Immunology (Lippincott Illustrated Reviews Series) 2nd Edition

Chapter 16: Autoimmunity

I. OVERVIEW

The innate immune system relies on a set of “hard-wired” genetically encoded receptors that have evolved to distinguish self from nonself. The adaptive immune system faces a much greater challenge in making such distinctions. The B-cell receptors (BCRs) and T-cell receptors (TCRs) of the adaptive immune system are randomly generated within each individual, without prior knowledge of the epitopes that may be encountered. As a result, some BCRs and TCRs recognize nonself and others recognize self. Several mechanisms are used to identify and control or eliminate cells that are potentially self-reactive. The failure of these mechanisms to inactivate or eliminate self-reactive cells leads to autoimmunity.

Rheumatoid arthritis, type 1 diabetes mellitus, multiple sclerosis, psoriasis, and systemic lupus erythematosus (SLE), to name only a few, are autoimmune diseases. Autoimmunity is complex. It may arise by different mechanisms, and its risk is affected by various environmental and genetic factors, many of which are as yet unidentified. Together, however, these various influences contribute to a breakdown in self-tolerance, that is, the ability of the immune system to effectively distinguish self from nonself and to refrain from attacking self.

II. SELF-TOLERANCE

Tolerance is the failure of the immune system to respond to an epitope in an aggressive way. Most self-tolerance results from the deliberate inactivation or destruction of lymphocytes bearing BCRs or TCRs that recognize and bind self-epitopes. Inactivation or destruction may occur during early development (central tolerance) or may be imposed on lymphocytes in the periphery (peripheral tolerance). An understanding of how the immune system naturally imposes self-tolerance can provide critical clues for the development of therapeutic strategies for autoimmune diseases caused by the loss of self-tolerance.

A. Central tolerance

Central tolerance occurs during the early differentiation of B cells in the bone marrow and T cells in the thymus. Normally, both B and T cells that bind self-epitopes at distinct early stages of development meet an apoptotic death, thus eliminating large numbers of potentially self-reactive cells before they enter the circulation (see Chapter 9).

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Figure 16.1

Anergy. Binding of antigen (for B cells) or pMHC (for T cells) can initiate either activation or anergy in lymphocytes.

B cells express surface IgM as their BCRs. Epitope recognition by BCRs of developing B cells within the bone marrow triggers their apoptotic death, a process known as negative selection. Likewise, the binding of peptide-MHC complex (pMHC I or pMHC II) by TCRs of single positive (CD4+CD8 or CD4CD8+) thymocytes causes them to undergo apoptotic death. This process removes many potentially autoreactive B and T cells before they enter the periphery (see Fig. 9.1). A major caveat imposed on central tolerance is that not all self-epitopes are to be found in the primary lymphoid organs, especially those self-epitopes that arise after lymphogenesis, such as those that arise during puberty. Other means are needed to prevent the autoreactive cells among them from inflicting damage on the body.

B. Peripheral tolerance

Several additional mechanisms, collectively called peripheral tolerance, control or eliminate autoreactive B and T cells after they exit the bone marrow or thymus. One such mechanism is the induction of anergy, a state of nonresponsiveness in lymphocytes after their receptors bind antigen (B cell) or pMHC (T cell) (Fig. 16.1 provides a whimsical view of anergy). Another mechanism is suppression, whereby regulatory cells inhibit the activity of other cells.

1. Anergy: Binding of TCRs to an appropriate pMHC I or pMHC II on the surface of antigen-presenting cells (APCs) provides the first signal for activation of T cells, but T cells must also receive second signals from the APCs (cytokines, etc.) for activation to proceed (see Chapter 10). Naive CD8+ T cells may recognize and bind to self-pMHC I on non-APCs as well as on APCs. In binding to non-APCs, engagement of their TCRs with pMHC I provides the first signal, but no second signals. Receipt of the first signal in the absence of second signals causes naive T cells to enter a state of inactivity known as anergy (Fig. 16.2). So profound is this state that anergized CD8+ T cells usually cannot be activated by subsequent encounters with both first and second signals. There are, however, circumstances in which anergy can be broken and self-reactive CD8+ T cells can become activated, resulting in some autoimmune diseases. It is unclear whether CD4+ T cells can or cannot be anergized by comparable mechanisms because almost all binding by TCRs of CD4+ T cells occurs with pMHC II complexes on APCs.

B cells can also undergo anergy. Some naive autoreactive B cells leave the bone marrow. Their subsequent activation in the lymph nodes requires interaction with T cells, providing the necessary soluble signals and surface ligands. Like naive CD8+ T cells, naive B cells can be anergized if their surface immunoglobulins bind to self-antigens in the absence of the additional necessary T-cell signals.

2. Suppression: Tolerance to self-epitopes can also be induced by regulatory cells (Fig. 16.3). The molecular bases for these regulatory actions are still unclear, but in most cases, the regulatory cells are T cells (see Chapter 12). Examples include the following:

• CD4+CD25+ T cells diminish the activity of T cells stimulated by various epitopes. They have been shown to have important roles in preventing development of inflammatory diseases (e.g., inflammatory bowel disease).

• Some CD8+ T cells are able to inhibit the activation and proliferation of CD4+ T cells, including some that mediate autoreactive type IV hypersensitivity (DTH) responses.

• CD8+ and CD4+ T cell subpopulations have been demonstrated, in various models, to inhibit antibody production.

Autoimmune responses vary in the pathologies they induce, and this sometimes depends on the Th1/Th2 balance in the responses (see Chapter 5) to a particular self-antigen. For example, a Th2 response to a particular self-epitope may produce little or no pathology, but a Th1 response may produce an injurious cell-mediated inflammatory response such as DTH. As a result, the overt autoimmune disease may be determined by the relative balance in Th1 and Th2 responses generated against the epitope, and factors that influence that balance may alter the risk. Such a situation exists in the intestinal mucosal immune system of the gut-associated lymphoid tissues (see Chapter 13). Here, intestinal epithelial cells and some intraepithelial lymphocytes produce anti-inflammatory Th2 cytokines (IL-4, IL-10, and TGF-β) that create a microenvironment promoting production of IgA antibodies and inhibiting inflammatory cellular responses. Changes that favor development of Th1-like cell-mediated inflammatory responses, perhaps triggered by pathogenic bacteria, may be the basis for autoimmune inflammatory bowel diseases such as Crohn disease and ulcerative colitis.

III. LOSS OF SELF-TOLERANCE

Despite the various mechanisms that are in place to prevent responses to self-epitopes, autoimmunity still occurs occasionally. How does this happen? What types of situations provide opportunities for self-reactive immune cells to escape the traps set for them and become free to attack the body’s cells and tissues? There are, in fact, several different situations that make this possible.

A. Molecular mimicry

Infection is frequently associated with development of autoimmunity. Experimental evidence in vitro has shown that under certain circumstances, the addition of high levels of exogenous cytokines can cause the activation of naive T cells in the absence of interactions with APCs, and in some cases, even anergized T cells can be activated. Inflammation at sites of infection, originating with activated phagocytes responding to the presence of infectious agents, can generate elevated levels of proinflammatory cytokines that may mimic the effects seen in vitro. Within this setting, T cells recognizing self-epitopes may receive sufficient stimulation to become activated, even if they are not directly interacting with APCs (Fig. 16.4). Although this mechanism has yet to be definitively demonstrated in vivo, the tendency for the development of autoimmune diseases to follow episodes of infection is suggestive.

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Figure 16.2

Induction of T-cell anergy by binding to non-APCs. Engagement of TCRs on naive CD8+ T cells by binding to pMHC I on non-APCs provides the first signal for activation. T cells receiving signal 1 in the absence of signal 2 are anergized.

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Figure 16.3

Regulatory cell inhibition. Regulatory cells (usually T cells) can prevent some responses by other lymphocytes. A. Autoreactive T cells that become activated can bind and attack host cells. B. Regulatory cells inhibit the activation of autoreactive cells and sometimes even of activated ones.

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Figure 16.4

Inflammation and autoimmunity. Under normal circumstances, autoreactive cells in the body are not activated by contact with self-molecules. Unless they are interacting with APCs, they are not also receiving cytokine signals necessary for activation. However, in inflammatory sites, local cytokine levels may be sufficient to activate autoreactive T cells when they are binding to self-epitopes on non-APCs.

Molecular mimicry is a process in which infection by particular microbes is associated with the subsequent development of specific autoimmune diseases. The antigenic molecules on some infectious agents are similar enough to some host self-molecules that B- and T-cell responses generated against the microbial antigens can result in damage to host cells bearing similar molecules (Fig. 16.5). The best understood example of this process is the cardiac damage resulting from rheumatic fever after infection by Streptococcus pyogenes (“strep,” the causative agent of strep throat) (Fig. 16.6). Group A β-hemolytic strains of S. pyogenes express high levels of an antigen known as the M protein, a molecule that shares some structural similarities with molecules found on the valves and membranes of the heart. If the levels of IgM and IgG generated against the M protein during infection reach sufficient levels, there may be sufficient binding to host cells to induce damage and reduced cardiac function. In addition to cardiac sites, antibodies against the M protein can also cross-react to some degree with molecules on host cells in the joints and kidneys. The accumulated damage to cardiac and other tissues may be fatal. It is therefore important that patients who present with sore throats be tested to determine whether strep is present and, if so, to begin antibiotic therapy to clear the infection before vigorous antibody responses against strep antigens can develop.

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Figure 16.5

Molecular mimicry. Some microbial antigens bear epitopes that are similar to or identical to some epitopes on host molecules. Strong responses against the microbial epitopes can result in sufficient binding of host epitopes to produce immune-mediated injury.

Molecular mimicry appears to be involved in several autoimmune diseases, including diabetes. Certain peptide fragments from Coxsackie virus and cytomegalovirus cross-react with glutamate decarboxylase, a major target of autoreactive T cells found in patients with type 1 diabetes. In addition, peptides from other several viruses (e.g., cytomegalovirus, measles, hepatitis C virus) are cross-reactive with phosphatase IA-2, an enzyme produced by the pancreatic β cells, and may provide the basis for some cases of diabetes.

An association with infectious organisms has been demonstrated for several autoimmune diseases. A group of inflammatory arthritic diseases known as reactive arthritis occur more frequently in individuals who have had food poisoning. Two of these diseases, ankylosing spondylitis (usually involving the lower spine) and Reiter disease (affecting the joints of the lower limbs and the gastrointestinal/genital/urinary tracts), have increased frequencies in individuals who carry the HLA-B27 gene and have been infected by Klebsiella. In fact, some structural similarities have been noted between the HLA-B27 molecule itself and certain proteins expressed by Klebsiella, suggesting a possible role for molecular mimicry. In addition, the acetylcholine receptor, the self-molecule that is targeted in autoimmune myasthenia gravis, shares some structural similarities with certain poliovirus proteins. As a whole, these data suggest that molecular mimicry could be an important factor in the generation of some autoimmune diseases.

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Figure 16.6

Association of cardiac damage and rheumatic fever. Rheumatic fever results from infection (usually of the throat) by Group A strep. High levels of antibodies can be generated against the bacterial M protein. IgG against M protein can cross-react with molecules on cardiac tissues that are highly cross-reactive with M protein. As a result, antibody-induced injury, especially to the valves and sarcolemma, can produce serious cardiac disease. Other tissues may also be affected.

B. Epitope spreading

Another phenomenon that may contribute to the influence of infectious organisms on autoimmunity is epitope spreading. The epitope that initiates a response leading to autoimmunity might not be the epitope that is targeted by immune responses that develop later during the pathogenesis of the disease. For example, initial responses against an infectious agent may result in damage that exposes self-epitopes in ways that subsequently trigger true autoimmune responses. In some animal models of human multiple sclerosis, responses to particular viral epitopes regularly precede the development of responses to specific epitopes associated with the myelin sheath that protects neuronal axons.

Additionally, the dominant self-epitope targeted by an autoimmune response does not necessarily remain constant over the course of the disease. In some experimental models of autoimmune diseases, in which a relapsing-remitting course of clinical signs may occur, these patterns may actually result from a series of independent responses generated against different self-epitopes rather than from alternating increased and decreased responses to a single epitope (Fig. 16.7). The possibility that the epitopes that initiate an autoimmune disease are different from those involved in the pathogenesis complicates attempts to devise therapies. Epitope spreading is suspected to play a role in several autoimmune diseases, including systemic lupus erythematosus, inflammatory bowel disease (Crohn disease and ulcerative colitis), multiple sclerosis, pemphigus vulgaris, and type 1 diabetes.

C. Loss of suppression

Suppressor cells of various types serve to maintain peripheral tolerance. Evidence suggests that the numbers of these suppressor cells decline with age, increasing the risk that previously suppressed autoreactive lymphocytes can become active. A pattern of increasing risk with increasing age is indeed seen in some autoimmune diseases, such as systemic lupus erythematosus (SLE). It can be difficult, however, to differentiate between an increase in risk because of changes that result from aging and the simple fact that increased age provides more opportunity for a disease to occur.

D. Sequestered antigens

Some self-molecules are “sequestered” and are normally never exposed to the immune system for various reasons. As a result, if they do become exposed, as a result of injury for example, the immune system may view them as foreign and attack them. Among the best understood examples of sequestered antigens are those associated with spermatogonia and developing sperm within the lumen of testicular tubules. The tubules are sealed off early in embryonic development, prior to development of the immune system, by enclosure within a sheath of tightly joined Sertoli cells. Immune cells do not penetrate the barrier presented by the Sertoli cells and therefore are never exposed to self-molecules that are unique to the testicular tubule lumen. If these are exposed by injury (or by procedures such as surgery or vasectomy), immune responses may occur against the self (but seemingly foreign) molecules. It is believed that some cases of male sterility are caused by this mechanism.

Collectively, sites in the body that are associated with some degree of isolation from the immune system are called immunologically privileged sites. In addition to the lumen of the testicular tubule, these sites include the cornea and the anterior chamber of the eye, the brain, and the uterine environment during pregnancy. The reduced vasculature of the cornea and the fluid-filled chamber of the anterior chamber of the eye, together with other immunosuppressive mechanisms, may help to protect the delicate structures of the eye from the damage and permanent injury that could follow strong inflammatory responses. For example, the fluid in the anterior chamber of the eye contains many anti-inflammatory molecules. In addition, cells in the anterior of the eye widely express the Fas-ligand molecule (CD178) on their surface. When Fas-ligand binds to Fas (CD95) on activated T cells, those T cells undergo an apoptotic death (Fig. 16.8). Thus, cells in the anterior chamber can protect themselves by killing autoreactive T cells that bind to them. Another mechanism helps to protect the brain. The blood–brain barrier consists of dense, tightly packed vascular endothelium that limits the flow of cells and large molecules from the vasculature into the brain, thus decreasing the ability of the immune system to infiltrate the brain. Again, the blood–brain barrier is thought to be beneficial because strong inflammatory responses could easily inflict irreparable damage on the brain.

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Figure 16.7

Association of autoimmune diseases with serial responses to different epitopes. A. Some autoimmune diseases have alternating periods of exacerbation and remission of clinical signs (relapsing-remitting pattern). B. In some models of human autoimmune disease, the relapsing phases of exacerbation have been shown to be caused by a series of newly generated responses to different epitopes.

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Figure 16.8

Role of Fas-ligand in protection of cells within immunologically privileged sites. Fas-ligand is widely expressed on cells in the anterior chamber of the eye. When autoimmune T cells attempt to bind to cells of the anterior chamber, Fas-ligand binds to Fas molecules expressed by T cells. This binding induces apoptotic death of the Fas-bearing cell (in this case, the T cell) and immune-mediated damage to the cells of the anterior chamber is avoided.

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Figure 16.9

Cryptic epitopes. Some epitopes may not be readily available to the immune system because they are protected within the three-dimensional structure of a molecule. A structural change in the molecule, such as cleavage or denaturation, may make these cryptic epitopes more accessible to antibodies.

Molecules may also sometimes possess a type of immunologically privileged site. The three-dimensional configurations of some molecules may shelter epitopes in the interior from contact with the immune system. If the molecule is altered by denaturation or cleavage, however, the “hidden” internal epitopes may become exposed and available for recognition and binding by antibodies (Fig.16.9). These are termed cryptic epitopes. The presence of rheumatoid factor, associated with inflammatory rheumatoid diseases, provides an example of this phenomenon (Fig. 16.10). The binding of IgG molecules trigger conformational changes in their Fc regions that expose “hidden” sites, some of which facilitate the binding of complement or Fc receptors and some of which expose cryptic carbohydrate structures that can be recognized and bound by IgM antibodies. IgM antibodies directed at the cryptic carbohydrate structures on antigen-bound IgG molecules are called rheumatoid factors. The binding of IgM to IgG augments the formation of immune complexes and the activation of complement (see Chapter 14). The presence of rheumatoid factor is associated with several inflammatory autoimmune diseases.

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Figure 16.10

Rheumatoid factor. Rheumatoid factor (IgM produced against IgG) results from recognition of cryptic epitopes. Binding of antibodies, including IgG, to their epitopes produce a conformational change in the Fc region, exposing sites that become available for the binding of complement and recognition by cellular Fc receptors. The exposed sites include previously cryptic carbohydrate structures that, once available, can be recognized and bound by IgM molecules. (IgM and IgG molecules are not drawn to scale.)

E. Neoantigens

Responses to neoantigens may mimic autoimmune responses. Neoantigens are self-antigens that have been modified by some extrinsic factor (e.g., binding of a reactive chemical) so that they appear foreign to the immune system. Thus, they are not true autoantigens, and the reactions against them are not truly autoimmune. However, the effects of responses to neoantigens can be nearly identical to those against autoantigens. Some responses that are currently classified as autoimmune may in fact be caused by neoantigens created by some unknown environmental agent. One feature that distinguishes responses against neoantigens from true autoimmune responses is that responses to neoantigens should cease if the agent responsible for creation of the neoantigens is removed. True autoantigens, by contrast, persist for the individual’s lifetime and continue to stimulate autoimmune responses unless they are destroyed and eliminated.

IV. AUTOIMMUNE DISEASES

Table 16.1 lists several human autoimmune diseases. These diseases involve numerous different molecules, cells, and tissues that are targeted by the autoimmune responses. Some autoimmune diseases are systemic or diffuse, because of the distribution of the target antigens. For example, SLE and rheumatoid arthritis affect various joints and other body tissues. Other diseases affect specific organs and tissues. Some autoimmune diseases, including SLE, Sjögren syndrome, and rheumatoid arthritis, occur more frequently in females than in males. Examples of autoimmune diseases include the following:

• Crohn disease (intestine)

• Goodpasture disease (kidney and lung)

• Hashimoto thyroiditis (thyroid gland)

• Insulin-dependent diabetes mellitus type 1 (β cells of the pancreas)

• Multiple sclerosis (white matter of the brain and spinal cord)

• Sjögren syndrome (tear ducts)

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CLINICAL APPLICATION

Multiple sclerosis

Mavis N., a 40-year-old woman, with a 3-year-history of progressive right leg weakness, presents with difficulty walking. Recently, she also has experienced intermittent blurred vision of her left eye.

She has no other neurological symptoms or medical problems. The physical examination is remarkable for weakness and difficulty walking, mainly with her right leg. She requires a cane to walk.

Laboratory examination reveals positive results for oligoclonal bands in the cerebrospinal fluid (CSF). The brain and spine magnetic resonance imaging shows lesions that are consistent with multiple sclerosis (MS).

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Clinical symptoms can include optic neuritis, which is an inflammation of the optic nerve that may cause a unilateral visual loss, and spastic weakness of the limbs. Oligoclonal bands are bands of IgG that are seen in the CSF of approximately 85% of patients with MS.

Medical treatment options for MS are listed in Table 18.1.

Autoimmune diseases can result from damage inflicted on cells and tissues by humoral responses, cell-mediated immune responses, or both. It should be noted that the assignment of humoral or cell-mediated damage is sometimes based on data from experimental models.

A. Humoral-associated autoimmune diseases

Some autoimmune diseases result from the binding of self-reactive antibodies, leading to type II and type III hypersensitivity responses. The antibodies responsible for initiating the diseases are usually of the IgG isotype, although IgM antibodies can contribute as well. The activation of complement and the opsonization of injured cells promote inflammatory responses that increase the damage inflicted on the targeted cells and tissues. Autoreactive T cells are typically present as well, but their role is primarily the activation of the autoreactive B cells rather than directly attacking host cells. Examples of these autoimmune diseases include the following:

• Autoimmune hemolytic anemia: type II hypersensitivity

• Goodpasture syndrome: type II hypersensitivity

• Hashimoto thyroiditis: type II hypersensitivity

• Rheumatic fever: type II hypersensitivity

• Rheumatoid arthritis: type III hypersensitivity

• Systemic lupus erythematosus: type II and type III hypersensitivity

CLINICAL APPLICATION

Rheumatoid arthritis

Grace D., a 53-year-old woman, presents with a 5-week history of fatigue associated with joint pain of her hands and feet and morning stiffness. She takes ibuprofen and acetaminophen without much relief.

The physical examination is remarkable for tenderness and swelling of the metacarpophalangeal joints bilaterally.

Laboratory examination reveals positive results for rheumatoid factor and anticyclic citrullinated peptide antibodies.

This patient has symptoms and blood tests consistent with rheumatoid arthritis (RA), which is a chronic inflammatory polyarthropathy and may affect many tissues and organs.

Further discussion of this disease and medical treatment options for RA are discussed in Chapter 18.

B. Cell-mediated autoimmune diseases

Type IV hypersensitivity responses involve cell-mediated injury leading to autoimmune disease. These may include cytotoxic T-cell responses or macrophages driven by DTH responses. The inflammation that is generated can eventually involve numerous simultaneously ongoing responses. In some diseases, particular antibodies may also be characteristically present, but they have not been demonstrated to contribute to the disease pathologies. The following are examples of autoimmune diseases involving type IV hypersensitivity responses. Rheumatoid arthritis provides an example of an autoimmune disease that involves both humoral and cell-mediated injury.

• Insulin-dependent diabetes mellitus (type 1)

• Multiple sclerosis

• Reactive arthritis

• Rheumatoid arthritis

V. HLA ASSOCIATION WITH AUTOIMMUNE DISEASES

The risks for many autoimmune diseases appear to be associated with the presence of particular HLA genes (Table 16.2). In some cases (e.g., HLA-B27 and HLA-DR3), a single HLA gene is associated with increased risk for multiple autoimmune diseases. The molecular mechanisms underlying these statistical associations are still uncertain but presumably involve some influence on processing and presentation of self-epitopes to self-reactive T cells.

The strength of the statistical association between a particular HLA gene and a particular autoimmune disease is expressed as the relative risk. The relative risk compares the frequency of the particular disease among carriers of a particular HLA gene with the frequency among noncarriers (Fig. 16.11). For example, the relative risk of six for the association of SLE with HLA-DR3 means that SLE occurs approximately three times more frequently among DR3+ individuals than among DR3 individuals. Relative risk calculations are made within defined populations, and results may vary among groups of different ethnic or geographic origin.

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Because genetics is only one of several possible factors contributing to the risk of a particular autoimmune disease, most relative risks are modest, in the range of two to five. However, some HLA genes display much higher associations. For example, HLA-B27 and ankylosing spondylitis have relative risks around 100, and over 90% of individuals with ankylosing spondylitis are B27+. The impact of relative risk should also be considered in the context of actual frequency. A disease occurring at a rate of three per million in one group and one per million in the other has a relative risk of three, but the practical impact is diluted by the rarity of the condition.

Chapter Summary

• Tolerance is the failure to respond in an aggressive way against an epitope recognized by the immune system.

• Autoimmunity results from a loss of self-tolerance through the failure to inactivate or eliminate self-reactive cells.

• Central tolerance occurs in the primary lymphoid organs (bone marrow and thymus) during the early development of B and T cells.

• Peripheral tolerance results from mechanisms that inactivate or eliminate B and T cells that are in circulation.

• Anergy (inactivation) of B and T cells occurs when naive lymphocytes bind via their BCR or TCR (“first signal”) but fail to receive the second signals provided by T cells (for B cells) and APCs (for T cells) that are necessary for activation.

• Suppressor T cells inhibit responses by other immune cells.

• Loss of self-tolerance may occur through molecular mimicry, epitope spreading, loss of suppression, or the exposure of sequestered antigens.

• Molecular mimicry involves the generation of responses to microbial epitopes that may cross-react with host epitopes that are structurally very similar to the microbial ones.

• Epitope spreading occurs when a response to an epitope leads to the generation of responses to one or more other epitopes.

• Suppressor T-cell numbers may decline with age, permitting other self-reactive cells to escape regulation and initiate autoimmune diseases.

• Sequestered antigens are located in anatomical sites that are normally sheltered from the immune system by specialized anatomic structures or other mechanisms.

• Neoantigens are not self-antigens but may lead to conditions that mimic autoimmunity. If the condition creating the neoantigens is removed, the condition should be resolved. Responses to true self-antigens, on the other hand, should be permanent as a rule.

• Numerous autoimmune diseases have been identified. Their effects are determined largely by the localization of the self-epitope. Some diseases, such as systemic lupus erythematosus and rheumatoid arthritis, are systemic and affect several body sites simultaneously. Others, such as Hashimoto thyroiditis and Sjögren syndrome, affect specific tissues or organs.

• Autoimmune pathology may result from antibody-initiated damage (hypersensitivity types II and III), cell-mediated responses (type IV hypersensitivity), or both.

• Some autoimmune diseases have elevated frequencies in individuals carrying certain HLA genes. The statistical association between the disease and the HLA gene is expressed as the relative risk.

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Figure 16.11

Relative risk. The statistical association between an autoimmune disease and a specific HLA gene is expressed as the relative risk. Relative risk is the ratio between the incidence of the disease among carriers of the gene in question and the incidence among noncarriers.

Study Questions

16.1. The failure to inactivate or eliminate self-reactive cells results in

A. autoimmunity.

B. positive selection.

C. negative selection.

D. suppression.

E. tolerance.

The correct answer is A. Autoimmunity results from the failure to inactivate or eliminate self-reactive immune cells. Positive selection is the promotion of lymphocytes that can function within the body. Suppression, negative selection, and tolerance are various mechanisms by which the immune system produces tolerance.

16.2. Failure of the immune system to respond against an epitope in an aggressive way is termed

A. autoimmunity.

B. positive selection.

C. negative selection.

D. suppression.

E. tolerance.

The correct answer is E. Tolerance is the failure to generate a destructive response against an epitope that the immune system recognizes.

16.3. Deliberate inactivation or destruction of lymphocytes bearing BCRs or TCRs capable of recognizing and binding specific self-epitopes results in

A. hypersensitivity.

B. autoimmunity.

C. molecular mimicry.

D. positive selection.

E. self-tolerance.

The correct choice is E. The inactivation or destruction of lymphocytes bearing particular antigen receptors is one of the mechanisms producing tolerance. Hypersensitivity responses are heightened and destructive. Autoimmunity results from the absence of self-tolerance. Mimicry is a means of breaking tolerance. Positive selection is the promotion of lymphocytes that bear receptors capable of particular self-molecules.

16.4. Lymphocytes expressing both the CD4 and CD25 markers on their surfaces function as

A. antigen-presenting cells.

B. autoantibody-secreting B cells.

C. cytotoxic T cells.

D. natural killer-like T cells.

E. T regulatory cells

The correct answer is E. CD4+CD25+ T cells are a regulatory subset of T cells. They do not act as antigen-presenting cells, nor do they secrete antibodies. Cytotoxic T cells are CD8+. They do not belong to the natural killer-like T-cell subset of T cells.

16.5. During an infection with Streptococcus pyogenes, an individual generated sufficiently high levels of IgM and IgG antibodies against a S. pyogenes antigen with structural similarity with molecules on the heart that cardiac damage was caused. In this example, the microbe contributed to autoimmunity via a process known as

A. anergy.

B. central tolerance.

C. epitope spreading.

D. loss of suppression.

E. molecular mimicry.

The correct answer is E. Molecular mimicry contributes to autoimmunity by triggering responses with microbial molecules that are cross-reactive with host molecules. Anergy and central tolerance are mechanisms for preventing autoimmunity. Epitope spreading involves the generation of responses to a series of different antigens, not to cross-reactive ones. The loss of suppression is a different mechanism by which tolerance can be broken.

16.6. A previously healthy 12-year-old female lost 8 pounds over the past several weeks without dieting. Her parents are concerned about this weight loss and believe that she has an eating disorder. The patient’s history reveals polydipsia (excessive thirst), polyuria (excessive urination), and nocturia (need to arise during the night for urination) over the last several weeks. A fasting blood glucose of 460 mg/dL is obtained (reference range: 70 to 100 mg/dL). The patient is diagnosed with an autoimmune disease. On the basis of these findings, which of the following conditions was most likely diagnosed in this patient?

A. Anorexia nervosa

B. Hyperthyroidism

C. Nephrolithiasis (kidney stones)

D. Type 1 diabetes mellitus

E. Urinary tract infection

The correct answer is D. Type 1 diabetes mellitus is the autoimmune disease, among those listed, that impairs regulation of blood glucose levels. Some forms of hyperthyroidism can result from autoimmune diseases attacking thyroid receptors. Anorexia nervosa, nephrolithiasis, and urinary tract infections are not autoimmune diseases.

16.7. In Question 16.6, a defect or deficiency in which of the following is associated with the patient’s condition?

A. Adipose tissue

B. Kidney tubules

C. Pancreatic β cells

D. Thyroid gland

E. Skeletal muscle

The correct answer is C. Destruction of pancreatic β cells reduces insulin production. The other tissues listed are not targets of the autoimmune attack, although they may incur later secondary damage if the primary disease is not appropriately treated and controlled.

16.8. A previously healthy 65-year-old female presents with complaints of frequent bowel movements, weight loss, and nervousness. Her physical examination was remarkable for slight exophthalmos (protrusion of the eyeball) and atrial fibrillation (abnormal heart rhythm). Laboratory findings supported a diagnosis of Graves disease. Which of the following tissues/organs will be most affected by the ensuing immune reactions?

A. Connective tissue

B. Joints of lower extremities

C. Heart valves

D. Kidneys

E. Thyroid gland

The correct answer is E. Graves disease results from autoimmune responses targeting the thyroid gland. The other tissues and organs listed are not targets of the autoimmune responses producing Graves disease.

16.9. Graves disease is an example of which of the following immunologic processes?

A. Autoimmune disease associated with HLA gene B27

B. Autoimmune disease associated with HLA gene DR3

C. Immune deficiency associated with HLA gene DR2

D. Immune deficiency associated with HLA gene DR4

E. Type III hypersensitivity associated with HLA gene Cw6

The correct answer is B. Graves disease is an autoimmune disease that is associated with the presence of the HLA-DR3 gene. It is not associated with HLA-B27, -DR2, -DR4, or -Cw6. It does not result from immunodeficiency.

16.10. A 35-year-old male presents with symptoms of fatigue, paresthesia (numbness and tingling) of his arms and legs, and occasional blurred vision of 2 months’ duration. Tests reveal several areas of demyelination within the central nervous system. Diagnosis of which of the following conditions is supported by these findings?

A. Ankylosing spondylitis

B. Hashimoto thyroiditis

C. Multiple sclerosis

D. Reactive arthritis

E. Systemic lupus erythematosus

The correct answer is C. Multiple sclerosis is an autoimmune disease that results in demyelination within the central nervous system. Ankylosing spondylitis and reactive arthritis involve joints, Hashimoto thyroiditis involves the thyroid gland, and systemic lupus erythematosus is a systemic disease with primary effects on joints, muscles, skin, and kidneys.

16.11. Which of the following is the underlying immunological process in ankylosing spondylitis?

A. Autoimmune disease associated with HLA gene B27

B. Development of autoantibodies against nucleic acids

C. Immune-mediated destruction of neurons

D. Immune deficiency associated with HLA gene DR4

E. Molecular mimicry of the acetylcholine receptor

The correct answer is A. Ankylosing spondylitis is an autoimmune disease in which over 90% of people with the disease carry the HLA-B27 gene. The autoimmune response does not target nucleic acids or acetylcholine receptors. It is not an immune deficiency disease.

16.12. A 30-year-old female presents with fatigue, weight loss, arthritis of her hands, and a malar (“butterfly”) rash. Blood tests reveal decreased hemoglobin and the presence of antinuclear antibodies. These findings support which of the following diagnoses paired with its underlying immunologic process?

A. Graves disease: autoantibodies to thyroid-stimulating hormone receptor

B. Myasthenia gravis: autoimmunity associated with HLA gene DR3

C. Reiter syndrome: immune-mediated destruction associated with HLA gene B27

D. Rheumatoid arthritis: immune deficiency associated with HLA gene DR4

E. Systemic lupus erythematosus: autoantibodies to chromosomal proteins

The correct answer is E. Systemic lupus erythematosus results from the generation of autoimmune antibodies against chromosomal proteins (and nucleic acids). It is associated with the presence of HLA-DR3, but not -B27 or -DR4. Myasthenia gravis results from autoantibodies against acetylcholine receptors on muscle cells. Reiter syndrome and rheumatoid arthritis target joints. The thyroid gland is not a target of the antinuclear antibodies.

16.13. A 55-year-old female presents with complaints of pain and stiffness in her hands and wrists that occurs mainly in the morning. Examination reveals tenderness and swelling in both wrists and hands. Testing reveals the presence of rheumatoid factor. The patient is diagnosed with rheumatoid arthritis. Resulting injury that will likely occur in this patient will result from

A. both cell mediated and humoral immunity.

B. both type II and type III hypersensitivity.

C. IgE-mediated immune responses only.

D. self-tolerance.

E. type II hypersensitivity only.

The correct answer is A. Rheumatoid arthritis involves damage inflicted by both antibody-driven type III hypersensitivity responses and cellular type IV hypersensitivity responses. It does not involve type II hypersensitivity responses or IgE mediated (type I) responses. It results from the loss of self-tolerance.

16.14. A 47-year-old-male has a history of end-stage renal failure and required a kidney transplant. Approximately 4 weeks after receiving his transplanted kidney, he developed oliguria (decreased production of urine), fever, hypertension, and pain or tenderness over the allograft. On the basis of these findings, the most likely underlying immunological process is

A. autoimmunity.

B. acute rejection.

C. chronic rejection.

D. hyperacute rejection.

E. peripheral tolerance.

The correct answer is B. The time span is appropriate for acute rejection of the transplanted organ but not for chronic or hyperacute rejection. There is no information suggesting autoimmunity. Peripheral tolerance is a mechanism for preventing responses to self-antigens.

16.15. A 20-year-old woman presents with right lower abdominal cramp-type pain associated with diarrhea and weight loss. Blood tests reveal a low hemoglobin level and high white blood cell counts. She is diagnosed with Crohn disease. The tissue that is most affected in this autoimmune disease is

A. connective tissue.

B. erythrocytes.

C. pancreatic β cells.

D. the small intestine.

E. the thyroid.

The correct answer is D. Crohn disease targets the small intestine. It is not directed at connective tissue, erythrocytes, pancreatic β cells, or the thyroid gland.