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).

Pathogenesis

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

with pathways of self-tolerance and lead to the persistence of self-reactive T and B lymphocytes. Environmental stimuli may cause cell and tissue injury and

inflammation and activate these self-reactive lymphocytes, resulting in the generation of effector T cells and

autoantibodies that are responsible for the autoimmune

disease.

Despite our growing knowledge of the immunologic

abnormalities that may result in autoimmunity, we still

do not know the etiology of common human autoimmune diseases. This lack of understanding results from

several factors: autoimmune diseases in humans usually

are heterogeneous and multifactorial; the self antigens

that are the inducers and targets of the autoimmune reactions often are unknown; and the diseases may manifest

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.

Genetic Factors

Inherited risk for most autoimmune diseases is attributable to multiple gene loci, of which the largest contribution is made by MHC genes. If an autoimmune

disease develops in one of two twins, the same disease

is more likely to develop in the other twin than in an

unrelated member of the general population. Furthermore, this increased incidence is greater among monozygotic (identical) twins than among dizygotic twins.

These findings prove the importance of genetics in the

susceptibility to autoimmunity. Genome-wide association studies have revealed some of the common variations (polymorphisms) of genes that may contribute to

different autoimmune diseases. Emerging results suggest that different polymorphisms are more frequent

(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)

alleles and autoimmune diseases in humans was recognized many years ago and was one of the first indications

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

action of CD4+ T cells, which are involved in both cellmediated and humoral immune responses to proteins as

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

Self-reactive

lymphocytes

Activation of

tissue APCs

Activation of

self-reactive

lymphocytes

Tissue

Self-reactive

effector

lymphocytes

Tissue injury

and

inflammation

Failure of

self-tolerance

Susceptibility

genes

Tissue injury:

autoimmune

disease

Fig. 9.11 Postulated mechanisms of autoimmunity. In this proposed model of organ-specific T cell–

mediated autoimmunity, various genetic loci may confer susceptibility to autoimmunity, probably by influencing the maintenance of self-tolerance. Environmental triggers, such as infections and other inflammatory

stimuli, promote the influx of lymphocytes into tissues and the activation of antigen-presenting cells (APCs)

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

self peptides to autoreactive T cells or that they are inefficient at displaying certain self antigens in the thymus,

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

sensor NOD-2 that cause reduced resistance to intestinal microbes are associated with Crohn disease, an

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

penetrance and lead to autoimmunity in most individuals who inherit these mutations, although the pattern of

inheritance varies. These genes, alluded to earlier, include

AIRE, FOXP3, FAS, and CTLA4 (see Fig. 9.13B). Mutations in these genes have been valuable for identifying

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

Influences

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

Disease Relative risk

Ankylosing spondylitis

Rheumatoid arthritis

Type 1

diabetes mellitus

Pemphigus vulgaris

HLA-B27

HLA-DRB1*01/*04/*10

HLA-DRB1*0301/0401

HLA-DR4

90

4-12

35

14

MHC allele

Fig. 9.12 Association of autoimmune diseases with alleles of the major histocompatibility complex

(MHC) locus. Family and linkage studies show a greater likelihood of developing certain autoimmune diseases in persons who inherit particular human leukocyte antigen (HLA) alleles than in persons who lack these

alleles (odds ratio or relative risk). Selected examples of HLA disease associations are listed. For instance,

in people who have the HLA-B27 allele, the risk of development of ankylosing spondylitis, an autoimmune

disease of the spine, is 90 to 100 times higher than in B27-negative people; other diseases show various

degrees of association with other HLA alleles. The asterisks indicate HLA alleles identified by molecular

(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

Disease association Mechanism

C2, C4

(Complement

proteins)

Defects in clearance of immune

complexes or in B cell tolerance?

NOD2 Defective resistance or abnormal

responses to intestinal microbes?

Crohn disease

CD25

(IL-2Ra)

Abnormalities in effector and/or

regulatory T cells?

MS, type 1 diabetes,

others

PTPN22 Abnormal tyrosine phosphatase regulation

of T cell selection and activation?

RA, several others

FCGRIIB

(FC?RIIb)

SLE Defective feedback inhibition of B cells

A

Gene(s)

B

AIRE Reduced expression of peripheral tissue

antigens in the thymus, leading to

defective elimination of self-reactive T cells

Autoimmune

polyendocrine

syndrome (APS-1)

FOXP3

CTLA4

Immune dysregulation, Deficiency of regulatory T cells

X-linked

polyendocrinopathy

and enteropathy (IPEX)

Impaired regulatory T cell function leading

to loss of B and T cell homeostasis

Autosomal dominant

immune dysregulation

syndrome

FAS Defective apoptosis of self-reactive T and

B cells in the periphery

Autoimmune

lymphoproliferative

syndrome (ALPS)

Genes that may contribute to genetically complex autoimmune diseases

SLE

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

IBD, PS, AS

T1D, RA

Fig. 9.13 Roles of non–MHC genes in autoimmunity. A, Select examples of variants (polymorphisms) of

genes that confer susceptibility to autoimmune diseases but individually have small or no effects. B, Examples of genes whose mutations result in autoimmunity. These are rare examples of autoimmune diseases

with Mendelian inheritance. The pattern of inheritance varies in the different diseases. APS-1 is autosomal

recessive, and in most patients, both alleles of the gene (AIRE) have to be abnormal to cause the disease.

IPEX is X-linked, so mutation in one allele of the gene (FOXP3) is sufficient to cause a defect in boys. ALPS

is autosomal dominant with highly variable penetrance, because FAS and FASL are trimeric proteins and

mutations in one of the alleles of either gene result in reduced expression of intact trimers. The disease

caused by CTLA4 mutations is also autosomal dominant, perhaps because mutation in one allele reduces the

expression of the protein enough to impair its function. AS, Ankylosing spondylitis; IBD, inflammatory bowel

disease; IL, interleukin; MS, multiple sclerosis; PS, psoriasis; RA, rheumatoid arthritis; SLE, systemic lupus

erythematosus; T1D, type 1 diabetes.

CHAPTER 9 Immunologic Tolerance and Autoimmunity 193

for developing autoimmunity. One cytokine produced

in innate immune responses to viruses is type I interferon (IFN). Excessive production of type I IFN has

been associated with the development of several autoimmune diseases, notably lupus. It may activate APCs

or lymphocytes, but what stimulates its production

and how it contributes to autoimmunity is not well

understood.

• 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

streptococci cross-react with a myocardial antigen

and cause heart disease.

• The innate response to infections may alter the chemical structure of self antigens. For example, some

Selftolerance

Induction of

costimulators

on APCs

Molecular

mimicry

Self-tolerance:

anergy or deletion

"Resting"

tissue APC T cell

Self

antigen

Self-reactive T cell

that also recognizes

microbial peptide

Selfreactive

T cell

B7

CD28

Microbe

Microbe

Microbial

antigen

A

B

Activation

of APC

Activation

of T cells

Self

tissue

Self

tissue

Self

antigen

Self

antigen

Autoimmunity

Autoimmunity

C