Buss 1999)? If we adopt the immunological
perspective suggested here, then the whole colony should be recognized as
the physiological individual because it is at the level of the colony that immu-
nological processes occur such as histocompatibility-based fusion/rejection
responses when two colonies meet (De Tomaso et al. 2005). Similarly, there
are many discussions about whether or not the microbiota is part of the
individual it inhabits (e.g., (Gilbert et al. 2012)). Our immunological account
tells us that all (and only) the microbes that are immunologically tolerated are
part of the physiological individual.
Crucially, organismality here is a product, not a given. Indeed, my claim is
not that the components of an already identified organism are tolerated by its
immune system. Instead, I propose that it is the identification of a local con-
centration of biochemical and immunological processes taken together that tells
us how to pick out organisms (understood as physiological individuals) in
nature on the basis of the capacity of the immune system to determine what
the constituents and boundaries of a living thing are. We start with an unin-
dividuated living mass (Botryllus schlosseri, for example), but the identification
of immunological processes allows us to single out and delineate quite precisely
a physiological individual.
Biological individuation, as we saw, can be realized at different levels. An
interesting aspect of immunological individuation is that it also can occur at
different levels. Multicellular organisms exhibit what can be called a multilevel
Figure 3.2 Rejection between two colonies of Botryllus schlosseri.

When two colonies of Botryllus schlosseri meet, they can reject (panel A) or
fuse (not shown). This occurs at the colony level. The brown zones show the
starting point of rejection. Panel B shows rejection at the more precise level of
ampullae. (Photographs courtesy of Tony De Tomaso, UCSB)
immunity: key immunological processes occur at the level of each cell (for
example, any cell of the organism infected by a virus will respond by triggering
a diversity of protective mechanisms, including the production of interferons
and other cytokines – a phenomenon often referred to as cell intrinsic immu-
nity – which can alter neighboring cells about the presence of the virus)
(Goubau et al. 2013) and at the level of each tissue. Most of the time, one can
distinguish degrees of immunological responses: in most multicellular organ-
isms, for instance, cell and tissue immunological responses are strongly con-
trolled and coordinated at the systemic level, so the systemic level seems to be
the level at which the highest degree of immunological integration is realized.
Interestingly, in some cases, the highest degree of immunological integration is
realized at the level of a colony rather than intuitively defined individuals. For
example, some data in a number of social insects such as termites and honey
bees suggest that key immunological processes occur at the colony level, which
has led to the concept of “social immunity” (Cremer et al. 2007; Jones et al.
2018) and has sometimes been used to support the superorganism hypothesis.
The conclusion of this discussion is that recent immunological research has
seen extensive revisions of its core concepts (particularly “self,” “tolerance,”
and “microbe”), which in turn have led to a significant reassessment of our
traditional understanding of biological individuality insofar as a living thing can
be seen as an immunologically unified chimera (Gill et al. 2006; Eberl 2010;
Bosch and McFall-Ngai 2011; Pradeu 2012). But do these changes have any
practical consequences? The short answer is that they have many practical
consequences, particularly from a therapeutic point of view. Let’s take two
examples of this – autoimmune diseases and ecological approaches to the

microbiome.
If the perspective presented here is correct, then autoimmunity is a physiological
process, which plays indispensable roles in the organism. Autoimmune diseases
must be perceived not as the result of the sudden appearance of an undesirable
autoimmune reaction (in the tradition of Ehrlich’s “horror autotoxicus”) and elim-
ination of immune cells responding to the self, but as the consequence of
a perturbation in the (cell-mediated, tissue-mediated, or system-mediated) regula-
tion of immunological processes that include, as a normal component, responses to
endogenous elements (Wing and Sakaguchi 2010). This means that, contrary to
what has been done over the last decades, the first question of researchers interested
in understanding autoimmune diseases should perhaps be not so much “what
triggers an immune response against the self ?” (e.g., why do self-reactive effector
T cells develop in this organism?) as “which aspect of the regulatory machinery that
normally keeps autoimmune responses in check has been disturbed, and why?”
(e.g., why do regulatory T cells no longer downregulate the activity of potentially
harmful autoreactive T cells?). The two strategies differ. The first acts at the level of
effector cells and consists in preventing the development of autoreactive cells.
The second acts at the level of the cells that regulate the activity of effector cells;
acknowledging the physiological nature of autoimmunity, it consists in preventing
the switch from physiological autoimmunity to pathological autoimmunity. One
can speculate that many factors could play a role in this disturbance of regulatory
mechanisms (especially regulatory T cells), including excessive hygiene in indus-
trialized societies (Bach 2002), modification of the microbiota, and disorganization
of the extracellular matrix in local tissues.
The second example of a therapeutic consequence of the renewed concep-
tion of immunity and individuality in recent immunology concerns the micro-
biota. Recognizing that most living things harbor myriad microbes, most of
which do not harm their hosts, a key clinical goal becomes to manage these
microbial communities instead of trying to kill all microbes. The develop-
ment of such ecological approaches in medicine is a difficult task because the
microbiota is in fact made of several highly complex local ecosystems in
which any perturbation is likely to have unpredictable consequences. That
being said, recent success with faecal transplantation in people infected with
Clostridium difficile (van Nood et al. 2013), despite major potential limits in
other contexts (Pamer 2014), suggests that such approaches are of increasing
interest to clinicians. Another approach in the same vein is to determine to
what extent, in a context of antibiotic resistance, it will be possible to
manipulate components of the microbiota to protect a host against pathogens
(Pamer 2016).
3.5 Combining Different Approaches to Biological Individuality

Immunology is clearly not alone in shedding light on biological individuality,
an issue to which many biological fields can contribute (Clarke 2011; Pradeu
2016a; Lidgard and Nyhart 2017). First, the contribution of immunology, as we
saw, concerns primarily the biological individual understood from
a physiological point of view, and moreover it is not the only field contributing
to that question (developmental biology, neuroscience, and many others also
contribute). Second, beyond physiological fields, other biological domains,
most prominently evolutionary biology, can shed light on the problem of
biological individuality. In the last four decades or so, especially after the
founding work of David Hull, most of the debates about biological individuality
among philosophers of biology and biologists have focused on evolutionary
individuality. This includes discussions over units of selection, the replicator/
interactor distinction (Hull 1980), Darwinian individuals (Godfrey-Smith
2009), the possibility of defining species as individuals (Hull 1978; Haber
2016), the question of how groups of entities can aggregate and form new
individuals (Buss 1987; Maynard Smith and Szathmáry 1995; Michod 1999), as
well as multilevel selection and the constitution of an organism from an evolu-
tionary viewpoint (Okasha 2006; Queller and Strassmann 2009). Other fields
also have much to say about the concept of a biological individual, including,
for instance, ecology (Huneman 2014).
Recently there have been many calls in favor of pluralistic and practice-
oriented approaches to biological individuality (Kovaka 2015). As useful as
these calls have been in undermining the idea that accounts of biological indivi-
duality based solely on a single scientific field (typically evolution, but the same
would apply to any other “monistic” approach) and on a purely theoretical
viewpoint would be sufficient, it is now important to take a step further. The
existence of a plurality of approaches to biological individuality, many of which
are rooted in certain scientific practices, is not disputable. The major challenge at
present is to determine whether it could be useful to combine different approaches
to biological individuality and, if so, how (Pradeu 2016b; Lidgard and Nyhart
2017). Some entities in the living world display a high degree of physiological
and/or metabolic individuality without displaying a high degree of evolutionary
individuality, or the other way around (Dupré and O’Malley 2009; Pradeu 2010).
Other entities, in contrast, may express a high degree of individuality on both
grounds. Perhaps determining which entities express a high degree of individual-
ity along several criteria tells us something important about their roles in the
living world. An equally important issue is to establish to what extent different
criteria of biological individuality are compatible or mutually exclusive. Indeed,
even if scientific practices of individuation vary from one scientific field to

another, there often is a significant overlap between the questions and criteria
used by different biologists when they talk about biological individuals (Guay
and Pradeu 2016). This constitutes a promising research program for philoso-
phers of biology interested in making comparisons across several scientific fields.
In summary, the immune system plays a major role across species in deter-
mining the boundaries, constitution, and cohesion of the biological individual.
Far from the original concepts of self and nonself, today’s immunology tells us
that a living thing can be seen as an immunologically integrated chimera.
Although certainly not unique, the contribution of immunology to the long-
standing debate over biological individuality is important, so much so that
philosophers and biologists interested in that debate cannot neglect this contribu-
tion. What immunology has to say about individuality has long-reaching con-
sequences for our understanding of what a living thing is, including what we are
as humans, and it also impacts health issues of central importance, from auto-
immune and inflammatory diseases to antibiotic resistance and transplantation.
4 Cancer as a Deunification of the Individual

Cancer kills millions of people every year and is one of humanity’s greatest health
challenges. By stimulating the inherent ability of our immune system to attack
tumor cells this year’s Nobel Laureates have established an entirely new principle
for cancer therapy. Allison and Honjo showed how different strategies for inhibit-
ing the brakes on the immune system can be used in the treatment of cancer. The
seminal discoveries by the two Laureates constitute a landmark in our fight against
cancer. (Excerpt of attribution of the 2018 Nobel Prize in Physiology or Medicine).
“Why don’t we get more cancer?” asks Mina Bissell, a prominent specialist in
cancer (Bissell and Hines 2011). Certainly, most of us think that we do see
enough cancer around us. After all, approximately 90 million people had cancer
in 2015 (Vos et al. 2016) and cancer kills around 8.8 million people each year
(Wang et al. 2016). The 2014 World Cancer Report of the World Health
Organization estimated that there were about 14 million new cases of cancer
each year and that the financial costs of cancer were above US $1.16 trillion
per year. In this context, asking why we don’t get more cancer may seem
surprising if not shocking.
Yet Bissell’s question is entirely legitimate. We probably all have occult
tumors (Bissell and Hines 2011) – what Folkman and Kalluri called “cancer
without disease” (Folkman and Kalluri 2004). Autopsies of people dead due to
reasons unrelated to cancer reveal the high frequency of tumors, which can be
large but do not spread and do not seem to threaten the host. Prostate tumors can
be found in 30 to 70 percent of men over 60 years old, breast tumors in 7 to
39 percent of 40- to 70-year-old women, and thyroid tumors in 36 to 100 percent

of 50- to 70-year-old adults (Welch and Black 2010).
So, if tumors are so frequent, why do only a limited number of them turn into
actual cancers? The reason we don’t get more cancer is that several systems of
regulation exist in the organism, systems that prevent the formation of
a cancerous tumor, its growth, and its invasion of distant tissues (metastases)
(Klein et al. 2007). These regulation mechanisms are diverse and located at
different molecular, cellular, and tissue levels (Hanahan and Weinberg 2011):
they include DNA maintenance and repair (Hoeijmakers 2001), regulation of
cell cycle (Sherr 1996), apoptotic signals sent to cancer cells by surrounding
cells (Letai 2017), and inhibitors of angiogenesis (formation of new vessels)
(Jain 2005), among many others.
The aim of the present section is to show that, among these regulation
mechanisms, the immune system plays a critical role (Binnewies et al. 2018)
and that, conversely, the immune system is certainly involved in every cancer.
The crucial point here is that cancer is a disease of multicellularity – or, more
precisely, cancer is a disease that results from a dysfunction of the mechanisms
that normally insure the cohesion of the multicellular individual, the very
mechanisms among which we have seen that the immune system is crucial
(see Section 3). A striking result of research done in the last twenty years is that
the immune system can both prevent and support cancer formation (de Visser
et al. 2006; Binnewies et al. 2018). Understanding how the immune system,
which we characterized in previous sections as essential for maintenance of the
cohesion of the organism, can in some circumstances promote cancer constitu-
tes a major challenge from a conceptual as well as a therapeutic point of view.
The outline of the section is as follows. First, I explain the progressive
construction of the idea that the immune system can restrain cancer. Second,
I explore how the immune system was subsequently described as capable of
both restraining and promoting cancer. Third, I sum up current views about
immune–cancer interactions and their clinical applications, especially immu-
notherapies. Finally, I examine the role of the immune system in the breakdown
of biological individuality often described as typical of cancer.
4.1 How the Immune System Restrains Cancer: The Complex

History of the Idea of Immunosurveillance
It is obviously difficult to make broad generalizations when discussing cancer.
Most of the time, when we talk about cancer, we refer to a set of significantly
heterogeneous diseases characterized by uncontrolled cell multiplication and
the cells’ potential to invade other parts of the organism. The heterogeneity of
cancer is a well-established point (Melo et al. 2013; Bertolaso 2016; Plutynski

2018). First, cancers found in humans are quite diverse. Solid tumors (e.g.,
a carcinoma, a cancer that develops from epithelial cells, which constitutes the
most frequent form of cancer) differ from liquid tumors (e.g., leukemia, a cancer
that develops from bone marrow–derived cells). Cancers also differ from organ
to organ: for example, a breast cancer can be quite unlike a skin cancer (this is
called intertumor heterogeneity) (Melo et al. 2013). Cancers affecting a given
organ, such as the breast for example, can have different characteristics
(Zardavas et al. 2015). Moreover, a cancerous tumor can exhibit a high level
of internal heterogeneity (“intratumoral heterogeneity”) (Fisher et al. 2013).
Last but not least, some tumors are benign, as they do not invade other body
parts. Second, beyond humans, cancers exist in a great number of multicellular
organisms, which further increases the diversity of cancer types and character-
istics. If cancer is defined as a breakdown of multicellular cooperation that
manifests itself by uncontrolled proliferation, inappropriate cell survival,
resource monopolization, deregulated differentiation, and degradation of the
environment, then it is found in many different groups, including starfish, hydra,
insects, and plants (Aktipis et al. 2015).
Despite the diversity and heterogeneity of cancers, the immune system has
been shown to be implicated in cancer progression in a large range of cancer
types in various vertebrates (and also, if perhaps more speculatively given the
limited number of studies, in invertebrates (Pastor-Pareja et al. 2008; Robert
2010)). Because of the publicity around cancer immunotherapies, most people
are now aware that the immune system plays a role in cancer. Yet much remains
to be done to understand the detailed mechanisms underlying this process.
Study of the interactions between cancer and the immune system has undergone
major transformations in the last two decades. To understand why the immune
system can participate in the rupture of cohesion that characterizes cancer, it is
essential to understand the nature of these recent transformations.
The history of the study of how the immune system influences cancer
progression is itself illuminating. In the 1890s William Coley (Coley 1893)
took advantage of the observation that spontaneous tumor regression could
follow infection with a pathogen to develop a killed bacterial vaccine for cancer,
a phenomenon in which immune components were thought to play a role (Cann
et al. 2003). At the beginning of the twentieth century, Paul Ehrlich suggested
that the immune system could recognize and eliminate malignant cells (Ehrlich
1909). In the mid-1950s, Lewis Thomas (at a symposium held in 1957, and
published two years later (Thomas 1959)) and Macfarlane Burnet (Burnet 1957)
argued that cellular immunity was, in the words of Thomas, “designed as
a useful and effective mechanism for the early sensing and early elimination
of neoplastic cells” (Thomas 1982, p. 330). Thomas was convinced that humans
produce tumors all the time but keep them under control, thanks to the action of
the immune system. Burnet later expanded this idea and coined the term
immunological surveillance (sometimes called immunosurveillance) (Burnet
1970). According to immunological surveillance, the immune system is capable
of detecting and eliminating the “altered self” (Houghton 1994), that is, “new
antigens” (Burnet 1970, p. 7) (antigens that are different from those of the body,
also called “neoantigens” (Schumacher and Schreiber 2015)). In the 1970s, the
idea of immunological surveillance started to decline because several experi-
ments suggested that immunodeficient mice did not have a higher susceptibility
to spontaneous or chemically induced tumors (Stutman 1974). As a result it was
almost entirely abandoned for several years. A clear indication of this is the fact
that the highly influential review on the “hallmarks of cancer” by Hanahan and
Weinberg published in 2000 (Hanahan and Weinberg 2000) ignores the role of
the immune system in cancer (this was corrected in (Hanahan and Weinberg
2011)).
At the beginning of the 2000s, a series of experiments showed the impact of
the immune system on cancer development (Shankaran et al. 2001; Dunn et al.
2002). The supposedly immunodeficient mice used in experiments from the
1970s onward to invalidate the idea of immunosurveillance in fact had an
immune system (they had NK cells, γδ T cells, and even some αβ T cells)
(Dunn et al. 2002). During this period, the involvement of both innate and
adaptive immune components in cancer control was demonstrated (immuno-
chemical or functional ablations of NKT, γδ T cells, NK cells, αβ T cells, IFN-γ,
and interleukin 12 all lead to increased susceptibility to cancer).
4.2 The Dual Action of the Immune System in Both Restraining

and Promoting Cancer: Immunoediting and Beyond
Although much emphasis has been put on the capacity of the immune system to
restrain cancer, the immune system can also, perhaps paradoxically, promote
cancer (de Visser et al. 2006). Here again, both the innate and adaptive compo-
nents of the immune system can participate in such cancer-promoting processes.
One important step in the realization that the immune system can favor cancer
development was the switch from the concept of immunosurveillance to that of
immunoediting (Dunn et al. 2002). Several researchers working on immuno-
surveillance noted that the action of the immune system could lead to the
selection of more resistant tumor cells. Highly immunogenic tumor cells are
eliminated by the immune system, but this process leaves behind tumor variants
of reduced immunogenicity (or that have acquired other mechanisms to evade
or suppress the immune response) and have a higher fitness in the immuno-
competent host (a process similar to the selection of more resistant pathogens).
Therefore, Robert Schreiber and colleagues proposed to use the term immu-
noediting instead of the traditional notion of immunosurveillance, reflecting the
fact that the immune system not only monitors tumors but also shapes them,
with both beneficial and detrimental consequences for the host (Dunn et al.
2002; Schreiber et al. 2011). Immunoediting is a more encompassing and more
accurate concept, especially because it emphasizes the diachronic character of
cancer development.
The concept of immunoediting is well-suited to describe the dual host-
protecting and tumor-sculpting actions of the immune system. According to
its proponents, immunoediting encompasses three different though largely
overlapping processes, referred to as the “3 e’s” (see Figure 4.1): “elimina-
tion” (which corresponds to the classic idea of immunological surveillance,
that is, the destruction of tumor cells by the immune system), “equili-
brium” (the immune system iteratively selects and/or promotes the genera-
tion of tumor cell variants with increasing capacities to survive immune
destruction), and “escape” (the immunologically sculpted tumor expands
beyond control in the host) (Dunn et al. 2002). In 2007, a landmark study
by Schreiber’s group confirmed the existence of the equilibrium phase
(Koebel et al. 2007).
The processes by which the immune system can have a tumor-promoting
effect go well beyond immunoediting and are actually quite diverse. In
particular, tumor-associated macrophages (TAMs) can sometimes be tumor-
suppressive, but in a majority of cases they favor tumor initiation, progres-
sion, and metastasis (Mantovani et al. 1992; Wynn et al. 2013). Indeed,
macrophages can sustain the chronic inflammation that often plays a role in
tumor initiation and promotion (Mantovani et al. 2008), skew adaptive
immune responses, and facilitate cell growth, angiogenesis (Murdoch
et al. 2008), matrix deposition, tissue remodeling (Mantovani et al. 2013;
Afik et al. 2016), and metastasis (Qian and Pollard 2010). The exact effects
of macrophages located in or around the tumor also depend on the tem-
poral sequence of events: tumor-preventing macrophages can switch to
a tumor-promoting role depending on the cues they receive from the
tumor microenvironment (Wynn et al. 2013). So-called myeloid-derived
suppressor cells (MDSCs) contribute to cancer and metastasis (Kumar et al.
2016), and tumor-associated neutrophils (Fridlender et al. 2009) as well as
regulatory T cells (Tanaka and Sakaguchi 2017) also, in many circum-
stances, can promote cancer.
Figure 4.1 The three phases of immunoediting. According to the concept of immunoediting, three phases must be distinguished in the
interactions between the immune system and the tumor: (a) elimination, which corresponds to the destruction of tumor cells by the immune
system; (b) equilibrium, in which the immune system selects and/or promotes the generation of immunologically resistant tumor cell
variants; and (c) escape, which corresponds to the expansion of the immunologically shaped tumor that is now beyond the control of the
immune system. (Figure drawn by Wiebke Bretting, after (Dunn et al. 2002)).
4.3 Immune–Cancer Interactions: Current Views

and Clinical Applications
Today, the evidence showing that the immune system plays a central role in
cancer development (either preventing or promoting cancer) is overwhelming
(Schreiber et al. 2011; Chen and Mellman 2017; Ribas and Wolchok 2018).
Many cellular and molecular immune components are involved in this process
of restriction or promotion of cancer. Additionally, these interventions of the
immune system can occur at different levels in or around the tumor (including
genes, cells, and the tumor microenvironment) and at every step of its progres-
sion, from initiation to neoplastic progression to metastasis. For example,
mouse models showed that tumor-associated macrophages promote angiogen-
esis and tissue remodeling, thereby favoring tumor growth. Clinical studies
show that extensive tumor-associated macrophage infiltration positively corre-
lates with cancer metastasis and poor clinical prognosis (Afik et al. 2016)
Investigations about the role of the immune system in cancer progression
have led to remarkable clinical applications. For example, several groups have
shown how, in a diversity of cancers, infiltration by certain immune components
had a better prognostic value than more traditional approaches (Galon et al.
2006). But most crucially, since the 2010s, the knowledge accumulated over
decades about immune-mediated control of cancerous tumors has turned into
specific clinical applications called “cancer immunotherapies,” which many
have described, rightly or wrongly, as “revolutionary” (Kelly 2018). After
extremely encouraging results obtained in melanoma and a few other cancer
types at the beginning of the 2010s (Hodi et al. 2010; Wolchok et al. 2013),
evidence in favor of the success of immunotherapies (increasingly, in fact,
a combination of immunotherapies) in several cancers has accumulated
(Ribas and Wolchok 2018). In a number of situations, the results have been
unprecedented and sometimes even spectacular, especially in cases of pre-
viously incurable cancers, raising much enthusiasm. Immunotherapies are
diverse but recently immune checkpoint inhibitors have been particularly
explored (Leach et al. 1996; Ribas and Wolchok 2018).
The most significant recognition of the work done in this area is undoubtedly the
2018 Nobel Prize in Physiology/Medicine awarded to James P. Allison and Tasuku
Honjo “for their discovery of cancer therapy by inhibition of negative immune
regulation,” which is centered on the blockade of immune checkpoints. This has
definitely convinced researchers working in all areas of cancer investigation and the
lay public that it is indispensable to pay attention to the role of the immune system in
cancer. It comes as no surprise that many newspapers have discussed these medical
advances, if perhaps sometimes hyperbolically (e.g., (Vonderheide 2018)).
Are immunotherapies really revolutionary, and what do they tell us about

immune–cancer interactions? From a strictly medical point of view, this enthu-
siasm is justified, although we should keep in mind that some important limits
exist. The first limit is the low percentage of responders: less than 15 percent on
average, though it depends on tumor type and on the category of immunother-
apy (Haslam and Prasad 2019). (Future research likely will significantly extend
the proportion of responders.) A second limit is the existence of sometimes
significant adverse effects (immunotherapies, in particular, increase the level of
inflammation and autoimmune responses, which can lead to colitis, hepatitis,
etc.) (Postow et al. 2018). A third limit is the currently exorbitant cost of some
treatments.
From a conceptual viewpoint, therapies based on immune checkpoint
inhibition constitute indeed a radical change in perspective (Lesokhin et al.
2015; Sanmamed and Chen 2018). At least two important features of
immune checkpoint therapies are worth emphasizing. First, the target of
the treatment is the immune system, not the tumor itself (as was the intention
with traditional treatments such as surgery, chemotherapy, and radiotherapy –
although, in fact, some of them are now known to act at least in part via
stimulation of the immune system (Galluzzi et al. 2012)). Second, the
objective is to break the state of immune tolerance that has been established
between the tumor and the immune system in the local tissue (Lesokhin et al.
2015; Ribas and Wolchok 2018) – partly as a consequence of the chronic
expression of cancer antigens (Pauken and Wherry 2015). More precisely,
the aim with immune checkpoint blockers is to downregulate inhibitory
signals in tumor–immune interactions. This constitutes a move from
enhancement of the immune system to “normalization” of the immune
system: in immune checkpoint inhibitor-based immunotherapies, especially
with anti-PD-L1, the aim is not, strictly speaking, to boost the immune
system beyond its normal rate of activation but to restore a local context in
which the immune system will be able to act as it normally does (Sanmamed
and Chen 2018).
Together, basic studies about the role of the immune system in cancer and
clinical studies in the domain of immunotherapies also have contributed to an
important change in perspective about what cancer is and how it develops
(Prendergast 2012). It is increasingly recognized that tumor-centric views of
cancer (with genetic mutations seen as the main cause of cancer) are insuffi-
cient: to understand (and cure) cancer, it is essential to consider not only the
tumor itself but also the tumor environment ((Bissell and Hines 2011;
Maman and Witz 2018); for conceptually and philosophically-oriented ana-
lyses, see (Bertolaso 2016; Laplane 2016; Plutynski 2018)). The tumor
environment includes the tissue context located at the vicinity of the tumor
(sometimes called the tumor microenvironment), but also elements located
quite remotely from the tumor in the organism (such as some immune-
associated organs and the microbiota, which recently has been proven to
influence cancer progression and therapies) (Zitvogel et al. 2018; Binnewies
et al. 2018; Laplane et al. 2018). Even authors who initially focused on
intrinsic molecular aspects of cancer development have later emphasized the
importance of the tumor microenvironment (Hanahan and Weinberg 2011).
Targeting the tumor microenvironment also offers enriched therapeutic stra-
tegies (e.g., (Joyce 2005)). There is a growing consensus that the immune
system plays a crucial role in the tumor microenvironment (Bissell and
Radisky 2001; Binnewies et al. 2018; Maman and Witz 2018). In fact,
given the centrality of immune components in the organization of, and
control over, the local tissue, it seems reasonable to say that every cancer
involves the immune system, which necessarily intervenes, at one point or
another, in the shaping of the local context that enables the tumor to emerge,
grow, and perhaps spread.
4.4 Role of the Immune System in the Breakdown

of Biological Individuality That Characterizes Cancer
With all this discussion over the tumor-restricting and tumor-promoting roles
of the immune system in mind, we can now return to the question with which
we started. What exactly is the role of the immune system in the prevention of
the breakdown of individuality that characterizes cancer, and how can the
immune system be involved, conversely, in the decohesion of the biological
individual?
The idea that cancer constitutes a breakdown of biological individuality is
widespread in the scientific and philosophical literature. Biologist Leo Buss was
instrumental in showing that biological individuality in multicellular organisms
must be understood as an outcome of evolution, by which, on several occasions
in life’s history, some cells aggregated and cooperated, and in which emerged
some control mechanisms over cells that would proliferate at the expense of the
whole organism (Buss 1987). Buss takes cancer as an example of a decohesion
of the biological individual, in which cancer cells are “re-individualized” in
a way that becomes harmful to the multicellular organism. This idea has
subsequently been explored by several biologists and philosophers of biology
(Frank 2007; Germain 2012; Plutynski 2018), often inspired by the study of
clonal evolution at the cell level in cancer (Nowell 1976; Greaves and Maley
2012). For example, Godfrey-Smith labels as “de-darwinization” the process by
which a higher-level individual prevents proliferation of lower-level individuals

(Godfrey-Smith 2009, pp. 100–103). From that point of view, cancer cells
appear as a result of a “re-darwinization” at the cell level.
However, the mechanistic details by which the multicellular organism exerts
control over cancer cells have remained vague. Michod (Michod 1999, p. 119)
cites programmed cell death and the immune system as the two main “policing
mechanisms” in the multicellular organism, but he does not give any detailed
explanation about how they work. An important lesson of what has been said in
this section is that immunological surveillance constitutes a convincing exam-
ple of a mechanistically precise process of maintenance of cohesiveness in the
organism (Prendergast 2012; Pradeu 2013). Thus, it offers an important con-
tribution to this long-standing debate concerning de-darwinization in cancer.
The details of how immune-mediated control works are well documented: in the
elimination phase of immunoediting, myriad immune cells and molecules
(macrophages, dendritic cells, NK cells, γδ T cells, CD4 and CD8 T cells,
IFN-γ, among many others) contribute to the destruction of the tumor (Dunn
et al. 2002). In addition, immune-mediated control contributes to coordinate
other control instruments, such as apoptosis and angiogenesis.
This, however, strengthens rather than solves the paradox: if immune-
mediated restriction is one of the main mechanisms ensuring the cohesion of
the organism, we need an explanation for why in some circumstances the
immune system favors tumor development (through the escape phase of immu-
noediting and/or through repair mechanisms that contribute to creating
a favorable tissue environment for the tumor). To better understand this phe-
nomenon, I propose here an extended view of immune-mediated cohesion and
decohesion.
The traditional view about immune-mediated cohesion, as represented in
classically defined immunological surveillance, is that the immune system can
eliminate abnormal cells such as cancer cells (Figure 4.2).
This view, however, is too narrow, because it neglects the diversity of
activities in which the immune system is involved, which include not only
defense but also development, tissue repair, clearance of debris, and mainte-
nance of tissue homeostasis, among others (see Section 2). In cancer, many of
these immunological activities are found. This leads to a much richer view of
immune-mediated cohesion and decohesion in cancer (Figure 4.3). In this view,
the immune system plays a major role in regulation of the organization of the
local tissue, and, together, the immune system and the tissue realize different
activities, including the elimination of abnormal cells, but also the containment
of abnormal cells (in that case, cells are not destroyed, they are simply kept
under control, which limits the damage they can do and/or their capacity to
Immune System
Eliminates
abnormal cells
Figure 4.2 The traditional view of immune-mediated cohesion, as proposed

by the immunological surveillance hypothesis. According to this view, the
immune system directly eliminates abnormal cells, such as cancer cells (in red)
in the tumor. (Figure drawn by Wiebke Bretting).
spread), the maintenance of chronic elements present in the local environment

(most of the time, these chronic elements are normal self components of the
organism, but chronically present tumor constituents can also lead to active
maintenance of the tumor by the immune system, which progressively sees
these elements as normal) (Pradeu et al. 2013; Pauken and Wherry 2015), and
the repair of the local tissue (in physiological conditions, this repair is
a necessary process insuring the integrity of the tissue, but in the context of
cancer repair mechanisms can favor cancer progression).
The crucial point here is that decohesion as seen in cancer can concern all
these different activities, not just elimination: the immune system, which in
most cases prevents cancer progression by elimination, containment, mainte-
nance, and repair, can in some circumstances promote cancer progression
because of deregulated elimination, containment, maintenance, and/or repair.
Moreover, all these activities must be understood diachronically: they do not all
intervene at the same time, and the immune system can switch from one effect to
the other (for example, it can initiate the destruction of abnormal components
and later contribute to their maintenance because they have become chronically
expressed in the tissue).
Does the immune system dysfunction when it promotes cancer progression
via a deficit in elimination or containment and/or via maintenance processes
and/or via repair processes? I suggest distinguishing two situations here. The
Immune System
Controls
Tissue Organization
Maintains Eleminates or contains Repairs

chronic elements abnormal cells
Decohesion can concern all these mechanisms
Figure 4.3 A richer view of immune-mediated cohesion and immune-

mediated decohesion in cancer. In this view, the immune system controls
tissue organization and, together, the immune system and the local tissue can
exert a variety of cohesion-promoting activities, including the elimination of
abnormal cells, but also the containment of abnormal cells, the maintenance of
chronic elements, and tissue repair. All these activities (not just elimination), in
pathological conditions, can promote decohesion of the organism. (Figure
drawn by Wiebke Bretting).
first situation corresponds to a dysfunctional immune system. An organism,

either structurally or provisionally (e.g., after a treatment with immunosuppres-
sive drugs), can have a defective immune system (e.g., a deficit in effector
T cells, or a disequilibrium in the respective numbers of its inflammatory and
regulatory macrophages – or, more specifically, of its macrophages distributed
along the inflammatory to “alternatively activated” spectrum (Gordon 2003;
Wynn et al. 2013)). Such abnormalities can contribute to explain the triggering
of cancer, and they could be targeted by a number of therapies, which precisely
aim at correcting these immune defects.
In the second situation, however, the immune system acts normally and
immune-mediated decohesion is due to an abnormal context. Pathogens,
Context
Mechanical
Pathogens Wounds
pressure
Immune System
Controls
Tissue Organization
Maintains Eleminates or contains Repairs

chronic elements abnormal cells
Decohesion can concern all these mechanisms
Figure 4.4 Decohesion in cancer induced by an abnormal context. Immune-

mediated decohesion may be due to an abnormal context rather than an
abnormal immune system. This abnormal context can be due to the presence of
pathogens, wounds, mechanical pressures, and carcinogens of environmental
origins, among many other resources; it can also be triggered by the tumor itself.
In many situations, the decohesion mediated by the immune system results from
abnormal realization of normal processes (such as maintenance and repair).
(Figure drawn by Wiebke Bretting).
wounds, mechanical pressure, and local modifications due to carcinogenic

environmental factors, among several other causes, can create an abnormal
local context (characterized by inflammation, perturbation of the extracellular
matrix, and so on) (Dolberg et al. 1985; Bissell and Radisky 2001; Mantovani
et al. 2008; Fernández-Sánchez et al. 2015). This local context influences the
immune system, which in turn responds as it usually does, that is, by maintain-
ing or repairing the tissue – even if the final, pathological, outcome is cancer
promotion (Figure 4.4). It has long been known, for instance, that tumors
resemble “wounds that do not heal” (Dvorak 1986, 2015; Schäfer and Werner
2008), which means that, in cancer, normal repair mechanisms are triggered but
generally without reaching the “resolution phase” (which, in the physiological
context, is indispensable to terminate the reparative process (Gurtner et al.
2008)). Furthermore, the tumor itself can be a major source of perturbation of
the local context: it can influence the immune system through a variety of
cytokines and can also increase inflammation and wounding, modify blood
vessels, reshape the extracellular matrix, or exert a mechanical pressure, among
many other possibilities. This is often described as the “hijacking” or “co-
option” by the tumor of physiological pathways and of the tissue microenvir-
onment (Kitano 2004a; Greaves 2007; Lean and Plutynski 2016). Despite its
importance, one must keep in mind that such co-option is only one of the many
ways in which the local context can become abnormal and favor the contribu-
tion of immune processes to cancer progression.
In all these contexts, immune-mediated decohesion results from the abnormal
realization of normal processes, and this can help explain why tumors largely
resemble organs (Egeblad et al. 2010) and are the products of classic develop-
mental (da Costa 2001; Radisky et al. 2001; Huang et al. 2009) and reparative
pathways (Bissell and Radisky 2001) realized in an abnormal context. There is no
doubt that the outcome is pathological (the promotion of a cancerous tumor,
including in some cases metastatic spread), but the immune system, in many of
these circumstances, does not strictly speaking “dysfunction”; it just does what it
always does (maintaining the local environment, repairing in case of wound, etc.).
If the view presented here is correct, then a much richer picture emerges
about how the immune system influences cancer and, ultimately, of potential
therapeutic opportunities as well. Indeed, the immune system influences cancer
through different processes (elimination, containment, maintenance, repair, and
so on), via many actors (not only lymphocytes, but also macrophages, neutro-
phils, and various cytokines), at several different levels (within the tumor, but
also around the tumor, in the whole tissue, and at a systemic level in the
organism), and at all temporal stages of cancer progression (initiation, neoplas-
tic progression, and metastasis). Additionally, the influence of the immune
system on the cancerous tumor can be negative (the immune system prevents
cancer progression) or positive (the immune system promotes cancer progres-
sion). All this suggests a whole series of new opportunities for investigating
immunotherapies, which could, at least in principle, target these different
processes, actors, levels, and temporal stages. Current immunotherapies (parti-
cularly immune checkpoint inhibitors and CAR-T cells (Joyce and Fearon 2015;
June and Sadelain 2018)) focus on lymphocytes in terms of actors and on
elimination and maintenance and rupture of chronicity in terms of processes,
but many other possibilities exist. Depending on where we are in the cycle of
cancer–immune system interactions and on the actors of the tumor microenvir-
onment involved, some therapeutic strategies will aim at normalization while
others will aim at denormalization. Examples of normalization include the
reduction of the level of inflammation in the tissue, the elimination of pathogens
and/or chronic wounds, the restoration of immune accessibility to the tumor,
and the facilitation of the resolving phase of tissue repair. In contrast, denorma-
lization would be a major aim when the immune system interacts with tumor
components as if they were normal constituents of the body, as, for example,
when the immune system is tolerogenic in the context of chronically present
tumor antigens or when the immune system continuously triggers repair path-
ways to respond to a local cancerous context that displays many features usually
associated with a wound.
In summary, this section has shown that focusing on the immune system is
essential for anyone studying cancer. Cancer is a disease of multicellularity
and, more specifically, of the cohesion of the multicellular organism.
Immunological surveillance constitutes one of the main and best described
mechanisms by which the multicellular organism exerts control over lower-
level entities. A major result of recent research is that the immune system can
both restrain and promote cancerous tumors, which may seem, at first sight,
paradoxical. Yet the situation becomes less paradoxical when one realizes that
immune-mediated decohesion is often due to an abnormal context rather than
a dysfunctional immune system. We have suggested here an extended view of
cancer–immune interactions, which opens up many opportunities for investi-
gating new mechanisms of tumor control and tumor promotion and, ulti-
mately, for developing novel therapeutic opportunities based on the action
of the immune system.
5 Neuroimmunology: The Intimate Dialogue between

the Nervous System and the Immune System
Whatever forces were operating to set immunology apart, recent data suggest that
much could be learned by studying immunoregulation as part of an integrated
network of adaptive processes including behaviour. If not now, when? (Ader and
Cohen 1985)
These exciting revelations place neuroimmunology at the forefront of biomedi-
cal research priorities. With the potential to affect such a diverse array of neuro-
logical ailments, many of which have no known therapy, the hope is that an
improved understanding of immune-CNS interactions will bring to light new
paradigms for preventing and treating neurological disease. (Mueller et al. 2016)
These findings suggest that the brain–cytokine system, which is in essence
a diffuse system, is the unsuspected conductor of the ensemble of neuronal circuits
and neurotransmitters that organize physiological and pathological behavior.

(Dantzer et al. 2008)
If you fall asleep reading this Element, this is probably simply because you are
tired or because its content is not entertaining enough. But if you are literally
falling asleep, then perhaps you have narcolepsy, a disorder estimated to affect
around one in 2,000 people. The symptoms of narcolepsy, which usually begin in
adolescence or early adulthood, include daytime sleepiness and, in some cases,
cataplexy – sudden muscle weakness during wakefulness that causes falls. Severe
forms of narcolepsy are associated with abnormally low numbers of neurons that
produce hypocretin, a protein that controls sleep–wake cycles. Recently, it was
suggested that narcolepsy might be the consequence of an autoimmune response
(following older work on association with some HLA alleles). Narcoleptic
patients have immune CD4+ memory T cells that target peptide fragments of
hypocretin, suggesting that autoimmunity could play a role in narcolepsy,
although the exact causal relationships remain to be determined (Liblau 2018).
A problem that affects many more people than narcolepsy is depression. All
readers of this Element certainly know somebody who has depression and/or
have experienced depression themselves. Depressive disorder, a multiform and
multifactorial condition, was estimated to affect 8.5 percent of people in Europe
(Ayuso-Mateos et al. 2001). For a long time, depression has been considered to
be a psychiatric disease, usually treated with serotonin-tweaking drugs like
Prozac. Yet a growing number of researchers look at depression from an
additional perspective based on immunology (Bullmore 2018; Dantzer 2018)
(more about this example below).
Such examples and many others suggest that the nervous system and the
immune system, far from being separated, can interact intimately in almost all
metazoans, including humans. The study of these interactions has given rise to
an interdisciplinary domain, neuroimmunology. My main objective in this
section is very modest: it is to offer a conceptual clarification of the different
issues raised by neuroimmunology, which often remain intertwined and insuffi-
ciently distinguished. To do so, after a short history of neuroimmunology,
I present important results concerning the interactions between the nervous
and the immune systems in health and disease. I then propose to distinguish five
different conceptual questions when dealing with neuroimmune interactions,
and finally I mention some important philosophical consequences neuroimmu-
nology can have, particularly about cognition. So, what will be said in this
section is no more than a preliminary conceptual and philosophical exploration
of the field of neuroimmunology. My hope is simply to convince some readers
to take up the challenge of immersing themselves in this fascinating domain.
5.1 From Psychoneuroimmunology and Neuroimmunology

to Present-Day Characterizations of the Dialogue between
the Nervous and the Immune Systems
Despite important preexisting research on interactions between the nervous and the
immune systems (relative to the blood–brain barrier, the idea of the brain as an
immune-privileged organ, and the role of microglia cells, in particular; more will be
said below about all these aspects), the fields of neuroimmunology and psychoneur-
oimmunology emerged in the 1970s and 1980s. The Neuroimmunology Branch of
the National Institute of Neurological Disorders and Stroke was established in 1975
(McFarland et al. 2017). The journal Neuroimmunology was founded in 1981. Terms
such as neuroinflammatory were already in use in the early 1980s (e.g., (Hartung and
Toyka 1983)). Psychoneuroimmunology was also born in the second half of the
1970s, following the work of Robert Ader (1932–2011) and a few others. The first
edition of the volume Psychoneuroimmunology, edited by Ader, was published in
1981 (Ader 1981) and several updated editions followed. In 1987 Ader founded the
journal Brain, Behavior, and Immunity, the official journal of the
Psychoneuroimmunology Research Society. Importantly, the domain of psycho-
neuroimmunology stemmed in part from psychosomatic medicine (Kiecolt-Glaser
et al. 2002).1
Despite considerable overlap between neuroimmunology and psychoneuroim-
munology, neuroimmunology tends to investigate the interactions between the
nervous and the immune systems, particularly at the cellular and molecular levels,
while psychoneuroimmunology explores how behavior influences and is influenced
by the immune system. Historically, psychoneuroimmunology has focused on the
conditioning of immune responses, the role of immune factors in mental disorders
such as schizophrenia, and the effect of psychological factors such as stress on
immune responses (Ader 2000). Later, the role of neuroimmune interactions in
fatigue and sickness behavior (the feeling of fever and nausea, for example, when we
are sick, and which is mediated by pro-inflammatory cytokines such as IL-1β)
became important topics in the field (Dantzer et al. 2008). As early as the 1970s,
interactions under investigation included not just two but three actors: the nervous
and the immune system, but also the endocrine system (Besedovsky and Sorkin
1977) (for a retrospective, see (Besedovsky and Rey 2007)). This explains why some
researchers talk about “psycho-neuro-endocrino-immunology” (Sivik et al. 2002).
Neuroimmunology, psychoneuroimmunology, and psycho-neuro-endocrino-
immunology all pay attention to both the central nervous system (CNS) and the
1
I thank Jan Pieter Konsman for many discussions about the history of neuroimmunology and
psychoneuroimmunology.
peripheral nervous system (PNS, the part of the nervous system that is outside the
brain and spinal cord).
Strikingly, the fields of neuroimmunology and psychoneuroimmunology,
since their inception, have given rise to controversies and have often been
accused of not following the most rigorous scientific standards. This accusation
has particularly targeted psychoneuroimmunology, as illustrated, for instance,
by the disagreement between (Maddox 1984) and (Ader and Cohen 1985), and
as discussed in detail by (Cohen 2006).
Here we will use neuroimmunology in an inclusive sense to refer to all the
approaches nowadays that study interactions between the nervous and the immune
system, at all levels, in health and disease, and with or without a focus on behavior.
5.2 Interactions between the Nervous and the Immune

System in Health
Until the 1990s, a widespread conviction was that the brain was an “immuno-
privileged” organ (Carson et al. 2006), understood as the idea that the brain is
devoid of immune cells. The brain and the immune system were thought to be
separated by a strict barrier, the blood–brain barrier (made of tightly packed
endothelial cells, restricting the passage of many substances into the parenchyma),
and the crossing of this barrier by immune cells was thought to be pathological and
dangerous. Yet as with all other organs thought to be immuno-privileged (see
Section 3), recent research has emphasized first that the brain has its own immune
system, and second that the blood–brain barrier is partially permeable.
The main cellular actors of the brain immune system are microglia, the
resident immune phagocytes of the CNS (see Figure 5.1). They constitute
about 10 percent of the total cells in the adult CNS. Although microglia were
documented as early as the 1920s, the conception of their roles and functioning
has been considerably extended during the last decade (Salter and Beggs 2014).
In the healthy CNS, microglia, long conceived as dormant, are in fact highly
active, continuously monitoring their environment with extremely motile pro-
cesses and protrusions (Nimmerjahn et al. 2005) and interacting with neurons
and other brain cells. Microglia initially were thought to simply react to CNS
injury, infection, or pathology, but recent work suggests that they play a key role
in synaptic remodeling both in development and in adult life, refining neuronal
circuitry and network connectivity, and contributing to neuronal plasticity (Wu
et al. 2015). Importantly, the immune complement (Stephan et al. 2012) and the
major histocompatibility complex class I molecule H2-Db (Lee et al. 2014) are
also instrumental in CNS synapse pruning. Overall, microglia constitute
a perfect illustration of what we described in Section 2, namely the fact that
Figure 5.1 Microglia and their many activities. Microglia are a major element
of the brain’s immune system. These resident immune phagocytes constantly
monitor their microenvironment and participate in many processes in health and
disease, including engulfment of neural progenitor cells (NPCs), acute response
to CNS damage, engulfment of synaptic material, and homeostatic surveillance.
(Figure drawn by Wiebke Bretting).
the activities of immune cells include but are not limited to defense, comprising
also development, repair, clearance of debris, and so on (Michell-Robinson
et al. 2015).
The long-dominant view has been that, in healthy conditions, the brain is
devoid of lymphocytes, as these cells could cause major damage. Recently,
however, a “peri-cerebral” adaptive immune system has been described
(Figure 5.2): the meninges contain lymphatic vessels that remove waste from
the parenchyma, can relay information about possible infections in the brain,
but also harbor peripheral immune cells that communicate with the brain via
cytokines (Louveau et al. 2015b; Kipnis 2016). This discovery confirms that
Figure 5.2 Immune communication between meninges and the brain. Apart
from microglia, immune cells are generally not present in the brain, as, in
nonpathological situations, they are thought to not cross the blood–brain barrier.
However, meninges contain lymphatic vessels and peripheral immune cells,
which communicate with the brain via cytokines. (Figure drawn by Wiebke
Bretting).
there is a rich immunological crosstalk between the brain and the rest of the
body, particularly via the meninges.
Collectively, these data confirm that there is a cellular and molecular immune
system of the brain. The actors and mechanisms just described come in addition
to various cell-intrinsic innate defense mechanisms used by neurons in case of
viral infections (Ordovas-Montanes et al. 2015).
Not only is there an immune system of the brain, but recent research confirms
that there are many interactions between the nervous and the immune system in
a healthy organism, with much richer communication pathways than initially
suspected (Figure 5.3). These interactions occur at various levels: molecules,
cells, organs, and at the systemic level. There is a dense sympathetic innervation
of all lymphoid organs (Dantzer 2018). The PNS regulates immunological
development (the sympathetic nervous system regulates haematopoiesis), prim-
ing (neurons influence the triggering of an immune response in lymph nodes),
and deployment (peripheral neurons associated with vessels can impact on
leukocyte recruitment into peripheral tissues) (Ordovas-Montanes et al.
2015). In response to pathogens or tissue perturbation, immune cells are
activated at the periphery and release cytokines and other inflammatory mole-
cules; these molecules have an impact on local sensory neurons and influence
signaling to the CNS (Chavan et al. 2017). Furthermore, pro-inflammatory
cytokines produced by immune cells at the periphery communicate with the
brain through afferent nerves, a process that leads to the production (by acti-
vated microglia) of other pro-inflammatory mediators in the brain itself. (Using
a perhaps slippery vocabulary, some authors say that the brain forms, via
neuromediators and immune mediators, an “image” of immune responses
occurring in peripheral tissues (Dantzer et al. 2008)).
Interactions between the nervous and the immune system can have important
functional consequences. For example, homeostatic circuits regulating tem-
perature maintenance, blood pressure, and intestinal mobility involve immune
cells. The vagus nerve is important for detecting and reporting on peripheral
immune responses and, in turn, efferent signals from the CNS are indispensable
for the regulation of inflammatory responses (Ordovas-Montanes et al. 2015).
Kevin Tracey in the 2000s proposed calling this neuroimmune network the
“inflammatory reflex” (reviewed in (Chavan et al. 2017)), a concept enriched
and discussed in subsequent research (Dantzer 2018).
Neuroimmune interactions can also involve additional actors. A major recent
example is research on the microbiome–gut–brain axis. Mouse and insect
models suggest that the microbiome influences brain development and behavior
(Sharon et al. 2016; Vuong et al. 2017; Schretter et al. 2018b), in part through
the mediation of the immune system (Fung et al. 2017). Whether this conclusion
may apply to humans remains an open question.
Crucially, neuroimmune interactions have recently been said to have an
impact on cognition. It has been proposed that cytokines play a critical role in
spatial memory (Sparkman et al. 2006) and that microglia are important for
learning and memory by promoting learning-related synapse formation through
brain-derived neurotrophic factor signaling (Parkhurst et al. 2013).
Furthermore, according to some authors, adaptive immunity influences cogni-
tion (Kipnis 2016). Mice deficient in T lymphocytes were found to exhibit
cognitive impairment in spatial learning/memory tasks and passive transfer of
mature T cells improves their cognitive function (Kipnis et al. 2004). A likely
Figure 5.3 Communication between the nervous and the immune system.
According to the initial view (top) neuroimmune interactions were thought to
occur via neuroendocrine mediators released in the general circulation.
According to the current view, however (down), long-distance interactions
between the nervous and the immune system are mediated by neural pathways
much more than by circulating neuroendocrine mediators, and the
communication is bidirectional. (Figure drawn by Wiebke Bretting, after
Dantzer 2018).
hypothesis is that pro-cognitive T cells are autoimmune cells stimulated by

brain-derived molecular cues (Kipnis et al. 2012). The influence of T cells on
cognition could be mediated by interleukin-4 (IL-4), as the learning behavior of
mice that do not express IL-4 is substantially lower than that of wild mice, and
Figure 5.3 (Cont.)
this effect can be reversed by injecting wild-type T cells but not T cells that do
not express IL-4 (Derecki et al. 2010). Another, nonexclusive, possibility is that
this effect is mediated by myeloid cells. More recently, it has been claimed that
mice deficient in adaptive immunity exhibit social deficits and hyperconnectiv-
ity of fronto-cortical brain regions, that social deficits are reversible via repo-
pulation with lymphocytes, and that interferon-γ is a probable molecular link
between meningeal immunity and neural circuits involved in social behavior
(Filiano et al. 2016). Further work is needed to unravel the exact molecular and
cellular mechanisms by which neuroimmune interactions affect cognition, but
data accumulated in the last decade is highly promising and may open up new
important avenues for research.
In summary, research in neuroimmunology over the last four decades has

shown that there are many interactions between the nervous and the immune
system. Neuroimmune interactions can be studied at different levels in the
organism (from molecules to systems and even with an attention to environ-
mental influences), at different scales (some neuroimmune communication
pathways are short-distance, others are long-distance), and through an attention
to different routes (direct interactions, but also indirect interactions, such as
those involving endocrine elements or the microbiota).
5.3 Interactions between the Nervous and the Immune

System in Pathological Contexts
According to some authors, neuroimmune interactions play a role not only in
physiological but also in pathological contexts. Many disorders classically
defined as neuronal and/or psychiatric are now said to possess a significant
immunological component (Kipnis 2016). This is the case, for example, for
some neurodegenerative disorders (Heneka et al. 2014) such as multiple sclero-
sis, which is an autoimmune disease (Dendrou et al. 2015), but also in
Alzheimer’s disease (Heppner et al. 2015). In addition, several lines of evidence
suggest that various psychiatric pathologies could be caused, at least in part, by
components of the immune system. Some authors emphasize that antineuronal
autoantibodies are found in the serum of 11.6 percent of 925 patients admitted to
acute psychiatric inpatient care (Schou et al. 2016), others that 20 to 40 percent
of acute psychiatric inpatients exhibit low-grade inflammation, suggesting the
possibility that inflammation can be relevant for many psychiatric disorders
(Osimo et al. 2018) (as typically recognized for schizophrenia (Khandaker et al.
2015)). Many of these observations are limited and only correlative, so more
work is needed to draw any conclusion here. An additional layer of complexity
is that some autoimmune diseases such as lupus are accompanied with neurop-
sychiatric manifestations, which may be due to the existence of brain-reactive
autoantibodies (Williams et al. 2010).
Several researchers propose that the immune system plays an important role
in major depressive disorder. In humans, one-third of patients treated with
cytokine therapies (IL-2 and IFN-α) for cancer or chronic viral hepatitis develop
major depressive disorders (Raison et al. 2006). Clinical observations, epide-
miological studies, and investigations in animal models have tended to confirm
that pro-inflammatory cytokines can induce depressive-like behaviors (Dantzer
et al. 2008). All this has contributed to the development of a non–brain-centric
view of depression. The causal involvement of indoleamine 2,3-dioxygenase
(IDO), an immune-inducible enzyme that metabolizes tryptophan along the
kynurenine pathway and plays a major role in immunoregulation, was shown in

animal models. Furthermore, pharmacological or genetic blockade of IDO
activation abrogated depression-like behavior in mice (Dantzer 2018).
Collectively, these investigations on the role of neuroimmune interactions in
psychiatric disorders have led to the emerging field of immunopsychiatry
(Pariante 2015). This domain has its origins in neuroimmunology and psycho-
neuroimmunology but focuses on the influence of immune mechanisms on
behavior rather than the other way around.
If confirmed by future results, research on the role of the immune system in
neurological and psychiatric diseases could have interesting and innovative
therapeutic consequences. It has the potential to expand traditional approaches
that see such diseases as purely mental and/or neurological, especially if future
investigations confirm that some of these diseases can be managed via targeting
of the immune system (among other components). This includes major depres-
sive disorder (Miller and Raison 2016; Bullmore 2018), bipolar disorder,
schizophrenia, and several others (Miller and Buckley 2017). The possibility
to treat neurodegenerative disorders via immunotherapies also is under intense
investigation (Weiner and Frenkel 2006).
Interestingly, an immunological approach could lead to redefined nomen-
clatures of psychiatric disorders and treatments. Diagnosis for psychiatric
disorders is currently based on descriptive nomenclature because of a lack
of clearly defined causal mechanisms. Yet some immunological mechan-
isms are common to psychiatric disorders belonging to different categories,
hence the suggestion to develop alternative nomenclatures based on immu-
nological characteristics as well as associated environmental factors
(Leboyer et al. 2016).
Reciprocally, some diseases traditionally classified as immune may be tar-
geted by acting on the nervous system. For example, in a recent clinical study,
electrical vagus nerve stimulation was successfully used to improve symptoms
in rheumatoid arthritis, a chronic inflammatory and autoimmune disease
(Koopman et al. 2016). Further investigations are needed, but some specialists
consider that bioelectronic devices can be used to modulate neural circuitries,
constituting a complement to drug treatment, especially in immune diseases
(Chavan et al. 2017)
The field of immunotherapy-based approaches to neurological and psychia-
tric diseases is still in its infancy. Yet if successful, it could contribute to
closing the gap between psychiatry and the rest of medicine, and it could lead
to a radical change in the way we traditionally conceive mental health
problems.
5.4 Mapping the Different Conceptual Questions Raised

by Neuroimmunology
Recent scientific literature abounds in bold claims about the relation between
the nervous and the immune system. These two systems are often said to have
strong interactions and many similarities, perhaps a common evolutionary
origin, while some suggest that they overlap to a great extent and even that
they could constitute a single system (see details below). I suggest that, even if
several of such claims are often formulated as if they were intimately connected
or even equivalent, it is crucial, for the sake of clarity, to disentangle these
claims. My analysis of this literature has led me to single out five dimensions of
neuroimmunology, each corresponding to a different question (Figure 5.4):
interaction, similarity, overlap, origins, and control. Importantly, distinguishing
five questions in neuroimmunology can serve not only as a mapping of the
various goals currently pursued by researchers in this domain but also as an
invitation to do further investigations to better address some questions that have
tended to remain in the background in the last two decades.
5.4.1 Interaction: How Do the Nervous and the Immune

System Interact?
The question of how exactly the nervous and the immune system interact is the
most basic and the most extensively discussed in neuroimmunology. Some of
the main results of this research have been presented in the previous two
sections. My aim here is not to give more details about this question but rather
to explain why it should not be confused with the four other questions that are
often raised in the scientific literature.
5.4.2 Similarity: Are the Nervous and the Immune System

Structurally and/or Functionally Similar?
The nervous and the immune systems are often said to be similar, that is, to
share several important features. Similarity can be at a structural level. Both
systems communicate via soluble ligands and receptors. Molecules that
mediate such communication include cytokines, chemokines, neuropeptides,
neurotransmitters, neurotrophins (Camacho-Arroyo et al. 2009), and their
receptors. Perhaps more distinctively, both systems make use of specific
structures called synapses. The term appeared in neurobiology in the late
nineteenth century and was subsequently adopted by immunologists in the
1980s to describe the extended communication surface platforms established
between two immune cells, particularly antigen-presenting cells and lympho-
cytes (Steinman 2004). Both types of synapses are stable adhesive junctions
Dantzer (2008, 2018); Ordovas-

Interaction How do the NS and IS interact? Montanes et al. (2015); Chavan
et al. (2017)
Are the NS and IS structurally Steinman (2004, 2012); Kioussis

Similarity
and/or functionally similar? and Pachnis (2009)
Neuroimmunology
To what extent do the NS and IS Petrovsky (2001); camacho-

Overlap overlap, or even constitute a Arroyo et al. (2009); Ransohoff
single system? (2009); Steinman (2012)
Do the NS and IS share common Ottaviani et al. (2007); Kioussis

Origins
evolutionary origins? and Pachnis (2009); Kipnis (2016)
Does the NS control the IS or the Pariante (2015); Chavan and

Control
other way around? Tracey (2017)
Figure 5.4 Neuroimmunology: A conceptual tree. This figure distinguishes five different questions raised by current scientific literature in
neuroimmunology, and which in general are insufficiently separated.
between two cells across which information is transmitted via secretory

molecules. The detailed resemblances and differences between the neural
and immunological synapses are an important object of study (Dustin and
Colman 2002).
The similarity can also be at the functional level. It is often said, for example,
that both systems recognize their target and display a form of memory insofar as
they respond differently to a second stimulation by a given stimulus, as if they
could remember a past experience (Kioussis and Pachnis 2009). Sometimes,
this functional comparison goes very far, as when it is suggested that the
immune system is, in itself, “cognitive” (Tauber 1997). The exact meaning of
this claim is unclear. It dates back to at least Niels Jerne (Jerne 1985). More
recently Irun Cohen (Cohen 2000, pp. 181–189) defended the view that the
immune system perceives signals and responds to them by a decision-making
process, itself based on a complex language and a capacity to remember
(immunological memory). It is uncertain how comparisons made at such
a level of generality may prove scientifically useful because they are difficult
to operationalize and test. They could perhaps generate novel avenues for
research, but they may also be experimentally sterile, as happened to a large
extent with Jerne’s views.
Other functional similarities often mentioned include plasticity and motility
(Kioussis and Pachnis 2009). Both neural and immune cells are plastic to a high
degree: depending on microenvironmental cues, they can differentiate into
phenotypically distinct subtypes. Moreover, cells of both systems are able to
carry information from and to distant parts of the body. Yet as we will see, they
use different means to do so.
Overall, similarities between the nervous and immune systems are numerous
and often informative. Moreover, there are many promising avenues for future
research in this area, including, for instance, a comparison between the pro-
cesses of epigenetic regulation in neural and immune cells.
Neuroimmunologists often switch from the idea that the nervous and the
immune system interact to the idea that the two systems are similar, or the other
way around (e.g., Steinman 2012; Ordovas-Montanes et al. 2015). It should be
clear, though, that interaction and similarity are two different things. Two
entities can have strong interactions without being similar, and it is perfectly
possible that two similar things have no interaction at all. As self-evident as
such distinctions might seem, they do point to some confusions that exist in the
scientific literature. For example, even if the immunological and the neural
synapses do not interact, it remains extremely interesting to study their simila-
rities. And even if an immune cell at the periphery and a neuron in the brain are
structurally and functionally dissimilar, understanding how they interact during
an infection or an autoimmune disease remains crucial. It is reasonable for

future neuroimmunological research, therefore, to study both similarities and
interactions even when they do not go hand-in-hand.
5.4.3 Overlap: To What Extent Do the Nervous and the Immune

System Overlap or Even Constitute a Single System?
Sometimes, comparisons between the nervous and the immune system go
beyond mere similarity, especially when functional features considered as
typical of one system are exhibited by the other system. A key discovery was
that immune cells express receptors for neuromodulators and neurons express
immune receptors, which is crucial for their capacity to influence each other.
Cytokines, classically attributed to the immune system, are also produced by
cells of the CNS (microglia, astrocytes, and neurons), where they regulate the
development of the nervous system as well as some of its most crucial physio-
logical processes, including neurotransmission (Camacho-Arroyo et al. 2009;
Ransohoff 2009). Conversely, neuropeptides, long thought to be specific to the
nervous system, are now known to be produced by immune cells as well
(Steinman 2004). Because of this overlap, traditionally conceived functions
are often blurred: elements classically defined as pertaining to the nervous
system play important immunological roles and vice versa.
Neuroimmunologists frequently put together the “interaction” question and
the “overlap” question (Ordovas-Montanes et al. 2015; Chavan et al. 2017).
However, overlap does not always come with interaction, as illustrated by many
cases of functional redundancy (where identical or nearly identical components
can realize a given function) and functional diversity (where heterogeneous
components can realize a given function) in studies on robustness (Kitano
2004b). Two engines in an airplane overlap functionally, but it is preferable
that they don’t have too strong an interaction, otherwise damage to one motor
might disrupt the other. Such fail-safe mechanisms abound in biology.
Reciprocally, interaction does not necessarily imply an overlap. If a cytokine
produced by the immune system interacts with the nervous system, it is impor-
tant to study it, even if it is not produced by the nervous system as well.
Furthermore, scientists enthusiastic about functional convergences between
the nervous and the immune system tend to switch from the idea of overlap to the
idea of unification, that is, the idea that the nervous and the immune system
(together with the endocrine system, in general) constitute one single system
(Petrovsky 2001; Steinman 2012). But here too, caution is in order: clearly two
systems can overlap without constituting a single system. This is illustrated,
again, by studies on biological robustness. Many cases of functional redundancy
and functional diversity rest on the fact that two systems realize entirely or
partially similar functions without being one and the same system because in
those cases distributivity is essential for maintaining robustness. For example, the
two systems will not be activated in the same circumstances or at the same time,
and/or the failure or insufficiencies of one system can be compensated by the
other. One promising research program for future neuroimmunology is to outline
and explain the circumstances in which the nervous and the immune system really
overlap in space and time, those in which they act at different moments or
different places, as well as those in which one system compensates for the other
or takes over from the other.
5.4.4 Origins: Do the Nervous and the Immune System Share

Evolutionary Origins?
When discussing interactions, similarities, and/or overlap between the nervous

and the immune system, many neuroimmunologists make claims about their
supposed common origins in evolution. Such claims are often made in general
terms (Kipnis 2016; Veiga-Fernandes and Pachnis 2017), but sometimes they
are more specific, as when it is suggested that a common origin is a likely
explanation for the fact that the two systems display a common capacity for
monitoring and responding to changes in the external and internal environments
(Kioussis and Pachnis 2009). Based on various techniques, including immuno-
chemistry and sequence analysis, Ottaviani and colleagues (Ottaviani et al.
2007) defended the view that there was a common evolutionary origin for the
immune and neuroendocrine systems.
As stimulating as these claims may be, it is important to remain careful about
them. First, the comparative study of the evolutionary history of the nervous and
immune systems is still in its infancy. Biologists often act as if both systems
appeared approximately at the same time, but this is clearly not the case.
Immune systems are much more widespread than nervous systems in the living
world and much older in life’s history. Plants and prokaryotes have an immune
system but they don’t have a nervous system. Metazoans all have an immune
system but not all have a nervous system. Sponges, which have an immune
system (Müller 2003), are generally considered to not have a nervous system,
even though they may possess neuro-sensory-like cells (Miller 2009). And if
one decides to focus on adaptive immune systems (as done by some neuroim-
munologists), then the reverse is true: countless animals, such as arthropods, for
example, possess a nervous system without having an adaptive immune system.
This is all the more important as, although neuroimmunologists have worked
mainly on mammals, intimate neuroimmune interactions have been found
across the animal kingdom. For example, recent work has shown that IL-17,
a pro-inflammatory cytokine, is a neuromodulator and contributes to behavior in
Caenorhabditis elegans (Chen et al. 2017). Thus, much more research is needed
about the history of the nervous and immune systems in all their diversity before
making a claim about their possible common origins.
Second, one cannot make direct inferences from similarity to common
evolutionary origins. There are obviously many different possible evolutionary
explanations for similarities, including homology (shared ancestry) and analogy
(convergent evolution). In future research deciding between these two options
at the system level will be important but it will also be difficult. The question has
also been raised at the cell level: did neural and immune cells evolve indepen-
dently but later co-opt functions from each other, or did they evolve from
a common ancestral cell able to recognize and interpret the environment,
communicate with other cells, and exhibit plasticity (Kioussis and Pachnis
2009)?
Additionally, evolutionary explanations will differ depending on whether we
want to explain interactions, similarities, or overlap between the nervous and
the immune system. This is more confirmation that one should be careful when
switching from one question to the other.
So, exciting research remains to be done for scientists and philosophers
interested in when and why nervous and immune (sub)systems emerged in
evolution and how they fit together. An interesting proposal has been made on
this topic by my colleague Jean-François Moreau (personal discussions). In his
view, the functioning and origins of the nervous and the immune system must be
put into the context of the emergence of multicellularity. Multicellularity pre-
supposes internal communication and in metazoans three types of long-distance
communication channels can be distinguished. The first resembles our electric
networks; it corresponds to the nervous system, and more specifically to
neurons, which can send information at a very high speed with a relatively
diverse content. The second resembles our water and/or sewage networks; it
corresponds to the blood and lymphatic vessels, where endocrine signals, in
particular, circulate. It delivers information at a relatively high speed with
a relatively diverse content. These first two systems (nervous and vascular)
are rigid: they can be modified (via neurogenesis and angiogenesis, for exam-
ple) but only at an extremely slow rate. The third system resembles our mail
carriers; it corresponds to immune cells, which are the uniquely mobile cells of
the organism and which can deliver information with extremely diverse content
everywhere in the organism, often over long distances though at a limited speed.
In addition to carrying information, immune cells can perform all sorts of
activities, including pathogen clearance, tissue remodeling, and tissue repair,
among many others (Eom and Parichy 2017). Overall, this view suggests
interesting and important distinctions about the different selective pressures
that might have existed at the origins of nervous, endocrine, and immune
systems in metazoans. It is likely that some types of messages can be delivered
by one system only: for example, high-speed communication is best realized by
the nervous network, while other processes such as pathogen clearance and
tissue repair require the unique mobility of immune cells. All this constitutes an
invitation to explore not only the similarities between the nervous, immune, and
endocrine systems but also their complementarities, as well as the means that
evolved to coordinate these systems characterized by their different commu-
nication channels. Among other benefits, such research could constitute an
important contribution to current scientific and philosophical discussions
about how and why nervous systems originated in the animal world (Miller
2009; Keijzer et al. 2013; Godfrey-Smith 2016) by enriching the context of this
question with considerations about possible complementarities (and possible
trade-offs as well) between the nervous system and other bodily systems.
5.4.5 Control: Does the Nervous System Control the Immune

System or the Other Way Around?
A question slightly different from the four others yet important in this discus-
sion is control. Many neuroimmunologists switch from the description of
intimate interactions between the nervous and the immune system to the idea
that one system controls the other (Chavan and Tracey 2017). When describing
what he sees as the emerging field of immunopsychiatry, Pariante (2015)
suggests that this domain, by giving prominence to the immune system, reverses
what “governs” and “is governed.”
It should be clear, however, that interactions between two systems and
control by one system over another are two entirely different things. It is not
because recent research has shown that the immune system could influence the
nervous system and its behavior that we should conclude that the immune
system controls the nervous system let alone behavior. More data would be
needed to demonstrate control though it is not entirely clear which data could be
considered conclusive in that case. Moreover, the choice between the “control-
ler” and the “controlled” seems to be more dependent on the disciplinary
background of the person making the claim than on anything else. Personally,
I don’t see the need to attribute control to one system or another.
In summary, we have singled out five questions in the neuroimmunological
literature and suggested that distinguishing them was useful not only as
a conceptual clarification of current research in that domain but also as an
invitation to further explore the questions that, as is typically the case with that
of evolutionary origins, have tended to remain in the background because their
specificities have not been sufficiently recognized.
5.5 Conclusion: Some Philosophical Consequences

Let’s end this section by drawing three philosophical consequences from this
exploration of neuroimmunology. First, neuroimmunology offers useful
(although not unique) lessons about interdisciplinarity. Two types of interdisci-
plinarity are found in neuroimmunology: horizontal (integration of different
disciplines – here neurobiology and immunology, to which one must actually
add endocrinology and psychology) and vertical (integration of different levels
of analysis, from molecules to systems, pertaining traditionally to distinct
domains). Neuroimmunology also illustrates exemplarily the well-known fact
that disciplines create mindsets and even norms of judgement and action. These
mindsets are difficult to overcome in basic research as well as in the clinic. For
example, few immunologists think about using neurostimulation to cure
patients with autoimmune diseases, and until recently few psychiatrists con-
sidered using immune-based therapies to treat mental disorders. In addition to
such epistemological questions, interdisciplinarity in neuroimmunology raises
an ontological question: are there really three systems (nervous, immune,
endocrine) in animals like us, or, as suggested, for example, by (Steinman
2012), are those only projections of our thought and language on the world?
Personally, I see the epistemological issue as more stimulating and pressing than
the ontological one, but both may converge to a large extent.
Second, what has been said here confirms the importance of adopting an
extended view of immunity, as argued in the previous sections. In the context of
neuroimmunology this extension has two dimensions. The first dimension has
to do with the diversity of activities achieved by the immune system. To the
various immunological activities already identified in the previous sections
(development, clearance of debris, repair, and so on) one must add that the
immune system could also influence the nervous system and cognitive func-
tions. The second dimension is that the immune system is extended in another
sense, namely insofar as it is connected with other systems (here the nervous
and endocrine systems) and sometimes overlaps with them.
Third, our discussion suggests that immunology makes a significant contri-
bution to the understanding of behavior and cognition and should therefore
attract the attention of philosophers of neuroscience and philosophers of cog-
nitive science. If the experimental results presented above are correct, then the
immune system influences various feelings, behaviors, and cognitive processes
either directly or indirectly (through its interactions with the CNS, PNS, endo-
crine system, and/or other systems). The immune system has an impact on
sickness behavior (Konsman et al. 2002) and major depressive disorder
(Dantzer 2018), and strategies are currently being developed to treat several
behavioral disorders by targeting the immune system. Another major example is
pain, a highly discussed topic in the philosophy of the neurosciences
(Hardcastle 1997) and in general philosophy as well. Activated immune cells
release pro-inflammatory cytokines, which sensitize sensory nerve endings,
leading to an amplification and prolongation of pain; but the pain response
also is downregulated via opioid-containing immune cells, as these cells release
opioid peptides, which interact with opioid receptors on sensory nerves (Stein
et al. 1990). All this corroborates the claim that pain is a highly complex process
with several feedback loops and involving several bodily systems (Hardcastle
1997). Last but not least, many researchers propose that the immune system, via
microglia, T cells, and cytokines, participates in cognition, particularly in
learning and spatial memory.
All these data contribute to question brain-centered and more generally
nervous system–centered views of behavior and cognition. Clearly, the nervous
system remains crucial in all the processes described above, but it would none-
theless be inadequate to consider only the nervous system when trying to
identify the biological basis of feelings, emotions, behaviors, and cognitive
states. Understanding these processes requires an integrative approach in which
the immune system could play an important role. Accordingly, neuroimmunol-
ogy lends more weight to the idea of embodied cognition, that is, the idea that
bodily elements distinct from the brain play a significant role in cognitive
processing (Shapiro 2010). It also offers additional arguments to those who
emphasize the importance of interoception (Craig 2002) insofar as it suggests
that the brain can form a representation of the immunological status of periph-
eral tissues.
One may wonder, though, whether the immune system is an essential com-
ponent of behavior and cognition. Here the answer will depend on what exactly
is meant by this question. If the question is whether the immune system could
influence behavior and cognition on its own, that is, independently of the
(central and peripheral) nervous system, then the answer is probably negative.
But if the question is whether the immune system is essential for proper
functioning of the nervous system in some behavioral and cognitive activities,
then the answer is affirmative, as exemplarily illustrated by microglia-mediated
synaptic remodeling. More specifically, I suggest that the immune system can
play three kinds of specific roles that are essential for the functioning of the
nervous system and particularly for the realization of some cognitive processes.
First, the immune system is an informant for the nervous system. It provides
vital information about infections, damage, and other perturbations that occur in
any part of the organism. If, as proposed in Section 2, the capacity to respond to
pathogens and other sources of damage constitutes one of the strongest evolu-
tionary pressures on organisms, then conveying information to the nervous
system about the immunological status of the host is vital. Second, the immune
system is an executant for the nervous system: it realizes distinctive activities
indispensable for the functioning of the nervous system, such as elimination of
dead cells, repair, and so on. Third, and most crucially, the immune system is
a messenger for the nervous system: not only does the nervous system resort to
the molecular communication pathways of the immune system (cytokines) but
it makes use of the unique feature of immune cells, namely their mobility, which
allows them to reach any part of the organism and to deliver complex messages
there. I suspect that, in coming years, cognitive functions mediated by this
unique mobility of immune cells will be uncovered.
Current research in neuroimmunology raises other philosophically interest-
ing issues, which could not be examined here due to space restrictions. These
include how the nervous and the immune system interact in the construction of
biological individuality and rethinking central physiological concepts such as
homeostasis in light of the crosstalk between these two systems, among many
other questions. Again, the aim of this section was simply to convince the reader
that neuroimmunology is full of philosophical promise.
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Acknowledgments
I would like to thank my colleague and friend Jean-François Moreau, Professor
of Immunology at the University of Bordeaux, for his continuously inspiring
“big picture” of immunology. It has been a pleasure and honor to work at his
side since 2014. Maël Lemoine and Jean-François Moreau read the entire
manuscript and helped me to make it sharper. Lucie Laplane, Jan Pieter
Konsman, and Anya Plutynski each read one specific section and made very
useful comments. I owe special thanks to Wiebke Bretting, who drew several
figures of this Element. William Morgan made very useful suggestions. Many
thanks for discussions about immunology and philosophy to Lynn Chiu, Marc
Daëron, Louis Du Pasquier, John Dupré, Gérard Eberl, Melinda Fagan, Scott
Gilbert, Peter Godfrey-Smith, Deborah Gordon, Paul Griffiths, Matt Haber,
Philippe Huneman, Akiko Iwasaki, Jonathan Kipnis, Philippe Kourilsky, Bruno
Lemaitre, Tim Lewens, Richard Lewontin, Margaret McFall-Ngai, Alberto
Mantovani, Sarkis Mazmanian, Ruslan Medzhitov, Michel Morange, Alvaro
Moreno, Samir Okasha, Susan Oyama, Philippe Sansonetti, Ken Schaffner,
Elliott Sober, Kim Sterelny, Joan Strassmann, Marie-Elise Truchetet, Skip
Virgin, and Eric Vivier. My gratitude and admiration go to Jean Gayon
(1949–2018), my supervisor and friend, who is so greatly missed. This project
has received funding from the European Research Council (ERC) under the
European Union’s Horizon 2020 research and innovation program – grant
agreement n° 637647 – IDEM. I thank all the past and present members of
that project. I also thank all the members of the Conceptual Biology and
Medicine group, as well as the ImmunoConcept lab as a whole, the CNRS,
and the University of Bordeaux. I am lucky to work in such a friendly and
inspiring interdisciplinary environment.
This Element is dedicated to Jean-François Moreau, who embodies
immunology.
Philosophy of Biology
Grant Ramsey
KU Leuven
Grant Ramsey is a BOFZAP research professor at the Institute of Philosophy, KU Leuven,
Belgium. His work centers on philosophical problems at the foundation of evolutionary
biology. He has been awarded the Popper Prize twice for his work in this area. He also
publishes in the philosophy of animal behavior, human nature and the moral emotions. He
runs the Ramsey Lab (theramseylab.org), a highly collaborative research group focused on
issues in the philosophy of the life sciences.
Michael Ruse
Florida State University
Michael Ruse is the Lucyle T. Werkmeister Professor of Philosophy and the Director of the
Program in the History and Philosophy of Science at Florida State University. He is Professor
Emeritus at the University of Guelph, in Ontario, Canada. He is a former Guggenheim fellow
and Gifford lecturer. He is the author or editor of over sixty books, most recently Darwinism
as Religion: What Literature Tells Us about Evolution; On Purpose; The Problem of War:
Darwinism, Christianity, and their Battle to Understand Human Conflict; and A Meaning to
Life.
About the Series

This Cambridge Elements series provides concise and structured introductions to all of the
central topics in the philosophy of biology. Contributors to the series are cutting-edge
researchers who offer balanced, comprehensive coverage of multiple perspectives, while
also developing new ideas and arguments from a unique viewpoint.
Philosophy of Biology
Elements in the Series

The Biology of Art
Richard A. Richards
The Darwinian Revolution
Michael Ruse
Ecological Models
Jay Odenbaugh
Mechanisms in Molecular Biology
Tudor M. Baetu
The Role of Mathematics in Evolutionary Theory
Jun Otsuka
Paleoaesthetics and the Practice of Paleontology
Derek D. Turner
Thomas Pradeu
A full series listing is available at: www.cambridge.org/EPBY

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PRADEU

Immunology is central to contemporary biology and

Cover image: Ascidiae from Kunstformen der Natur (1904)

Cambridge University Press is part of the University of Cambridge.

Elements in the Philosophy of Biology

Abstract: Immunology is central to contemporary biology and

Keywords: immune system, self, individuality, cancer, neuroimmunology

© Thomas Pradeu 2019

1. ImmunoConcept (UMR5164), CNRS and University of Bordeaux, France.

1 Introduction: The Centrality of Immunity in Biology

2 Immunity: A Matter of Defense? 3

3 The Unity of the Individual: Self–Nonself,

4 Cancer as a Deuniﬁcation of the Individual 29

5 Neuroimmunology: The Intimate Dialogue between

1 Introduction: The Centrality of Immunity in Biology

diseases (Hansson and Hermansson 2011), neurodegenerative disorders

BOX 1.1 MAIN CLAIMS MADE IN THE PRESENT ELEMENT

This Element tries to talk simultaneously to philosophers, scientists, and med-

2 Immunity: A Matter of Defense?

promptly eliminated, then antigen-presenting cells, typically dendritic cells,

BOX 2.1 SIMPLIFIED PRESENTATION OF THE MAIN CELLULAR AND MOLECULAR

Macrophages: phagocytosis, elimination of pathogens, clearance of debris,

Effector T lymphocytes: stimulation of other immune cells, destruction of

Complement: phagocytosis, inﬂammation, membrane attack.

2.1 Historically, Immunity Has Been Understood As

BOX 2.2 IMPORTANCE OF THE ECOLOGICAL AND EVOLUTIONARY CONTEXT WHEN

An infectious microorganism is not intrinsically pathogenic (Casadevall

2 An Ever-Going “Arms Race” Occurs between Hosts and

3 Immune Defense Comes at a Cost

Historically, the deﬁnition of immunity as defense against pathogens is

BOX 2.3 THE DISTINCTION BETWEEN INNATE AND

2.2 Defensive Immune Mechanisms Have Been Identiﬁed

modes of recognition (including nucleotide-binding domain, leucine-rich repeat

2.3 Extended Immunity: Immunity Goes Well Beyond Defense

2.4 Accounting for the Evolution of Immunological Processes

Figure 2.2 Extended immunity: overview of the various, partly

functional ascription in the case of the immune system. It increasingly appears

transition from unicellular to multicellular organisms where, again, the constitution

2.5 Is It Still Possible to Oﬀer a Precise and Simple

become extremely challenging nowadays. Focusing on defense against patho-

3 The Unity of the Individual: Self–Nonself, Autoimmunity,

which became unbearable for him. Hallam interrupted immunosuppressive

individual. Finally, I make a claim for combining immunology’s lessons about

3.1 From Early Reﬂections about Immunological

3.2 Autoimmunity, Tolerance, and Symbiotic

debris, many immune-mediated repair mechanisms, and the downregulating

BOX 3.1 THE IMPORTANCE OF RESEARCH ON SYMBIOSIS IN RECENT BIOLOGY AND

from that of healthy individuals, is this difference a cause or

The upshot is that the self–nonself theory is inadequate or at least incomplete,

3.3 Immunology’s Contribution to the Deﬁnition

among philosophers of biology and biologists. Accounts of these three

Immune system Biological individuality

Filtering over entry Countability

detection of abnormal molecular patterns, cell stress, aberrant cellular prolif-

3.4 The Role of the Immune System in Turning a Set of

This reasoning allows us to propose an immunological deﬁnition of the

Figure 3.2 Rejection between two colonies of Botryllus schlosseri.

examples of this – autoimmune diseases and ecological approaches to the

3.5 Combining Diﬀerent Approaches to Biological Individuality