Autoimmunity is defined as an immune response
against self (autologous) antigens. It is an important
cause of disease, estimated to affect 5% to 10% of the
population in developed countries, and the prevalence
of several autoimmune diseases is increasing. Different
autoimmune diseases may be organ-specific, affecting
only one or a few organs, or systemic, with widespread
tissue injury and clinical manifestations. Tissue injury
in autoimmune diseases may be caused by antibodies
against self antigens or by T cells reactive with self antigens (see Chapter 11).
The principal factors in the development of autoimmunity are the inheritance of susceptibility genes
and environmental triggers, such as infections (Fig.
9.11). It is postulated that susceptibility genes interfere
autoantibodies that are responsible for the autoimmune
Despite our growing knowledge of the immunologic
abnormalities that may result in autoimmunity, we still
several factors: autoimmune diseases in humans usually
are heterogeneous and multifactorial; the self antigens
clinically long after the autoimmune reactions have been
initiated. Recent advances, including the identification
of disease-associated genes and better techniques for
studying immune responses in humans, hold promise
for providing answers to the enigma of autoimmunity.
disease develops in one of two twins, the same disease
is more likely to develop in the other twin than in an
These findings prove the importance of genetics in the
(predisposing) or less frequent (protective) in patients
than in healthy controls. The likelihood of a particular
autoimmune disease in people with versus without a
particular HLA allele is expressed as the odds ratio or
relative risk. The importance of these polymorphisms is
reinforced by the finding that many of them affect genes
involved in immune responses, and the same genetic
190 CHAPTER 9 Immunologic Tolerance and Autoimmunity
polymorphism may be associated with more than one
autoimmune disease. However, these polymorphisms
are frequently present in healthy individuals, and the
individual contribution of each of these genes to the
development of autoimmunity is very small, so many
risk alleles together are needed to cause the disease.
Many autoimmune diseases in humans and inbred
animals are linked to particular MHC alleles (Fig. 9.12).
The association between human leukocyte antigen (HLA)
that T cells played an important role in these disorders
(because the only known function of MHC molecules
is to present peptide antigens to T cells). The incidence
of numerous autoimmune diseases is greater among
individuals who inherit particular HLA allele(s) than in
the general population. Most of these disease associations
are with class II HLA alleles (HLA-DR and HLA-DQ),
perhaps because class II MHC molecules control the
well in regulating immune responses. It is important to
point out that, although an HLA allele may increase the
risk of developing a particular autoimmune disease, the
HLA allele is not, by itself, the cause of the disease. In fact,
the disease never develops in the vast majority of people
who inherit an HLA allele that does confer increased risk
of the disease. Despite the clear association of MHC alleles
with several autoimmune diseases, how these alleles
contribute to the development of the diseases remains
Genetic susceptibility Reaction to environmental stimuli
Fig. 9.11 Postulated mechanisms of autoimmunity. In this proposed model of organ-specific T cell–
and subsequently of self-reactive T cells, resulting in tissue injury.
CHAPTER 9 Immunologic Tolerance and Autoimmunity 191
unknown. Some hypotheses are that particular MHC
alleles may be especially effective at presenting pathogenic
leading to defective negative selection of T cells.
Polymorphisms in non-HLA genes are associated
with various autoimmune diseases and may contribute
to failure of self-tolerance or abnormal activation of
lymphocytes (Fig. 9.13A). Many such disease-associated
genetic variants have been described:
• Polymorphisms in the gene encoding the tyrosine
phosphatase PTPN22 (protein tyrosine phosphatase
N22) may lead to uncontrolled activation of both B
and T cells and are associated with numerous autoimmune diseases, including rheumatoid arthritis,
SLE, and type 1 diabetes mellitus.
• Variants of the innate immune cytoplasmic microbial
inflammatory bowel disease, in some ethnic populations.
• Other polymorphisms associated with multiple autoimmune diseases include genes encoding the IL-2
receptor a chain (CD25), believed to influence the
balance of effector and regulatory T cells; the receptor
for the cytokine IL-23, which promotes the development of proinflammatory Th17 cells; and CTLA-4,
a key inhibitory receptor in T cells discussed earlier.
Surprisingly, many of these polymorphisms are in
the regulatory regions of the genes (promoters and
enhancers) and not in the coding sequences, suggesting that they influence expression of the genes.
Some rare autoimmune disorders are Mendelian in
origin, caused by mutations in single genes that have high
inheritance varies. These genes, alluded to earlier, include
key molecules and pathways involved in self-tolerance.
However, these Mendelian forms of autoimmunity are
exceedingly rare, and common autoimmune diseases are
not caused by mutations in any of these known genes.
Role of Infections and Other Environmental
Infections may activate self-reactive lymphocytes,
thereby triggering the development of autoimmune
diseases. Clinicians have recognized for many years that
the clinical manifestations of autoimmunity sometimes
are preceded by infectious prodromes. This association
between infections and autoimmune tissue injury has
been formally established in animal models.
Infections may contribute to autoimmunity in several ways (Fig. 9.14):
• An infection in a tissue may induce a local innate
immune response, which may lead to increased
production of costimulators and cytokines by tissue APCs. These activated tissue APCs may be able
to stimulate self-reactive T cells that encounter self
antigens in the tissue. In other words, infection may
break T cell tolerance and promote the activation of
self-reactive lymphocytes. This may lead to disease if
it occurs in people who are already genetically at risk
Fig. 9.12 Association of autoimmune diseases with alleles of the major histocompatibility complex
(DNA-based) typing instead of the older serologic (antibody-based) methods.
192 CHAPTER 9 Immunologic Tolerance and Autoimmunity
Single-gene defects that cause autoimmunity (Mendelian diseases)
Gene(s) Disease association Mechanism
Defects in clearance of immune
complexes or in B cell tolerance?
NOD2 Defective resistance or abnormal
responses to intestinal microbes?
Abnormalities in effector and/or
PTPN22 Abnormal tyrosine phosphatase regulation
of T cell selection and activation?
SLE Defective feedback inhibition of B cells
AIRE Reduced expression of peripheral tissue
antigens in the thymus, leading to
defective elimination of self-reactive T cells
Immune dysregulation, Deficiency of regulatory T cells
Impaired regulatory T cell function leading
to loss of B and T cell homeostasis
FAS Defective apoptosis of self-reactive T and
Genes that may contribute to genetically complex autoimmune diseases
CTLA4 Inhibitory receptor of T cells, effector
molecule of regulatory T cells
IL23R Component of IL-23 receptor; role in
generation and maintenance of Th17 cells
Fig. 9.13 Roles of non–MHC genes in autoimmunity. A, Select examples of variants (polymorphisms) of
erythematosus; T1D, type 1 diabetes.
CHAPTER 9 Immunologic Tolerance and Autoimmunity 193
for developing autoimmunity. One cytokine produced
or lymphocytes, but what stimulates its production
and how it contributes to autoimmunity is not well
• Some infectious microbes may produce peptide
antigens that are similar to, and cross-react with,
self antigens. Immune responses to these microbial
peptides may result in an immune attack against self
antigens. Such cross-reactions between microbial
and self antigens are termed molecular mimicry.
Although the contribution of molecular mimicry
to autoimmunity has fascinated immunologists,
its actual significance in the development of most
autoimmune diseases remains unknown. In some
disorders, antibodies produced against a microbial protein bind to self proteins. For example, in
rheumatic fever, a fairly common disease before the
widespread use of antibiotics, antibodies against
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