What is immunity

Immunity is the capability of multicellular organisms to resist harmful microorganisms and

pathogens. Pathogens are foreign disease-causing substances, such as bacteria and viruses,
and people are exposed to them every day. Antigens are attached to the surface of pathogens
and stimulate an immune response in the body. An immune response is the body’s defence
system to fight against antigens and protect the body. Immunity involves both specific and
nonspecific components. The nonspecific components act as barriers or eliminators of a wide
range of pathogens irrespective of their antigenic make-up. Other components of the immune
system adapt themselves to each new disease encountered and can generate pathogen-specific
immunity. Immunity is a complex biological system that can recognize and tolerate whatever
belongs to the self, and to recognize and reject what is foreign (non-self).

Types of Immunity

i. Innate immunity:

Innate or natural immunity is the immunity with which all organisms are born with.
including physical barriers (skin, body hair), defense mechanisms (saliva, gastric acid), and
general immune responses (inflammation). It is the body’s first line of defense against germs
and pathogens. It includes physical barriers, such as skin and mucous membranes, and special
cells and proteins that can recognize and kill germs. This type of immunity is present in all
metazoans, The innate component of the immunity system involves the recognition of certain
foreign (non-self) molecules to generate one of two types of innate immune responses:
inflammatory responses and phagocytosis. It contributes to the activation of adaptive immune
response and does not adapt to specific external stimulus or a prior infection, but relies on
genetically encoded recognition of particular patterns.

ii. Adaptive immunity:

It is a type of immunity that develops from immunological memory. Adaptive immunity is

protection that your body builds when it meets and remembers antigens. Antigens are germs
and other foreign substances in the body. The body is exposed to a specific antigen (which is
attached to a pathogen) and develops antibodies to that specific antigen. The next time the
body sees that antigen, it recognizes and releases it antibodies to fight the antigen. Adaptive
immunity only occurs in vertebrate. Adaptive immunity involves more advanced lymphatic
cells that can distinguish between specific "non-self" substances in the presence of "self". The
reaction to foreign substances is etymologically described as inflammation while the non-
reaction to self-substances is described as immunity. Adaptive immunity can be acquired
either 'naturally' (by infection) wherein a person gets a disease and develops immunity as a
result or 'artificially' (through deliberate actions such as vaccination) wherein the vaccine
mimics a particular disease, causing an immune response in the vaccinated individual without
getting them ill. Adaptive immunity can also be classified as 'active' or 'passive'.

a. Active immunity:  antibodies that develop in a person's own immune system after the
body is exposed to an antigen through a disease or when you get an immunization (i.e.
A flu shot). This type of immunity lasts for a long time.
b. Passive Immunity: antibodies given to a person to prevent disease or to treat disease
after the body is exposed to an antigen. Passive immunity is given from mother to
child through the placenta before birth, and through breast milk after birth. It can also
be given medically through blood products that contain antibodies, such as immune
globulin. This type of immunity is fast acting but lasts only a few weeks or months.

Immunity against Parasitic Helminths

Helminth infections and the corresponding host immune responses are products of a
prolonged dynamic co-evolution between the host and parasite. For parasites, it is
advantageous to trick the host into developing an ineffective immune response, to find a
suitable niche for maturation and propagation, and to do so without killing or unduly harming
the host. Conversely, the host has to ideally generate an effective immune response to expel
the parasite, and minimize its harmful effects, while not sacrificing its ability to effectively
respond to other pathogens. The host immune system evolved in the context of a parasite-
replete environment, and the balance of immune effector and regulatory cell populations are
at least partly a consequence of ongoing responses to infectious organisms that can often
simultaneously invade host tissues.  Although such dynamic host–pathogen interactions exist
throughout much of the world, in industrialized countries infectious diseases are better
controlled as a result of increased hygiene, the administration of vaccines at an early age and
the widespread use of antibiotics. Although this has resulted in marked reductions in chronic
and severe disease, recent studies indicate a possible adverse effect of this enhanced control
of infectious diseases that leads to an increase in inflammatory disorders. One mechanism by
which this unfavourable result occurs has been suggested by an extension of the hygiene
hypothesis, which proposes that a dysregulated immune response might develop in
individuals who were not exposed to chronic helminth infections, increasing the likelihood of
the development of allergic and autoimmune diseases. Studies shows that this model of
administration of helminth downmodulated autoimmune and allergic inflammation, whereas
clearance of helminth infection can result in a resurgence of these diseases. Understanding
the helminth-induced immune regulatory mechanisms that control certain inflammatory
diseases might point the way towards future treatments for these increasingly common
immune disorders.

The protective immune response against many helminth parasites has been variously referred
to as the type 2 response, TH2 (T helper 2) response or TH2-type response. Here, we use the
term TH2-type response to refer to the combined immune response, which includes both
innate and adaptive components, to clearly distinguish it from the adaptive T H2-cell response.
TH2-type responses are typically characterized by increases in the levels of interleukin-4 (IL-
4) and other TH2-type cytokines (including IL-5, IL-9, IL-13 and IL-21), activation and
expansion of CD4+ TH2 cells, plasma cells secreting IgE, eosinophils, mast cells and
basophils, all of which can produce several types of T H2-type cytokine. The IL-17-related
cytokine IL-25 (also known as IL-17E) is also associated with the T H2-type response and can
promote TH2-cell differentiation and nematode parasite expulsion. Whether IL-25 is also a
TH2-type cytokine or identifies another TH-cell subset remains unclear. By contrast,
interferon-γ (IFNγ)-dominant TH1-type responses are typically evoked by microbial
infections, including bacteria and viruses, and are associated with increases in the numbers of
TH1 cells, cytotoxic CD8+ T cells, neutrophils and macrophages. Although IL-10 was initially
characterized as a TH2-type cytokine, recent findings show that this cytokine is also
produced in vivo, and can by TH1 cells and regulatory T cells downregulate both TH1-type and
TH2-type responses. Several cytokines that are preferentially expressed during the T H2-type
response, including IL-4, IL-13, IL-21 and IL-25, can also downregulate TH1-type and TH17-
type responses and their associated inflammation.

An example of this TH2-type response was found in vitro studies using nematodes;
Heligmosomoides polygyrus and trematode; Schistosoma mansoni.  Infection with these
parasites triggers a TH2-type response, although the resultant mechanisms of protection differ
greatly, with each providing unique insights. In the highly polarized T H2-type response to the
hookworm model parasite, H. polygyrus, protective responses mediate parasite stress that
leads to expulsion of the worm. In S. mansoni infection, the protective TH2-type response
primarily downregulates an otherwise pathological TH1-type response. Therefore, the immune
responses to these two helminth species exemplify distinct functions of protective T H2-type
immune responses, one leading to worm expulsion and the other contributing to the control of
pathological inflammation.

Granuloma formation in Helminth

Granulomas are traditionally associated with localized TH1-type inflammatory responses that
develop around a nidus, such as an invading microorganism or parasite. In schistosomiasis,
perioval granulomatous inflammation is mediated by CD4+ T cells that are specific for
antigens derived from parasite eggs. The initial T H1-type response to the acute schistosome
infection targets adult parasites, but typically transitions to a T H2-type response after the
parasite’s eggs are produced. Both co-stimulatory molecules and B cells are required for this
switch. The failure to develop an effective TH2-type response after egg deposition results in
exacerbated granulomatous inflammation driven by TH1 and TH17 cells; this causes
substantial damage to the surrounding hepatic parenchyma, and can result in death. Typically,
a well-established TH2-type response prevails and is associated with mild lesions consisting
of small and well-circumscribed granulomas composed of eosinophils, macrophages and
lymphocytes with an increasingly fibrotic extracellular matrix (referred to herein as mild
pathology). In chronic schistosomiasis, even the subsequent T H2-type response eventually
subsides and newly forming egg granulomas are diminished in size; this regulation of the
immune response is termed ‘immunomodulation’. However, tissue fibrosis, which is largely
stimulated by the cytokine IL-13, can also become pathological and therefore represents a
potential downside of the ongoing TH2-type response to chronic infection. It has been
proposed that the formation of granulomas around schistosome eggs facilitates the migration
of the eggs through the intestinal wall. Although the formation of a parasite-enveloping
granuloma secludes the parasite, the immune cells contained in the granuloma still appear to
cause parasite damage and probably also contribute to the healing process after the adult
parasite migrates back to the intestinal lumen.

Innate effector cells in Helminth

Innate immune cells are essential for both the initiation and effector phases of T H2-type
immune responses. CD4+ TH2 effector cells instruct and amplify the innate effector-cell
response primarily through the secretion of cytokines; once activated, innate-cell populations
in turn help to sustain and promote expansion of the TH2 effector-cell population. This
 crosstalk results in an overall effector response composed of interacting cells that coordinate
and fine-tune targeted effector functions against the invading helminth parasite.

i. Neutrophils and macrophages: first responders in TH2-type inflammation

Macrophages are conventionally associated with TH1-type responses to infectious bacteria

and viruses. Classically activated macrophages engulf and destroy microorganisms through
pathways that are dependent on inducible nitric oxide synthesis (iNOS). Macrophages were
believed to be relatively quiet during TH2-type responses, having a secondary role to
eosinophils, basophils and mast cells. However, recent studies have shown pronounced
alternative macrophage activation and rapid recruitment to sites of infection during T H2-type
responses to helminths. IL-4, IL-13, IL-10 and IL-21 trigger the alternative activation of
macrophages, which can readily be distinguished by the high expression levels of markers
such as arginase-1, IL-4 receptor α-chain (IL-4Rα), the mannose receptor CD206 and the
absence of iNOS expression.

Given their large size, parasitic helminths can potentially cause significant tissue damage by
migrating through and residing within specific sites. Alternatively activated macrophages
might contribute to wound healing by clearing matrix and cell debris and by releasing
cytokines, growth factors and angiogenic factors that promote fibroplasia and angiogenesis
even at sterile sites. Some genes expressed by alternatively activated macrophages are
associated with wound healing, these include resistin-like molecules and extracellular matrix
proteins.

In addition to wound repair, alternatively activated macrophages may also mediate more
direct effects on tissue-dwelling helminths, for example, by targeting the glycan chitin that is
frequently expressed by helminths, but not by mammals. The chitinase and fizz family
member proteins (ChaFFs), which include chitinase and chitinase-like secreted proteins and
are secreted by alternatively activated macrophages, are prime candidates for mediating host
resistance. Although antiparasitic properties for many of these proteins have not been
described, some have surprising roles in mediating TH2-type inflammation. Therefore,
ChaFFs have evolved multiple functions that may contribute to resistance to helminth
infection, including enzymatic and other activities that potentially damage certain parasites
and promote the TH2-type inflammatory response.

Neutrophils are also activated and are recruited to sites of infection during tissue invasion by
helminths.  Classically and alternatively activated neutrophils have recently been
 distinguished following bacterial infections and it will be important for future studies to
determine the phenotypes of the neutrophils that are associated with helminth infection.
Studies have suggested a possible role for neutrophils in mediating resistance to H. polygyrus
in vivo and damaging parasites in vitro. More recent reports indicate an important role for
neutrophils in the killing of the larval stages of Strongyloides stercoralis. It was shown that
neutrophils were rapidly recruited to diffusion chambers containing S. stercoralis larvae,
where they killed larvae in the absence of other cell types, although eosinophils were also
required for optimal killing. During infection with S. mansoni, neutrophils seem to have little
effect, as their depletion did not influence the severity of disease. Generally, however,
neutrophils are increasingly recognized as important components of the TH2-type response
elicited during helminth infection. Following their rapid recruitment to sites of parasitic
helminth invasion, neutrophils, working in coordination with other cell populations, including
eosinophils and macrophages, can potentially directly damage tissue-dwelling helminths.

ii. Eosinophils:

The innate immune cell populations typically associated with TH2-type responses,
eosinophils, basophils and mast cells, have an integral role in antihelminth responses and in
the allergic cascade. Following helminth infection, eosinophil numbers increase dramatically
in the blood, and these eosinophils rapidly migrate to the site of infection, where they
degranulate, releasing eosinophil secondary granule proteins (ESGPs).

Until recently, eosinophil was studied by blocking or inhibiting IL-5, a CD4+ T-cell-derived

cytokine that is required for eosinophilia. These studies showed continued resistance to a
variety of helminths despite the reduced eosinophil numbers. However, not all eosinophils
were eliminated using these approaches, and other cell populations, including neutrophils,
might also respond to IL-5, and their function might therefore have been altered by these
treatments. More recently, several eosinophil-deficient mouse models have been developed.
These include mice in which the eosinophil peroxidase promoter drives expression of the
diphtheria toxin (referred to as TgPHIL mice), and mice that have deletion of a GATA1
binding sequence (referred to as ΔdblGATA mice). In these mouse models, primary
responses to schistosomes and to the intestinal nematode parasite Nippostrongylus
brasiliensis are unaffected. However, eosinophils mediated parasite damage during N.
brasiliensis challenge, even in the absence of CD4+ T cells. Depletion of eosinophils with
antibodies specific for CC-chemokine receptor 3 (CCR3) enhanced susceptibility to primary
 infection with Strongyloides stercoralis. Similar results were obtained from a model of
filarial disease, although mice deficient in ESGPs remained resistant, suggesting that
eosinophils also mediate protection through an ESGP-independent mechanism. Eosinophils
can also have a regulatory role through the production of cytokines, including IL-4 and IL-13,
and can function in vitro to present antigens to T cells in a S. stercoralis model; however, in
general, eosinophil depletion does not appear to markedly impair the development of the in
vivo TH2-type response to most parasitic helminths. A major effector function of eosinophils
and their ESGPs might be in tissue remodelling and debris clearance following tissue injury,
a general activity that might help to mediate the wound healing response following parasite
tissue invasion.

iii. Basophils and mast cells:

Basophils increase in number in the blood and tissues. Following N. brasiliensis infection,

IL-4-producing basophils are readily detected in the lungs, liver and spleen, but have not been
detected in the lymph nodes or Peyer’s patches; it is possible that they infiltrate lymph nodes
at an unidentified time. Basophils and eosinophils might be a major source of IL-4 at early
stages of the TH2-cell response, suggesting that they promote the development of T H2 cells or
their recruitment to sites of inflammation. To further understand basophil biology and the role
of these cells in helminth infection, it will be important to develop an effective method for
selectively depleting basophils

Mast cells share many characteristics with basophils, including the cell-surface expression of
the high-affinity Fc receptor for IgE (FcεRI) and the Toll-like receptors (TLRs) TLR2 and
TLR4, the release of mediators upon activation and IL-4 secretion, they have also been
shown recently to derive from a common progenitor. However, unlike basophils, which
circulate in the blood, mast cells reside in peripheral tissues and are thus well situated to
respond immediately to invasive agents. Increased numbers of mucosal mast cells are often
observed in affected tissues during helminth infections and this increase is dependent on T H2-
type cytokines that are primarily derived from CD4 + T cells; specifically, IL-4-dependent
mucosal mastocytosis is associated with a resistant phenotype to H. Polygyrus.

A role for mast cells in helminth immunity has been described in Trichinella spiralis; studies
using w/wv mice or stem-cell factor (SCF)-specific antibodies that impair mast-cell function
showed that SCF is required for mucosal mastocytosis during helminth infection, and is
important for effective helminth expulsion. Furthermore, mice deficient in mouse mast-cell
 protease 1 (mMCP-1; also known as β-chymase and Mcpt1) are unable to expel T.
spiralis indicating the antihelminth properties of mast-cell cytoplasmic granules; however,
mMCP-1 has little effect on N. brasiliensis host resistance. mMCP-1 might function to impair
epithelial-cell barriers by degrading the tight junction protein occludin and thereby increasing
luminal fluid flow.

Although most helminths induce pronounced basophil and mast-cell responses, the
importance of these cells in mediating resistance to these parasites varies greatly. This
variation may be related to the distinct microenvironments that are occupied by different
intestinal nematodes. For example, adult T. spiralis — unlike adult H. polygyrus and N.
brasiliensis, which inhabit the intestinal lumen — reside in intestinal epithelial-cell syncytia,
raising the possibility that mast-cell mediators might be more important in expelling tissue-
dwelling nematodes, possibly by increasing vascular permeability.

Adaptive immunity: T and B cells

Helminths potently induce the development of effector T H2 cells following infection. The
ensuing cytokine response by TH2 cells has broad effects, promoting antihelminth effector
functions in a variety of bone-marrow-derived and non-bone-marrow-derived cell
populations and tissues.

i. CD4+ T helper effector cells

Effector TH2 cells induced by helminths are characterized by the production of the cytokines
IL-4, IL-5, IL-9, IL-13 and the recently identified T H2-type cytokine IL-21, and the absence
of IFNγ and IL-17 production. In immune response to S. mansoni, but usually not to H.
polygyrus, TH2 cells can also produce IL-10. Following infection with different species of
bacteria and viruses, naive T cells differentiate along a reciprocal pattern, with high levels of
IFNγ and low levels of IL-4, that is largely shaped by adjuvant microbial pathogen-associated
molecular patterns (PAMPs) that bind to TLRs and other innate receptors expressed by DCs
and other antigen-presenting cells. The role of DCs in preferentially promoting TH2-cell
differentiation during helminth infection remains unclear, although several studies indicate
that DCs activated following exposure to schistosome egg antigen (SEA) preferentially
support TH2-cell differentiation.

During helminth infections, TH2 cells orchestrate the activation and expansion of leukocytes
primarily through the production of cytokines, an essential function that serves to amplify and
 sustain the TH2-type response. In addition, IL-4 and IL-13 can directly affect cell populations
that express IL-4R but that are not derived from the bone marrow, such as small-intestine
smooth-muscle cells, epithelial cells and myenteric neurons. IL-4R signalling is largely
dependent on the actions of signal transducer and activator of transcription 6 (STAT6).  H.
polygyrus infection induces STAT6-dependent changes in epithelial-cell function, increased
smooth-muscle contractility, increased mucus production, and enhanced fluids in the gut
lumen.

The host-specific CD4+ T-cell response to schistosome infection stimulates parasite

development, and results in an inflammatory environment that is required for translocation of
parasite eggs from the intravascular compartment into the intestinal lumen. The controlled
hepato-intestinal granulomatous inflammation around the eggs in this T H2-type-polarized
milieu might represent a compromise between the parasite and the vertebrate host, allowing
the parasite to complete its life cycle while at the same time protecting the host from severe,
lethal disease. In certain mouse strains, the host–parasite balance is not achieved, and this
results in a severe pathological inflammatory response mediated by CD4+ TH1 and TH17 cells.

These studies shows that in schistosomiasis, TH2 cells primarily downregulate harmful TH1-
and TH17-type inflammatory responses either directly or through innate immune cell
populations. By comparison, the TH2-type immune response to H. polygyrus, which is not
associated with an underlying TH1-type response, instead contributes to parasite resistance
and eventual helminth expulsion from the gut. The lack of harmful T H2-cell-mediated
pathology following H. polygyrus infection is probably a consequence of the relatively short
8 days period of tissue residence.

ii. Regulatory T cells (TReg)

Nematode infections can induce and expand naturally occurring regulatory T cells (TReg cells)
in humans and mice, suggesting a role for these TReg cells in helminth-induced modulation of
inflammatory diseases. Hyporesponsiveness associated with infection of mice with the filarial
parasite Litomosoides sigmodontis was blocked following in vivo depletion of TReg cells,
which resulted in increased killing of parasites. These studies suggest that T Reg cells induced
during filarial parasite infection have an important role in immunosuppression induced by
filarial parasites and in increased worm survival. Recently, CD8+ lamina propria T cells
induced by infection with H. polygyrus were shown to inhibit T-cell proliferation and the
development of experimentally induced colitis, suggesting that other regulatory T-cell
 populations are also important in nematode infections. TReg cells have been suggested to have
an important role in the suppression of the TH1-type inflammatory response to SEA. Initial
reports have suggested this effect was mediated through IL-10; however, more recent
findings indicate that these TReg cells can function through as yet unidentified IL-10-
independent mechanisms as well. TReg cells might also be instrumental in controlling T H2-
type responses in chronic S. mansoni infection. Further studies should examine the role of the
TH2 cells, TReg cells, alternatively activated macrophages and perhaps other innate cell
populations, in the control of TH1- and TH17-cell-mediated inflammation and the upregulation
of the TH2-type response. It is possible that several or all of these different cell populations
interact to mediate the evolution of a potentially pathological T H1-type response into a
protective TH2-type response following egg deposition in chronic schistosomiasis.

iii. B cells and antibody responses

During polarized TH2-type responses, IL-4 mediates B-cell class switching to IgE, a primary
mediator of acute allergic and asthmatic reactions that binds FcεRI on mast cells and
basophils. Antigen crosslinking of FcRεI-bound IgE triggers mast-cell degranulation and the
release of soluble mediators. IL-4 and IL-13 signalling through the IL-4R can increase the
sensitivity of target cells to basophil- and mast-cell-derived mediators. Therefore, IgE effects
are amplified in the presence of these T H2-type cytokines and this results in enhanced
responses including increased vascular permeability, smooth muscle contractility, and also
the recruitment of TH2-type effector cells, including eosinophils and TH2 cells.

Interestingly, neither IgE nor mast cells appear to have an essential role in the development of
the host protective immune response to either H. polygyrus or N. Brasiliensis. By contrast,
mast cells are required for protective immunity against T. spiralis; however, parasite-specific
IgE does not have an essential role, as recent studies have demonstrated that effective
expulsion is achieved in B-cell-deficient mice. In these cases, T H2-type cytokines and perhaps
other factors must be sufficient for mast-cell degranulation.

Antibody classes other than IgE have been described in nematode infection. Secreted IgM
was essential for timely expulsion of filarial parasites. This is the primary antibody type that
recognizes larval parasites, and might be produced in a T-cell-independent manner. As
macrophages express Fc receptors for IgM, IgM might also be important for macrophage
recognition of filarial parasites.
Schistosome infections elicit strong host antibody responses against multiple components of
the parasite, the majority of which are glycan determinants. Although it seems unlikely that
the antibodies have a significant antiparasitic effect, B cells can generally support the
establishment of the TH2-type response, thereby contributing to reduced pathology in
schistosomiasis, and correlations between IgE production and protective immune responses
have been reported in human schistosomiasis. Therefore, although the humoral antibody
response is typically associated with TH2-type responses during infectious disease, in many
cases antibodies do not appear to have an essential role in helminth protective responses that
either involve parasite expulsion or that down-regulate harmful TH1-type responses. As it is
clear that specific components of the TH2-type response that actually mediate protection vary
greatly with the specific parasitic helminth and developmental stage of the host, it is very
possible that an essential role for antibodies will be identified as such parasitic infections are
examined.
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