Chapter 66: Tolerance & Autoimmune Disease

Immune tolerance is the lack of responsiveness to a specific antigen that could otherwise elicit an immune response. The best example of antigen tolerance is a host’s normal absence of response for “self” antigens, while those same antigens might be considered “foreign” if transplanted to a different host. Because it applies to responses to antigens, tolerance is a feature of adaptive immunity, although certain antigen-presenting cells can have a tolerogenic effect on T cells. In this chapter, we will discuss how immune tolerance to “self” develops and what happens when that tolerance is broken.

Whether an antigen will induce tolerance rather than sensitization is largely determined by:

1. The immunologic maturity of the immune system. In general, antigens that are present during early development do not stimulate an immunologic response (i.e., we are tolerant to those antigens). On the other hand, antigens that are not present during the process of immune maturation (i.e., that are encountered first when the body is more immunologically mature) are considered “foreign” and usually elicit an immunologic response.

2. The structure of the antigen. For example, simple molecules (small proteins) are more likely to induce tolerance than complex molecules (polysaccharides).

3. The antigen’s potential to cross-react with other immunogenic antigens. T-cell and B-cell receptors are highly specific, but occasionally, they can confuse one antigen with another. When this happens, an appropriate response against a foreign antigen can inappropriately begin to target self-antigens, causing host tissue damage.

4. The presence of proinflammatory signals, such as those induced by pathogen-associated molecular patterns (PAMPs) (see Chapter 58), or anti-inflammatory treatment, such as the immunosuppressive drugs described below and in Chapter 62.

5. The duration of antigen exposure. Tolerance is maintained best if the antigen to which the immune system is tolerant continues to be present.

T-Cell Tolerance

Although both B cells and T cells participate in tolerance, it is T-cell tolerance that plays the primary role. The main process by which T lymphocytes acquire the ability to distinguish self from nonself occurs in the thymus (see Chapter 59). Tolerance to self-antigens acquired within the thymus is called central tolerance. This process, which includes positive and negative clonal selection, involves the killing of T cells (“negative selection”) that react strongly to antigens presented to them in the thymus. How do thymic cells display peptides from proteins that are usually found in the pancreas, lung, or salivary glands? A transcription factor called the autoimmune regulator (AIRE) causes enhanced synthesis of various self-proteins in the thymus. Mutations in the gene encoding the AIRE protein result in the development of an autoimmune disease called autoimmune polyendocrinopathy in which the immune system inappropriately attacks multiple organs.

Note that the thymus is usually a protected space where “truly foreign” proteins are rarely found. But experiments in mice have shown that if an exogenous protein is introduced into the thymus, either by injection or by generating a mutant mouse strain in which the thymus cells produce a nonmouse protein, this protein is treated as “self” by the T-cell selection process. The result is that the strongly self-reactive cells die by a process of programmed cell death called apoptosis.

Tolerance acquired outside the thymus is called peripheral tolerance. Peripheral tolerance is necessary because some self-antigens are not expressed in the thymus, and therefore, some self-reactive T cells are not eliminated by negative selection. In addition, there are foreign antigens, such as those from commensal organisms on the barriers of our skin and gastrointestinal tract, which are harmless. An immune response to these antigens would be pathogenic (i.e., a hypersensitivity reaction; see Chapter 65).

There are several mechanisms involved in peripheral tolerance: (1) if T cells are activated in the absence of co-stimulation, they become anergic (a state of nonresponsiveness); (2) activation of naïve T cells to become effector cells can be suppressed by nearby regulatory T cells, resulting in anergy or apoptosis; and (3) the naïve T cells themselves can undergo differentiation into T regulatory cells (Tregs) at the time of their activation (Figure 66–1).

There are a number of proposed mechanisms by which Tregs suppress other T cells (see Figure 66–1C). For example, Tregs have high baseline levels of the high-affinity interleukin (IL)-2 receptor, meaning they act as a competitive “sink” that reduces the amount of IL-2 available to other T cells. Also, Tregs have high levels of the protein cytotoxic T lymphocyte antigen-4 (CTLA-4), which they use to block or remove the co-stimulatory “signal 2” that B7 provides (recall that CTLA-4 has higher affinity for B7 than CD28, as discussed in Chapter 59). Tregs also secrete cytokines such as IL-10 and transforming growth factor-beta (TGF-β) that may be immunosuppressive in certain contexts. These signals and others can induce T cells to become anergic or induce them to undergo apoptosis.

B-Cell Tolerance

B-cell clones are also tolerant to self-antigens due to precursor negative selection, which occurs primarily in the bone marrow (see Chapter 59). However, tolerance in B cells is less complete than in T cells, an observation supported by the finding that most autoimmune diseases are accompanied by self-reactive autoantibodies.

B-cell precursors bearing an antigen receptor that strongly binds a self-protein are subject to clonal deletion (apoptosis) or anergy. However, the clones can escape this fate by a process called receptor editing (see Chapter 59). 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 allows the B-cell precursor a chance to exit the bone marrow as a mature B-cell clone and reduces the risk of autoimmune diseases. It is estimated that as many as 25% to 50% of B cells that were initially self-reactive undergo receptor editing. T cells do not undergo receptor editing.

The adult host usually exhibits tolerance to self-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.

In all autoimmune diseases, the most important step in the loss of tolerance is the activation of self-reactive (autoreactive) CD4-positive T cells. If this occurs, these self-reactive T cells can differentiate into effector/helper T cells (e.g., Th-1, Th-2, and Th-17 cells) that cause inappropriate inflammation in tissues. They can also differentiate into follicular helper T cells (Tfh cells), which provide inappropriate help to autoantibody-producing B cells. As described in Table 66–1, most autoimmune diseases are associated with autoantibodies. In some cases, the disease is directly mediated by the antibodies, and in other cases, the disease is the result of immune complex deposition or T-cell–derived cytokines, and the antibodies may only be a marker of loss of tolerance.

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, certain alleles of the HLA-DR gene increase the risk of having rheumatoid arthritis, and individuals with these alleles may also have more severe disease. This allele, and other alleles of HLA-DR and HLA-DQ, increases the risk of having autoimmune (type 1) diabetes. Ankylosing spondylitis is 100 times more likely to occur in people who carry HLA-B27 than in those who do not carry that gene. These associations underscore the importance of T-cell antigen recognition in the development of autoimmunity.

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 major histocompatibility complex (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 because they bind poorly to those class I or class II MHC proteins in the thymus.

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-DR risk alleles do not develop rheumatoid arthritis). In general, class II MHC-related diseases (e.g., rheumatoid arthritis, Graves’ disease [hyperthyroidism], and systemic lupus erythematosus [SLE]) occur more commonly in women, whereas class I MHC-related diseases (e.g., ankylosing spondylitis and reactive arthritis) 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 SLE 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. In some cases, there is a known molecular mimic in the infectious agent that induces an immune response that cross-reacts with self-proteins (see Molecular Mimicry below). However, in many cases, the causal link between a particular infection and the autoimmune disease is observed but unexplained (see Table 66–2 for examples). It is speculative at this time, but members of the bowel flora are thought to play a role in the genesis, or the maintenance, of inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis. Other environmental triggers include certain drugs such as procainamide or hydralazine, which cause SLE.

In summary, the current theory is that most 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, reactive arthritis 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 Streptococcus pyogenes and the myosin of cardiac muscle. Antibodies against certain M proteins cross-react with cardiac myosin, leading to the heart damage seen in 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 SLE is an example of this mechanism.

Release of Sequestered Antigens

Certain tissues (e.g., the testes, central nervous system, and the lens and uveal tract of the eye) are kept isolated from so that their antigens are less exposed to the immune system. These are known as immunologically privileged sites. When antigens from these organs do enter the circulation accidentally (e.g., after damage), they can elicit immune 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.

Intracellular antigens, such as DNA, histones, and mitochondrial enzymes, are also normally sequestered from the immune system. However, cellular damage from bacterial or viral infection, radiation, and chemicals may cause the release of these sequestered antigens, which then elicit an immune response. Once autoantibodies are formed, new cells can be targeted and damaged, and ongoing release of sequestered antigens results in the formation of immune complexes and the symptoms of the autoimmune disease. Sunlight is known to exacerbate the skin rash in patients with SLE. 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. 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

As described earlier, Tregs are CD4-positive cells that suppress the inflammatory effects of other T cells. Rare Mendelian deficiencies, such as mutations of the gene AIRE or the gene FOXP3 (required for Treg differentiation), cause autoimmunity through deficiency of Tregs. Deficiency of FOXP3 causes immunodysregulation polyendocrinopathy X-linked (IPEX) syndrome. Similarly, rare mutations in genes encoding proteins involved in T-cell receptor signaling can cause both immunodeficiency and autoimmunity due to complex effects on thymic selection.

Diseases

Table 66–1 lists some 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. 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 in persons who are genetically susceptible (e.g., those with the HLA-DRB1 allele). There is suggestive evidence that Epstein–Barr virus may be a trigger, but this is not conclusive.

   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 are used to prevent flares and suppress them when they do occur (see Table 66–3 in the “Treatment” section). In addition to glucocorticoids, other treatments include antibodies against the IL-2 receptor (daclizumab; see Table 62–2), antibodies against CD20 found on B cells (ocrelizumab), and antibodies against integrin α4 involved in leukocyte homing to sites of inflammation (natalizumab).

   Three other notable multiple sclerosis treatments are interferon-β, making it one of the few US Food and Drug Administration (FDA)-approved indications for type I interferon treatment, dimethyl fumarate, which is an oral drug that has various suppressive effects on pro-inflammatory immune cells, and glatiramer, which is a cocktail of synthetic peptides thought to mimic myelin basic protein. (The mechanism of glatiramer is not well understood, but it is known to be presented with class II MHC proteins and shift the CD4-positive T-cell response from one dominated by Th-1/Th-17 cells to one with more Treg cells.)

2. Chronic thyroiditis—Hashimoto’s thyroiditis is an autoimmune disease in which antibodies are formed against thyroglobulin and thyroid peroxidase. These antibodies may provoke an inflammatory process that leads to fibrosis of the gland. There is also evidence of Th-1 cell and cytotoxic T-cell activation, and the combined effect of these cells causes inflammation and thyroid cell death. Treatment entails thyroid hormone replacement.

3. Anemias, thrombocytopenias, and granulocytopenias—Various forms of these disorders have been attributed to the attachment of autoantibodies to cell surfaces and subsequent cell destruction.

   Immune 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, i.e. autoantibodies directed against erythrocytes attach and result in cell destruction. Treatment of these conditions generally involves immunosuppression.

   Pernicious anemia is not hemolytic; it is caused by antibodies to intrinsic factor, a protein secreted by parietal cells of the stomach that facilitates the absorption of vitamin B₁₂. Treatment involves vitamin B₁₂ replacement.

4. Type I diabetes mellitus—In this disease, autoreactive T cells destroy the insulin-producing islet cells of the pancreas. A main antigen against which the T-cell attack is directed is the islet cell enzyme, glutamic acid decarboxylase. There may also be a role for autoantibodies targeting islet cell antigens, including insulin itself.

   Infection with Coxsackie virus B4 has been shown to be a trigger of insulin-dependent diabetes mellitus 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.) The mainstay of treatment is insulin replacement, but immune-based therapies that aim to restore immune tolerance of islet cells are under investigation.

5. 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 block neuromuscular junction signaling. 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.

6. 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 infection with Campylobacter jejuni. Infection with C. jejuni, which causes enteritis and diarrhea, is considered to be the most common antecedent to Guillain-Barré syndrome. Antibodies against membrane gangliosides are formed, complement is activated, and the membrane attack complex destroys the myelin sheath, resulting in a demyelinating polyneuropathy. (Unlike multiple sclerosis, this neuropathy occurs in peripheral nerves.) The main symptoms are those of a rapidly progressing ascending paralysis. The treatment involves either intravenous immunoglobulins or plasmapheresis, which replaces the patient’s plasma, removing the harmful antibodies; glucocorticoids have not been an effective treatment.

7. 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. Treatment entails immunosuppression, either with topical or systemic glucocorticoids.

8. 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. Most patients have antibodies to tissue transglutaminase, and these are often used to aid in making the diagnosis. These autoantibodies may have a role in the disease, but the destruction of enterocytes, which cause villous atrophy, inflammation, and malabsorption, are primarily caused by cytotoxic T cells that react to the protein antigen gliadin. Patients who carry certain alleles of HLA-DQ are predisposed to celiac disease. A gluten-free diet typically results in marked improvement.

9. 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 rectosigmoid colon (in ulcerative colitis). It is thought that the chronic inflammation is caused by an abnormal immune response to certain members of the normal intestinal flora. Dysregulated Th-1 and Th-17 cells are involved in the pathogenesis of these diseases. Corticosteroids, DNA synthesis inhibitors (see Table 62–2), and tumor necrosis factor (TNF) inhibitors are commonly used therapies. Monoclonal antibodies that block IL-12 and IL-23 have been effective. (These are cytokines that drive Th-1 and Th-17 activation, respectively, as described in Chapter 60.) Natalizumab and vedolizumab (see Table 66–3) block integrin-mediated leukocyte recruitment and may induce remission of active disease.

10. 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. The glomeruli are lined with immune complexes containing IgA. The course of the disease varies widely. Some patients are asymptomatic, some have mild symptoms, and others progress rapidly to kidney failure. 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.

11. Psoriasis—Psoriasis is a chronic autoimmune skin disease characterized by raised erythematous plaques with silvery scales, often on the extensor surfaces of the arms and legs (i.e., elbows, shins, and knees). Skin lesions are the most common manifestation, but psoriatic arthritis also occurs. The inflammatory infiltrate in the skin lesions consists of dendritic cells, macrophages, and T cells. (In contrast, atopic dermatitis, covered in Chapter 65, is often characterized by eosinophilic infiltrate.) There is a strong genetic component to psoriasis susceptibility, with individuals carrying the HLA-Cw6 allele of class I MHC being particularly predisposed. The environmental trigger is unknown. There are many treatment modalities. Topical corticosteroids and UV phototherapy with psoralen are two common modes. Methotrexate, cyclosporine (see Table 62–2), dimethyl fumarate, and TNF inhibitors are also used.

Diseases Involving Multiple Organs (Systemic Diseases)

1. Systemic lupus erythematosus—SLE is a chronic inflammatory autoimmune disease that affects the skin of the face, the joints, and the kidneys. Antibodies are formed against DNA and other components of the nucleus of cells. Antibodies against double-stranded DNA are the hallmark of SLE. These antibodies form immune complexes that activate complement. Complement activation produces C5a, which attracts neutrophils that release enzymes, thereby damaging tissues (see Chapter 63). “Lumpy” glomerular deposits can be seen that are similar to those caused by other types of glomerulonephritis.

   Most of the clinical findings are caused by immune complexes that activate complement and, as a consequence, damage tissues. 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 SLE 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. However, the anemia, leukopenia, and thrombocytopenia are caused by cytotoxic antibodies rather than immune complexes. The diagnosis is supported by detecting antinuclear antibodies (ANAs) with fluorescent antibody tests and antidouble-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.

   SLE primarily affects women between the ages of 20 and 60 years. Individuals with HLA-DR2 or HLA-DR3 genes are predisposed. The agent that induces these autoantibodies in most patients is unknown. However, two drugs, procainamide and hydralazine, are known to cause SLE. Treatment of SLE varies depending on the severity of the disease and the organs affected. Aspirin, nonsteroidal anti-inflammatory drugs, and corticosteroids (see Table 62–2) are commonly used.

2. Rheumatoid arthritis—Rheumatoid arthritis (RA) is a systemic disease involving not only the joints but other organs as well, most often the lung and pericardium. Serum and synovial fluid of patients often contain rheumatoid factor, which is an antibody (usually IgM but occasionally IgG, IgD, IgA, or IgE) whose Fab recognizes and binds to the Fc fragment of normal human IgG. Rheumatoid factor is associated with RA but is not specific for it.

   Deposits of immune complexes (containing the normal IgG and rheumatoid factor) on synovial membranes and in blood vessels activate complement and attract polymorphonuclear cells, causing inflammation. The main clinical finding is inflammation of the proximal interphalangeal and metacarpophalangeal joints of the hands, the small joints of the feet, and the cervical spine, knees, and shoulders. 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-6.

   RA affects primarily women between the ages of 30 and 50 years. People with HLA-DR4 genes are predisposed to RA. The agent that induces rheumatoid factor is unknown. In addition to the joints, RA can affect the lung and pericardium, although unlike many of the immune complex-related disorders, RA is an exception in that it does not involve the kidney. The diagnosis is supported by finding high titers of rheumatoid factor and low titers of complement in serum, especially during periods when the disease is most active. Detection of antibody to citrullinated peptide in the serum also supports the diagnosis.

   Treatment of RA typically involves aspirin, nonsteroidal anti-inflammatory drugs, immunosuppressive drugs (especially methotrexate), or corticosteroids (see Table 62–2). TNF inhibitors have proven particularly helpful in suppressing inflammation before it causes joint destruction and deformity. Table 62–2 describes some of the anti-TNF therapies that have different clinical uses. Other therapies targeting IL-1 and IL-6 and therapies that block T-cell co-stimulation (abatacept, a CTLA-4 mimic similar to belatacept; see Table 62–2) and that deplete B cells (rituximab, anti-CD20) are also used.

3. Vasculitis—Inflammation of the walls of blood vessels, which can include large, medium, and small arteries and veins, is called vasculitis. A number of multisystem autoimmune diseases manifest with vasculitis caused by immune complexes: polyarteritis nodosa, Henoch-Schönlein purpura (IgA vasculitis), cryoglobulin-related vasculitis, and the vasculitis that occurs in SLE. An important example of a cryoglobulin-related vasculitis occurs in hepatitis C virus infection.

   One of the more common examples is granulomatosis with polyangiitis (formerly called Wegener’s granulomatosis). The main pathologic finding in this disease is 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 corticosteroids (see Table 62–2) is effective for treating disease flares.

   In contrast, some diseases, such as giant cell arteritis (GCA), are caused by T cells infiltrating the arterial wall. The most common form of GCA is temporal arteritis that involves the temporal artery.

   The symptoms and signs of vasculitis vary depending on the organ affected. Nonspecific findings include fever, weight loss, arthralgia, myalgia, and abdominal pain. Some findings often associated with vasculitis are palpable purpura and mononeuritis multiplex, which often manifests as foot or wrist drop. As with the other immune complex-related diseases, vasculitis often involves the kidney glomeruli. A complete description of the diseases in which vasculitis occurs is beyond the scope of this book.

4. Reactive arthritis—Reactive arthritis is an acute inflammation of the joints that follows 1 to 3 weeks after various bacterial infections. However, importantly, the infectious agents themselves are not cultured from the joint fluid. The inflammation is caused either by cross-reactive immune responses to self- antigens or by immune complexes with foreign antigens that deposit in the joints. 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. Men are more commonly affected, and those who carry the HLA-B27 allele are at higher risk. Antibiotics directed against the organism have no effect. Anti-inflammatory agents are typically used. Reactive arthritis often presents as part of a triad of arthritis, conjunctivitis, and urethritis (formerly called Reiter’s syndrome). 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 carrying particular HLA-DR2 alleles 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 glomerular basement membranes. 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. Other collagen vascular diseases—Other multisystem autoimmune diseases include ankylosing spondylitis (which, like reactive arthritis, is common in people carrying the HLA-B27 allele), polymyositis and dermatomyositis, scleroderma, polyarteritis nodosa, and Sjögren’s syndrome.

Treatment

The conceptual basis for the treatment of autoimmune diseases is to reduce the patient’s immune response or inflammatory response sufficiently to eliminate the symptoms. Immunosuppressive therapy must be given cautiously because of the risk of opportunistic infections. Long-term immunosuppression requires concurrent treatment with antimicrobials to prevent opportunistic infections.

Many of the drugs used for autoimmunity are also used to treat acute transplant rejection, and these were covered in Chapter 62 (see Table 62–2). These include corticosteroids, including prednisone, and antimetabolites, such as methotrexate and azathioprine, that inhibit DNA synthesis in the immune cells. Other drug classes described in Chapter 62 include calcineurin inhibitors and molecules that block cytokines and activation signals, such as B7-CD28. Table 66–3 lists some other therapies, not included in Chapter 62, that are FDA-approved for autoimmune diseases.

Nonsteroidal anti-inflammatory drugs are used for certain autoimmune and inflammatory diseases. These act by inhibiting cyclooxygenase (COX) enzymes, blocking the production of inflammatory mediators, particularly prostaglandins.

Other approaches to therapy 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 RA 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.

Monoclonal antibodies against the cytokine IL-17 and the IL-17 receptor block Th-17 cell function. In addition, antibodies that block Th-1 and Th-17 cell activation by neutralizing IL-12 and IL-23. Various antibodies from this family are approved for psoriasis, RA, ankylosing spondylitis, and Crohn’s disease.

Rituximab and ocrelizumab are monoclonal antibodies against CD20, a protein located on the surface of B cells but not plasma cells. These antibodies causes the death of B cells either by complement-mediated killing (complement-dependent cytotoxicity), by the attack of natural killer cells (antibody-dependent cell-mediated cytotoxicity), or by directly inducing cell death (apoptosis).

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. The mechanism of how high-dose intravenous IgG (IVIG) suppresses inflammation is not completely understood. One hypothesis is that it binds to Fc receptors on the surface of neutrophils, monocytes, and macrophages and blocks the attachment of the inflammatory immune complexes that activate these cells. 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. A third hypothesis is that the IVIG preferentially binds inhibitory Fc receptors, which counteracts the immune activation.