CHAPTER CONTENTS
Tolerance
T-Cell Tolerance
B-Cell Tolerance
Induction of Tolerance
Autoimmune Diseases
Genetic Factors
Hormonal Factors
Environmental Factors
Mechanisms
Diseases
Treatment
Self-Assessment Questions
Practice Questions: USMLE & Course Examinations
TOLERANCE
Tolerance is specific immunologic unresponsiveness (i.e., an immune response to a certain antigen [or epitope] does not occur, although the immune system is otherwise functioning normally). In general, antigens that are present during embryonic life are considered “self” and do not stimulate an immunologic response (i.e., we are tolerant to those antigens). The lack of an immune response in the fetus is caused by the deletion of self-reactive T-cell precursors in the thymus (Figure 66–1). On the other hand, antigens that are not present during the process of maturation (i.e., that are encountered first when the body is immunologically mature) are considered “nonself” and usually elicit an immunologic response. Although both B cells and T cells participate in tolerance, it is T-cell tolerance that plays the primary role.
FIGURE 66–1 Production of T-cell tolerance in the thymus.
T-Cell Tolerance
The main process by which T lymphocytes acquire the ability to distinguish self from nonself occurs in the fetal thymus (see Chapter 58). This process, called clonal deletion, involves the killing of T cells (“negative selection”) that react against antigens (primarily self major histocompatibility complex [MHC] proteins) present in the fetus at that time. (Note that exogenous substances injected into the fetus early in development are treated as self.) The self-reactive cells die by a process of programmed cell death called apoptosis. Tolerance to self acquired within the thymus is called central tolerance, whereas tolerance acquired outside the thymus is called peripheral tolerance.
For negative selection and clonal deletion to be efficient, the thymic epithelial cells must display a vast repertoire of “self” proteins. A transcriptional regulator called the autoimmune regulator (AIRE) enhances the synthesis of this array of self proteins. Mutations in the gene encoding the AIRE protein result in the development of an autoimmune disease called autoimmune polyendocrinopathy. The AIRE transcription factor also functions in the peripheral lymphoid organs such as the spleen and lymph nodes, where it contributes to peripheral tolerance.
Peripheral tolerance is necessary because some antigens are not expressed in the thymus and therefore some self-reactive T cells are not killed in the thymus. There are several mechanisms involved in peripheral tolerance: Some self-reactive T cells are killed, some are not activated, and others are suppressed by regulatory T cells producing inhibitory cytokines. Clonal anergy is the term used to describe self-reactive T cells that are not activated because proper costimulation does not occur (Figure 66–2). Clonal ignorance refers to self-reactive T cells that ignore self antigens. These self-reactive T cells are either kept ignorant by physical separation from the target antigens (e.g., the blood–brain barrier) or ignore self antigens because the antigens are present in such small amounts.
FIGURE 66–2 Clonal anergy outside the thymus. A: B7 protein on the antigen-presenting cell interacts with CD28 on the helper T cell, and full activation of the helper T cell occurs. B: B7 protein on the antigen-presenting cell is not produced; therefore, CD28 on the helper T cell does not get a costimulatory signal. Anergy of the helper T cell occurs despite interaction of the T-cell receptor (TCR) with the antigen.
Although T cells that are clonally anergic are nonreactive, they can become reactive and initiate an autoimmune disease if conditions change later in life. The mechanism of clonal anergy involves the inappropriate presentation of antigen, leading to a failure of interleukin-2 (IL-2) production. Inappropriate presentation is due to a failure of “costimulatory signals” (e.g., sufficient amounts of IL-1 might not be made, or cell surface proteins, such as CD28 on the T cell and B7 on the B cell, might not interact properly, leading to a failure of signal transduction by ras proteins). For example, the inhibitory protein CTLA-4 on the surface of the T cells may displace CD28 and interact with B7, resulting in a failure of T-cell activation. Furthermore, B7 is an inducible protein, and failure to induce it in sufficient amounts can lead to anergy. In addition, the costimulatory proteins, CD40 on the B cell and CD40L on the helper T cell, may fail to interact properly.
The failure of costimulatory signals most often occurs when there is an insufficient inflammatory response at the site of infection. The presence of microbes typically stimulates the production of proinflammatory cytokines such as tumor necrosis factor (TNF) and IL-1. However, if the inflammatory response is insufficient (i.e., if the adjuvant effect of the cytokines is inadequate, the T cells will die instead of being activated).
B-Cell Tolerance
B cells also become tolerant to self by two mechanisms: (1) clonal deletion, probably while the B-cell precursors are in the bone marrow, and (2) clonal anergy of B cells in the periphery. However, tolerance in B cells is less complete than in T cells, an observation supported by the finding that most autoimmune diseases are mediated by antibodies.
B cells bearing an antigen receptor for a self protein can escape clonal deletion (apoptosis) by a process called receptor editing. In this process, a new, different light chain is produced that changes the specificity of the receptor so that it no longer recognizes a self protein. This reduces the risk of autoimmune diseases and increases the repertoire of B cells that can react against foreign proteins. It is estimated that as many as 50% of self-reactive B cells undergo receptor editing. T cells do not undergo receptor editing.
INDUCTION OF TOLERANCE
Whether an antigen will induce tolerance rather than an immunologic response is largely determined by the following:
(1) The immunologic maturity of the host (e.g., neonatal animals are immunologically immature and do not respond well to foreign antigens; for instance, neonates will accept allografts that would be rejected by mature animals).
(2) The structure and dose of the antigen (e.g., a very simple molecule induces tolerance more readily than a complex one, and very high or very low doses of antigen may result in tolerance instead of an immune response). Purified polysaccharides or amino acid copolymers injected in very large doses result in “immune paralysis”—a lack of response.
Other aspects of the induction or maintenance of tolerance are as follows:
(1) T cells become tolerant more readily and remain tolerant longer than B cells.
(2) Administration of a cross-reacting antigen tends to terminate tolerance.
(3) Administration of immunosuppressive drugs enhances tolerance (e.g., in patients who have received organ transplants).
(4) Tolerance is maintained best if the antigen to which the immune system is tolerant continues to be present.
AUTOIMMUNE DISEASES
The adult host usually exhibits tolerance to tissue antigens present during fetal life that are recognized as “self.” However, in certain circumstances, tolerance may be lost and immune reactions to host antigens may develop, resulting in autoimmune diseases. The most important step in the production of autoimmune disease is the activation of self-reactive helper (CD4) T cells. These self-reactive Th-1 or Th-2 cells can induce either cell-mediated or antibody-mediated autoimmune reactions, respectively. As described in Table 66–1, most autoimmune diseases are antibody-mediated.
TABLE 66–1 Important Autoimmune Diseases
Genetic Factors
Many autoimmune diseases exhibit a marked familial incidence, which suggests a genetic predisposition to these disorders. There is a strong association of some diseases with certain human leukocyte antigen (HLA) specificities, especially the class II genes. For example, rheumatoid arthritis occurs predominantly in individuals carrying the HLA-DR4 gene. Ankylosing spondylitis is 100 times more likely to occur in people who carry HLA-B27, a class I gene, than in those who do not carry that gene.
There are two hypotheses offered to explain the relationship between certain HLA genes and autoimmune diseases. One is that those genes encode class I or class II MHC proteins that present autoantigens with greater efficiency than do the MHC proteins that are not associated with autoimmune diseases. The other hypothesis is that autoreactive T cells escape negative selection in the thymus because they bind poorly to those class I or class II MHC proteins on the surface of the thymic epithelium.
It should be noted, however, that whether a person develops an autoimmune disease or not is clearly multifactorial, because people with HLA genes known to predispose to certain autoimmune diseases nevertheless do not develop the disease (e.g., many people carrying the HLA-DR4 gene do not develop rheumatoid arthritis). That is to say, HLA genes appear to be necessary but not sufficient to cause autoimmune diseases. In general, class II MHC-related diseases (e.g., rheumatoid arthritis, Graves’ disease [hyperthyroidism], and systemic lupus erythematosus) occur more commonly in women, whereas class I MHC-related diseases (e.g., ankylosing spondylitis and Reiter’s syndrome) occur more commonly in men.
Hormonal Factors
Approximately 90% of all autoimmune diseases occur in women. Although the explanation for this markedly unequal gender ratio is unclear, there is some evidence from animal models that estrogen can alter the B-cell repertoire and enhance the formation of antibody to DNA. Clinically, the observation that systemic lupus erythematosus either appears or exacerbates during pregnancy (or immediately postpartum) supports the idea that hormones play an important role in predisposing women to autoimmune diseases.
Environmental Factors
There are several environmental agents that trigger autoimmune diseases, most of which are either bacteria or viruses. For example, pharyngitis caused by Streptococcus pyogenes predisposes to rheumatic fever. Other examples are described in Table 66–2. It is speculative at this time, but members of the normal flora of the bowel are thought to play a role in the genesis of inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis.
TABLE 66–2 Microbial Infections Associated with Autoimmune Diseases
Certain infections cause autoimmune diseases in animals (e.g., Coxsackie virus infection in mice causes type 1 diabetes) but have not been established as a cause in humans. Other environmental triggers include certain drugs such as procainamide, which causes systemic lupus erythematosus, and certain heavy metals such as gold and mercury, which cause autoimmune diseases in experimental animals.
There are two main mechanisms by which environmental factors could trigger autoimmune diseases. One is molecular mimicry, which proposes that infectious agents possess antigens that elicit an immune response that cross-reacts with components of human cells. The other is that tissue injury releases intracellular (sequestered) antigens that elicit an immune response. These mechanisms are described in more detail in the next section.
In summary, the current model is that autoimmune diseases occur in people (1) with a genetic predisposition that is determined by their MHC genes and (2) who are exposed to an environmental agent that triggers a cross-reacting immune response against some component of normal tissue. Furthermore, because autoimmune diseases increase in number with advancing age, another possible factor is a decline in the number of regulatory T cells, which allows any surviving autoreactive T cells to proliferate and cause disease.
Mechanisms
The following main mechanisms for autoimmunity have been proposed.
Molecular Mimicry
Various bacteria and viruses are implicated as the source of cross-reacting antigens that trigger the activation of autoreactive T cells or B cells. For example, Reiter’s syndrome occurs following infections with Shigella or Chlamydia, and Guillain-Barré syndrome occurs following infections with Campylobacter. The concept of molecular mimicry is used to explain these phenomena (i.e., the environmental trigger resembles [mimics] a component of the body sufficiently that an immune attack is directed against the cross-reacting body component). One of the best-characterized examples of molecular mimicry is the relationship between the M protein of S. pyogenes and the myosin of cardiac muscle. Antibodies against certain M proteins cross-react with cardiac myosin, leading to rheumatic fever.
Additional evidence supporting the molecular mimicry hypothesis includes the finding that there are identical amino acid sequences in certain viral proteins and certain human proteins. For example, there is an identical six–amino acid sequence in the hepatitis B viral polymerase and the human myelin basic protein.
Alteration of Normal Proteins
Drugs can bind to normal proteins and make them immunogenic. Procainamide-induced systemic lupus erythematosus is an example of this mechanism.
Release of Sequestered Antigens
Certain tissues (e.g., sperm, central nervous system, and the lens and uveal tract of the eye) are sequestered so that their antigens are not exposed to the immune system. These are known as immunologically privileged sites. When such antigens enter the circulation accidentally (e.g., after damage), they elicit both humoral and cellular responses, producing aspermatogenesis, encephalitis, or endophthalmitis, respectively. Sperm, in particular, must be in a sequestered, immunologically privileged site, because they develop after immunologic maturity has been reached and yet are normally not subject to immune attack.
Intracellular antigens, such as DNA, histones, and mitochondrial enzymes, are normally sequestered from the immune system. However, bacterial or viral infection may damage cells and cause the release of these sequestered antigens, which then elicit an immune response. Once autoantibodies are formed, subsequent release of sequestered antigens results in the formation of immune complexes and the symptoms of the autoimmune disease. In addition to infection, radiation and chemicals can also damage cells and release sequestered intracellular components. For example, sunlight is known to exacerbate the skin rash in patients with systemic lupus erythematosus. It is thought that ultraviolet (UV) radiation damages cells, which releases the normally sequestered DNA and histones that are the major antigens in this disease.
Epitope Spreading
Epitope spreading is the term used to describe the new exposure of sequestered autoantigens as a result of damage to cells caused by viral infection. These newly exposed autoantigens stimulate autoreactive T cells, and autoimmune disease results. In an animal model, a multiple sclerosis–like disease was caused by infection with an encephalomyelitis virus. Note that the self-reactive T cells were directed against cellular antigens rather than the antigens of the virus.
Failure of Regulatory T Cells
Regulatory T cells (Tr) suppress the proinflammatory effects of other T cells. Tr cells are characterized as CD4 positive, CD25 positive, and FoxP3 positive. An important function of Tr cells is to produce IL-10, which inhibits proinflammatory Th-1 cells. Patients with a mutation in the FoxP3 gene have an increase in autoimmune diseases, such as systemic lupus erythematosus, because they have lost the function of their regulatory T cells.
Diseases
Table 66–1 describes several important autoimmune diseases according to the type of immune response causing the disease and the target affected by the autoimmune response. Some examples of autoimmune disease are described in more detail next.
Diseases Involving Primarily One Type of Cell or Organ
1. Allergic encephalitis—A clinically important example of allergic encephalitis occurs when people are injected with rabies vaccine made in rabbit brains. The immune response against the foreign myelin protein in the vaccine cross-reacts with human myelin, leading to inflammation of the brain. Although rare, this is a serious disease, and rabies vaccine made in rabbit brain is no longer used in the United States (see Chapter 39). Allergic encephalitis can also occur following certain viral infections (e.g., measles or influenza) or following immunizations against these infections. These reactions are rare, and the basis for the autoimmune reaction is uncertain. Allergic encephalitis can be reproduced in the laboratory by injecting myelin basic protein into a rodent’s brain, which initiates a cell-mediated response leading to demyelination.
2. Multiple sclerosis—In this disease, autoreactive T cells and activated macrophages cause demyelination of the white matter of the brain. The trigger that stimulates the autoreactive T cells is thought to be a viral infection. There is molecular evidence that the polymerase of Epstein–Barr virus may be the trigger. People with certain alleles in the HLA-DR region have an increased risk of contracting multiple sclerosis.
The clinical findings in multiple sclerosis typically wax and wane and affect both sensory and motor functions. Magnetic resonance imaging (MRI) of the brain reveals plaques in the white matter. Oligoclonal bands of IgG are found in the spinal fluid of most patients. Immunosuppressive drugs (e.g., prednisone, methotrexate, or beta interferon) are effective in reducing the severity of some of the symptoms.
3. Chronic thyroiditis—When animals are injected with thyroid gland material, they develop humoral and cell-mediated immunity against thyroid antigens and chronic thyroiditis. Humans with Hashimoto’s chronic thyroiditis have antibodies to thyroglobulin, suggesting that these antibodies may provoke an inflammatory process that leads to fibrosis of the gland.
4. Hemolytic anemias, thrombocytopenias, and granulocytopenias—Various forms of these disorders have been attributed to the attachment of autoantibodies to cell surfaces and subsequent cell destruction. Pernicious anemia is caused by antibodies to intrinsic factor, a protein secreted by parietal cells of the stomach that facilitates the absorption of vitamin B12. Idiopathic thrombocytopenic purpura is caused by antibodies directed against platelets. Platelets coated with antibody are either destroyed in the spleen or lysed by the membrane attack complex of complement.
Several drugs, acting as haptens, bind to the platelet membrane and form a “neoantigen” that induces the cytotoxic antibody that results in platelet destruction. Penicillins, cephalothin, tetracyclines, sulfonamides, isoniazid, and rifampin, as well as drugs that are not antimicrobials, can have this effect. Autoimmune hemolytic anemia caused by penicillins and cephalosporins is due to the same mechanism.
5. Insulin-dependent diabetes mellitus (IDDM)—In this disease, autoreactive T cells destroy the islet cells of the pancreas. The main antigen against which the T-cell attack is directed is the islet cell enzyme, glutamic acid decarboxylase. Infection with Coxsackie virus B4 has been shown to be a trigger of IDDM in mice, but it is yet to be established as a cause in human diabetes. There is a six–amino acid sequence in common between a Coxsackie virus protein and glutamic acid decarboxylase. Antibodies against various antigens of the beta cells also are produced, but the major damage is T-cell mediated.
6. Insulin-resistant diabetes, myasthenia gravis, and hyperthyroidism (Graves’ disease)—In these diseases, antibodies to receptors play a pathogenic role. In insulin-resistant diabetes, antibodies to insulin receptors have been demonstrated that interfere with insulin binding. In myasthenia gravis, which is characterized by severe muscular weakness, antibodies to acetylcholine receptors of neuromuscular junctions are found in the serum. Muscular weakness also occurs in Lambert-Eaton syndrome, in which antibodies form against the proteins in calcium channels. Some patients with Graves’ disease have circulating antibodies to thyrotropin receptors, which, when they bind to the receptors, resemble thyrotropin in activity and stimulate the thyroid to produce more thyroxine.
7. Guillain-Barré syndrome—This disease is the most common cause of acute paralysis in the United States. It follows a variety of infectious diseases such as viral illnesses (e.g., upper respiratory tract infections, human immunodeficiency virus [HIV] infection, and mononucleosis caused by Epstein–Barr virus and cytomegalovirus) and diarrhea caused by Campylobacter jejuni. Infection with C. jejuni, either symptomatic or asymptomatic, is considered to be the most common antecedent to Guillain-Barré syndrome. Antibodies against myelin protein are formed, complement is activated, and the membrane attack complex destroys the myelin sheath, resulting in a demyelinating polyneuropathy. The main symptoms are those of a rapidly progressing ascending paralysis. The treatment involves either intravenous immunoglobulins or plasmapheresis.
8. Pemphigus—Pemphigus is a skin disease characterized by bullae (blisters). It is caused by autoantibodies against desmoglein, a protein in the desmosomes that forms the tight junctions between epithelial cells in the skin. When the tight junctions are disrupted, fluid fills the spaces between cells and forms the bullae. One form of pemphigus, pemphigus foliaceus, is endemic in rural areas of South America, which lends support to the idea that infection with an endemic pathogen is the environmental trigger for this disease.
9. Reactive arthritis—Reactive arthritis is an acute inflammation of the joints that follows infection with various bacteria, but the joints are sterile (i.e., the inflammation is a “reaction” to the presence of bacterial antigen elsewhere in the body). Reactive arthritis is associated with enteric infections caused by Shigella, Campylobacter, Salmonella, and Yersinia and with urethritis caused by Chlamydia trachomatis. The arthritis is usually oligoarticular and asymmetric. The bacterial infection precedes the arthritis by a few weeks. People who are HLA-B27 positive are at higher risk for reactive arthritis. Antibiotics directed against the organism have no effect. Anti-inflammatory agents are typically used. (Reiter’s syndrome includes a reactive arthritis, but the syndrome affects multiple organs and is described in the next section.)
10. Celiac disease—Celiac disease (also known as celiac sprue and gluten enteropathy) is characterized by diarrhea, painful abdominal distention, fatty stools, and failure to thrive. Symptoms are induced by ingestion of gliadin, a protein found primarily in wheat, barley, and rye grains. Gliadin is the antigen that stimulates a cytotoxic T-cell attack on enterocytes, resulting in villous atrophy. A gluten-free diet typically results in marked improvement.
11. Inflammatory bowel disease (Crohn’s disease and ulcerative colitis)—These diseases are characterized by diarrhea, often bloody, and crampy lower abdominal pain. These symptoms arise from chronic inflammation, primarily in the ileum in Crohn’s disease and in the colon in ulcerative colitis. It is thought that the chronic inflammation is caused by an abnormal immune response to the presence of normal flora of the bowel. There is evidence that a type of helper T cell called Th-17 and IL-23 are involved in the pathogenesis of these diseases. Natalizumab, a monoclonal antibody against α-integrin, is effective in inducing remission in active Crohn’s disease.
12. IgA nephropathy—This disease is one of the most common types of glomerulonephritis and is characterized primarily by hematuria, but proteinuria and progression to end-stage renal disease can occur. Immune complexes containing IgA are found lining the glomeruli. Symptoms are temporally related to viral infections, especially pharyngitis, but no specific virus has been identified. No treatment regimen is clearly effective. Fish oil has been tried, with variable results.
13. Psoriasis—Psoriasis is a chronic autoimmune skin disease characterized by raised erythematous plaques with silvery scales, often on the elbows or knees. Skin lesions are the most common manifestation, but psoriatic arthritis also occurs.
The inflammatory infiltrate in the skin lesions consist of dendritic cells, macrophages, and T cells. Individuals with the class I MHC protein, HLA-Cw6, are predisposed to psoriasis. The environmental trigger is unknown.
There are many treatment modalities. Topical corticosteroids and UV phototherapy with psoralen are two common modes. Methotrexate, cyclosporine, and TNF inhibitors such as etanercept and infliximab are also used. There is evidence that monoclonal antibody against either IL-17 or the IL-17 receptor is also effective.
Diseases Involving Multiple Organs (Systemic Diseases)
1. Systemic lupus erythematosus—In this disease, autoantibodies are formed against DNA, histones, nucleolar proteins, and other components of the cell nucleus. Antibodies against double-stranded DNA are the hallmark of systemic lupus erythematosus. The disease affects primarily women between the ages of 20 and 60 years. Individuals with HLA-DR2 or-DR3 genes are predisposed to systemic lupus erythematosus. The agent that induces these autoantibodies in most patients is unknown. However, two drugs, procainamide and hydralazine, are known to cause systemic lupus erythematosus.
Most of the clinical findings are caused by immune complexes that activate complement and, as a consequence, damage tissue. For example, the characteristic rash on the cheeks is the result of a vasculitis caused by immune complex deposition. The arthritis and glomerulonephritis commonly seen in systemic lupus erythematosus are also caused by immune complexes. The immune complexes found on the glomerulus contain antibodies (IgG, IgM, or IgA) and the C3 component of complement but not fibrinogen. However, the anemia, leukopenia, and thrombocytopenia are caused by cytotoxic antibodies rather than immune complexes.
The diagnosis of systemic lupus erythematosus is supported by detecting antinuclear antibodies (ANAs) with fluorescent antibody tests and anti–double-stranded DNA antibodies with enzyme-linked immunosorbent assay (ELISA). Antibodies to several other nuclear components are also detected, as is a reduced level of complement. Treatment of systemic lupus erythematosus varies depending on the severity of the disease and the organs affected. Aspirin, nonsteroidal anti-inflammatory drugs, and corticosteroids are commonly used.
2. Rheumatoid arthritis—In this disease, autoantibodies are formed against IgG. These autoantibodies are called rheumatoid factors and are of the IgM class. Rheumatoid arthritis affects primarily women between the ages of 30 and 50 years. People with HLA-DR4 genes are predisposed to rheumatoid arthritis. The agent that induces these autoantibodies is unknown. Within the inflamed joints, the synovial membrane is infiltrated with T cells, plasma cells, and macrophages, and the synovial fluid contains high levels of macrophage-produced inflammatory cytokines such as TNF, IL-1, and IL-8.
The main clinical finding is inflammation of the small joints of the hands and feet. Other organs, such as the pleura, pericardium, and skin, can also be involved. Most of the clinical findings are caused by immune complexes that activate complement and, as a consequence, damage tissue. The diagnosis of rheumatoid arthritis is supported by detecting rheumatoid factors in the serum. Detection of antibody to citrullinated peptide in the serum also supports the diagnosis.
Treatment of rheumatoid arthritis typically involves aspirin, nonsteroidal anti-inflammatory drugs, immunosuppressive drugs (especially methotrexate), or corticosteroids. Anticytokine therapy consisting of a fusion protein of TNF receptor and the Fc fragment of human IgG (etanercept, Enbrel) is also available. The soluble TNF receptor neutralizes TNF, which is an important inflammatory mediator in rheumatoid arthritis. Etanercept is particularly effective in combination with methotrexate in reducing the severity of joint inflammation in patients with persistently active rheumatoid arthritis. The monoclonal antibodies infliximab (Remicade) and adalimumab (Humira) are useful for the treatment of rheumatoid arthritis. These antibodies neutralize TNF, thereby decreasing the joint inflammation. Table 62–2 describes infliximab and other monoclonal antibodies that have different clinical uses.
Patients who have an inadequate response to these anti-TNF drugs have demonstrated significant improvement with abatacept (Orencia). Abatacept is CTLA-4-IG, a fusion protein composed of CTLA-4 and a fragment of the Fc domain of human IgG. CTLA-4 binds strongly to B7, which displaces CD28 from its binding to B7. This results in a reduction of the helper T-cell activity and the inflammatory response.
3. Rheumatic fever—Group A streptococcal infections regularly precede the development of rheumatic fever. Antibodies against the M protein of group A streptococci that cross-react with myosin in cardiac muscle and proteins in joint and brain tissue are involved in the pathogenesis of rheumatic fever.
4. Reiter’s syndrome—This syndrome is characterized by the triad of arthritis, conjunctivitis, and urethritis. Cultures of the affected areas do not reveal a causative agent. Infection by one of the intestinal pathogens (e.g., Shigella, Salmonella, Yersinia, and Campylobacter), as well as other organisms such as Chlamydia, predisposes to the disease. Most patients are men who are HLA-B27 positive. The pathogenesis of the disease is unclear, but immune complexes may play a role.
5. Goodpasture’s syndrome—In this syndrome, autoantibodies are formed against the collagen in basement membranes of the kidneys and lungs. Goodpasture’s syndrome (GS) affects primarily young men, and those with HLA-DR2 genes are at risk for this disease. The agent that induces these autoantibodies is unknown, but GS often follows a viral infection.
The main clinical findings are hematuria, proteinuria, and pulmonary hemorrhage. The clinical findings are caused by cytotoxic antibodies that activate complement. As a consequence, C5a is produced, neutrophils are attracted to the site, and enzymes are released by the neutrophils that damage the kidney and lung tissue. The diagnosis of GS is supported by detecting antibody and complement bound to basement membranes in fluorescent antibody test. Because this is a rapidly progressive, often fatal disease, treatment, including plasma exchange to remove the antibodies and the use of immunosuppressive drugs, must be instituted promptly.
6. Wegener’s granulomatosis—The main pathologic finding in this disease is a necrotizing granulomatous vasculitis that primarily affects the upper and lower respiratory tracts and the kidneys. Common clinical findings include sinusitis, otitis media, cough, sputum production, and arthritis. Glomerulonephritis is one of the main features of this disease. The diagnosis is supported by finding antineutrophil cytoplasmic antibodies (ANCAs) in the patient’s serum. Immunosuppressive therapy with cyclophosphamide and prednisone is effective.
7. Other collagen vascular diseases—Other diseases in this category include ankylosing spondylitis, which is very common in people carrying the HLA-B27 gene, polymyositis-dermatomyositis, scleroderma, periarteritis nodosa, and Sjögren’s syndrome.
Treatment
The conceptual basis for the treatment of autoimmune diseases is to reduce the patient’s immune response sufficiently to eliminate the symptoms. Corticosteroids, such as prednisone, are the mainstay of treatment, to which antimetabolites, such as azathioprine and methotrexate, can be added. The latter are nucleoside analogues that inhibit DNA synthesis in the immune cells. Immunosuppressive therapy must be given cautiously because of the risk of opportunistic infections.
Two approaches to therapy that do not involve systemic suppression of the immune system include antibody to TNF and soluble receptor for TNF that acts as a decoy. Both infliximab and adalimumab (antibody to TNF) as well as etanercept (TNF receptor) have been shown to ameliorate the joint inflammation of rheumatoid arthritis and the skin lesions of psoriasis. However, these anti-TNF therapies increase the risk of infections, such as activating latent tuberculosis, serious infections caused by Legionella and Listeria, and skin and soft tissue infections caused by pyogenic bacteria. These drugs increase the risk of activating latent fungal infections such as histoplasmosis as well.
Certain antibody-mediated autoimmune diseases, such as Guillain-Barré syndrome and myasthenia gravis, can be treated either with plasmapheresis, which removes autoimmune antibodies, or with high doses of IgG pooled from healthy donors. One hypothesis regarding the mode of action of high-dose intravenous IgG is that it binds to Fc receptors on the surface of neutrophils and blocks the attachment of immune complexes that activate the neutrophils. Another hypothesis is that excess IgG saturates the FcRn receptor on the surface of vascular endothelial cells, which accelerates the catabolism of IgG, thereby reducing the level of autoimmune antibodies.
SELF-ASSESSMENT QUESTIONS
1. Regarding immunologic tolerance, which one of the following is the most accurate?
(A) Clonal deletion occurs with T cells but not with B cells.
(B) Tolerance to certain self antigens occurs by negative selection of immature T cells in the thymus.
(C) The presence of B7 on the surface of the antigen-presenting cell is one of the essential steps required to establish tolerance.
(D) Tolerance is easier to establish in adults than in newborns because more self-reactive T cells have undergone apoptosis in adults than in newborns.
(E) Once tolerance is established to an antigen, it is permanent (i.e., that individual cannot react against that antigen even though the antigen is no longer present).
2. Antibodies against normal components of the body typically occur in autoimmune diseases. In which one of the following sets of two diseases do antibodies against DNA occur in one disease and antibodies against IgG occur in the other disease?
(A) Myasthenia gravis and systemic lupus erythematosus
(B) Pernicious anemia and rheumatic fever
(C) Rheumatic fever and myasthenia gravis
(D) Rheumatoid arthritis and pernicious anemia
(E) Systemic lupus erythematosus and rheumatoid arthritis
3. Regarding the pathogenesis of autoimmune diseases, which one of the following is the most accurate?
(A) In Reiter’s syndrome, neuropathy occurs following viral respiratory tract infections.
(B) In myasthenia gravis, antibodies are formed against acetylcholine at the neuromuscular junction.
(C) In Goodpasture’s syndrome, antibodies are formed against the synovial membrane in the large weight-bearing joints.
(D) In autoimmune hemolytic anemia, the red cells are destroyed by tumor necrosis factor produced by activated macrophages.
(E) In Graves’ disease, antibodies bind to the receptor for thyroid-stimulating hormone, which stimulates the thyroid to produce excess thyroxine.
4. Your patient is a 25-year-old woman with a fever, a malar facial rash, alopecia, and ulcerations on two fingertips. Urinalysis shows proteinuria. You suspect she has systemic lupus erythematosus. Which one of the following is the most likely explanation for her proteinuria?
(A) Cytotoxic T cells attack the glomerular basement membrane.
(B) An IgE-mediated response releases histamine and leukotrienes that damage the tubules.
(C) A delayed hypersensitivity response consisting of macrophages and CD4-positive T cells damages the glomeruli.
(D) Immune complexes are trapped by glomeruli and activate complement, then C5a attracts neutrophils that damage the glomeruli.
ANSWERS
1. (B)
2. (E)
3. (E)
4. (D)
PRACTICE QUESTIONS: USMLE & COURSE EXAMINATIONS
Questions on the topics discussed in this chapter can be found in the Immunology section of PART XIII: USMLE (National Board) Practice Questions starting on page 713. Also see PART XIV: USMLE (National Board) Practice Examination starting on page 731.