䡵 Autoimmune Diseases

Mechanisms of Autoimmunity
—Recent concept—
JMAJ 47(9): 403–406, 2004

Kazuhiko YAMAMOTO

Professor, Department of Allergy and Rheumatology, The University of Tokyo

Abstract: Autoantibodies and autoreactive T cells, which exist even in healthy

individuals, are usually regulated by a mechanism called immunological tolerance.
For example, peripheral T cells are subject to various types of regulatory
mechanisms, including clonal deletion, anergy, clonal ignorance, and T cells with
regulatory functions. It is believed that autoimmune response may initiate when
such regulated immune responses are pathologically activated by a certain trigger,
probably a limited antigenic stimulation. Thereafter, other factors that promote
autoimmune responses combine to develop an autoimmune disease. It is esti-
mated that T cells are closely involved in these reactions.
Key words: Immunological tolerance; Molecular mimicry; Epitope spreading

assumes that the immune system definitely

Introduction
distinguishes between self and non-self, and
Autoimmunity is generally defined as a phe- that autoreactive B and T cell clones are
nomenon in which antibodies or T cells react eliminated before they mature. However,
with autoantigens. Autoimmunity induces auto- recent studies have demonstrated that this
immune diseases. Recent studies have revealed theory, although basically correct, does not
that such autoantibodies or autoreactive T cells always hold true. B and T cells that react with
exist even in healthy individuals. The immune autoantigens exist in the peripheral blood of
system has various mechanisms to suppress the healthy individuals.
immune response to the self, and the distur- For example, T cells that react with auto-
bance of these mechanisms results in auto- antigens, such as myelin basic protein (MBP)
immune diseases. of myelin sheath and type II collagen of car-
tilage, can be separated from the peripheral
Autoimmunity and blood of healthy individuals. Furthermore, auto-
immune diseases such as thyroiditis can be
Autoimmune Diseases
induced in normal animals by immunizing them
The conventional clonal deletion theory with organ-specific antigens such as thyro-

This article is a revised English version of a paper originally published in

the Journal of the Japan Medical Association (Vol. 129, No. 7, 2003, pages 895–898).

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K. YAMAMOTO

globulin, indicating that lymphocytes that react Mechanisms of

with the autoantigens exist in normal animals.
Immunological Tolerance
Therefore, it is believed that the existence of
autoantibodies or autoreactive T cells is not Immunological tolerance is defined as a state
enough to elicit autoimmune diseases. In in which the immune system does not posi-
addition, it has been recently speculated that tively respond to autoantigens. The concept of
auto-reactivity at a low level is physiological immunological tolerance for autoreactive T
and necessary for a normal immune response. and B cells has been changing rapidly as new
It has been reported that the weak reactivity experimental systems have been established.
to autoantigens presented by major histo- T cells, which play a central role in acquired
compatibility complexes (MHC; for humans, immunity, undergo clonal deletion by apo-
HLA) might be necessary for the survival of ptosis when they are exposed to a sufficient
peripheral mature T cells and maintenance of amount of autoantigens in the thymus where
homeostasis. they differentiate. This is called central toler-
Considering these factors, it is important to ance. It has been revealed recently that some
distinguish specific autoimmune responses that molecules previously considered to be expressed
cause various autoimmune diseases from the only in a specific organ are also expressed in
existence of autoreactive lymphocytes or simple medullary epithelial cells of the thymus. This
autoimmune response. For example, injection indicates that the thymus is intended to express
of spermatozoa into an animal results only in as many autoantigens as possible in the body
the production of autoantibodies against sper- to induce tolerance for them. However, this
matozoa, but it does not cause any disease. mechanism is limited by the fact that not all
However, the immunization of an animal with autoantigens are expressed in the thymus.
spermatozoa mixed with an adjuvant that Furthermore, T cells that weakly react with
strongly stimulates an immune response results autoantigens can migrate into peripheral tissue.
in autoimmune testitis. Therefore, autoimmune Each antigen should have multiple amino acid
diseases are distinguished from mere auto- sequences that can bind to antigen-presenting
immune response not by the presence/absence MHC molecules. These sequences are called
of autoimmune response, but by the different epitopes or antigenic determinants. However,
quality and quantity of the autoimmune some epitopes are not presented as antigens
response. under usual conditions probably due to the
Autoimmune diseases are divided into two relationship with other epitopes or proteolysis
groups: the organ-specific autoimmune diseases, in the cells. Such epitopes are called “cryptic
in which the target antigens and the tissue dis- epitopes,” which means hidden antigenic deter-
orders are localized in one organ, and the minants. T cells cannot become tolerant to
systemic autoimmune diseases, in which the them.1)
response to a certain type of antigens that are T cells that migrate into peripheral tissues
expressed widely in the body, such as an undergo clonal deletion by apoptosis in the
intranuclear antigen and multiple organs are similar way as in the thymus when the stimulus
involved. There are several autoimmune dis- of autoantigens is strong. When the stimulus is
eases that stand between these two groups. It not strong enough, T cells undergo clonal
remains unclear whether these two groups of anergy (clonal paralysis). When the amount of
autoimmune diseases result from the same or autoantigens is further reduced, T cells become
substantially different mechanisms. ignorant (non-tolerant and unresponsive). In
this regard, it is important that naïve T cells
circulate only in lymphoid organs without

404 JMAJ, September 2004—Vol. 47, No. 9

 MECHANISMS OF AUTOIMMUNITY

entering other organs to maintain the state of triggered by the development or activation of
ignorant. CD4Ⳮ helper T cells that react with a specific
It has also been reported that tolerance may autoantigen. Based on various evidence, it is
be actively suppressed by regulatory T cells. now proposed that a specific antigenic stimulus
Recent studies have reported T cells with vari- is the first trigger of autoimmunity. This is
ous regulatory functions, including those that called the “single initiating antigen hypoth-
produce cytokines with suppressive effects, esis”.2) For example, molecular mimicry in
such as interleukin (IL)-10 and transforming which immune response occurs to both an
growth factor (TGF)-␤, and those that have external microbial antigen and an autoantigen
CD4Ⳮ and CD25Ⳮ surface markers and pro- because of their homology is considered one of
vide suppressive effect through cell-cell contact. the mechanisms of initiating autoimmunity.
These various suppressive T cells may play Microbial infection may initiate autoimmune
different roles, depending on the activation of response not only through molecular mimicry,
autoreactive T cells. but also with polyclonal activation and release
Thus, autoreactive T cells are under sub- of isolated autoantigen. Lipopolysaccharide
stantially different conditions of tolerance, (LPS), a product of infectious microbes, bac-
depending on the quality and quantity of auto- terial DNA, and viruses serve as an adjuvant
antigens. For example, many autoantigens are to immune response. They bind to Toll-like
too isolated from the immune system to activate receptors (TLRs) on the surface of macro-
potential autoreactive T cells. Autoantigens phages or dendritic cells to stimulate natural
expressed on non-hematopoietic cells may not immunity and inflammatory cytokine pro-
stimulate T cells because they do not have co- duction, enhancing immune response by in-
stimulatory molecules. Another mechanism creasing the expression of MHC antigen or
has also been revealed in which the lymph co-stimulatory molecules, such as B7-2 and
nodes around organs have dendritic cells that OX40L. These responses are usually helpful for
take antigens to induce tolerance of auto- inducing acquired immunity, but may stimulate
reactive T cells in the steady state condition. potential autoreactive T cells. Through these
B cells have been reported to undergo anergy processes, it is also possible that cryptic epitopes
in response to soluble autoantigens and clonal not expressed under usual conditions are
deletion in response to stronger autoantigens, expressed to trigger an autoimmune response.
such as those on cell surfaces in the bone Non-infectious factors are also considered
marrow where they differentiate. B cells that as a trigger of autoimmunity. For example,
strongly react with soluble antigens such as estrogen exacerbates systemic lupus erythema-
self-molecules at the germinal center of periph- tosus (SLE) in a mouse model, while drugs,
eral tissues are also deleted through apoptosis. such as procaine amide and hydralazine, induce
B cells have been reported to cause a phenom- the production of antinuclear antibodies, caus-
enon called receptor editing in which B cells ing an SLE-like pathologic state. The amount
that react with an autoantigen rearrange the of iodine intake is an important environmental
gene of the antigen receptor (immunoglobulin) factor in autoimmune thyroid disease.
once again to make another non-autoreactive
receptor. Mechanisms of Development of
Autoimmune Diseases
Mechanism of Initiation of
Triggering autoimmunity alone probably
Autoimmunity
results in a transient event and is insufficient to
It is generally believed that autoimmunity is induce autoimmune disease. Studies in mouse

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K. YAMAMOTO

models have shown that CD4Ⳮ T cells may be have also shown from the analyses of T cell
required to complete the pathological state of clonality infiltrating into organs that reactive
most autoimmune diseases. Animal experiments epitope is not always spread during the prog-
have demonstrated that the onset of auto- ress of a disease. Probably, such positive and
immune diseases can be suppressed by removing negative balance of immune responses with
or inhibiting the function of CD4 cells with regard to reactive epitopes may be involved
anti-CD4 monoclonal antibodies. Furthermore, in the persistence and progression of auto-
the importance of antigen-specific CD4 cells in immune diseases.
pathological autoimmune condition has been
suggested from the association with MHC class
Conclusions
II antigens (such as DR antigen of HLA in
humans), infiltration of CD4Ⳮ cells in many Autoimmune disease is generated through
organ-specific autoimmune diseases, and pro- the disturbance of immunological tolerance.
duction of autoantibodies of IgG type. Activation of autoreactive lymphocytes, and
Although various factors are associated with various positive and negative immune responses
the progression of autoimmune diseases, one of are involved in each of these processes. Geneti-
the important phenomena is epitope spreading. cally, individuals with lower threshold to these
Epitope spreading refers to a phenomenon responses are more susceptible to autoimmune
in which autoantigens (antigen determinants) disease, although various environmental factors
detected by T and B cells increase during the that induce such immune responses are also
process from the initial activation of auto- significant. It is thus necessary to understand in
reactive lymphocytes to the chronic phase. This detail autoimmune phenomena in each patient
concept is important for explaining, for example, to establish a proper therapy that suppress
the mechanism by which autoimmune response pathological immune responses without affect-
induced by one cryptic epitope leads to com- ing normal immune functions.
plete autoimmune response. Both B and T cells
are involved in this phenomenon. Particularly,
B cells play an important role as antigen- REFERENCES
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