Autoimmune Disorders

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Autoimmune Disorders

The major autoimmune diseases, e.g., systemic lupus erythematosus (see Chapter 29), rheumatoid arthritis (see Chapter 30), diabetes type 1, and multiple sclerosis share many common features. Chronic and other intermittent inflammation contributes over time to the destruction of target organs that contain inciting antigens or are the sites of immune-complex deposition. Although the adaptive immune system has long been the focus of attention, innate immune mechanisms are now viewed as central to the pathogenesis of these disorders. New genetic findings emphasize the identification of environmental components that interact with host genetic factors are being important to developing a deeper understanding of autoimmunity.

What is autoimmunity?

Autoimmunity represents a breakdown of the immune system’s ability to discriminate between self and nonself. The term autoimmune disorder refers to a varied group of more than 80 serious, chronic illnesses that involve almost every human organ system. In all these disorders, the underlying problem is similar; the body’s immune system becomes misdirected, attacking the organs it was designed to protect.

Autoimmune disorders remain among the most poorly understood and poorly recognized of any category of illnesses. Individually, autoimmune disorders occur infrequently, except for thyroid disease, diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Overall, autoimmune disorders represent the fourth largest cause of disability in Europe and the United States.

The term autoimmune disorder is used when demonstrable immunoglobulins (autoantibodies) or cytotoxic T cells display specificity for self antigens, or autoantigens, and contribute to the pathogenesis of the disorder (Table 28-1). Autoimmune disorders are characterized by the persistent activation of immunologic effector mechanisms that alter the function and integrity of individual cells and organs. The sites of organ or tissue damage depend on the location of the immune reaction. The variety of signs and symptoms seen in patients with autoimmune disorders reflects the various forms of the immune response.

Table 28-1

Autoimmune Disorders and Associated Abnormalities

Clinical Diagnosis Autoantigen
Addison’s disease P-450 enzymes
Crohn’s disease p-ANCA, pancreatic acinar cells
Ovarian failure/infertility P-450 enzymes
Pernicious anemia Parietal cells
Ulcerative colitis p-ANCA

It is also important to note that autoantibodies may be formed in patients secondary to tissue damage or when no evidence of clinical disease exists. Unlike autoimmune disorders, autoantibodies can occur as immune correlates of conditions such as blood transfusion reactions. In addition, autoantibodies can be demonstrated in hemolytic disease of the newborn and graft rejection and can result from disorders such as serum sickness, anaphylaxis, and hay fever when the immune response is clearly the cause of the disease.

Spectrum of Autoimmune Disorders

Many disorders are believed to be related to immunologic abnormalities and additional diseases are continually being identified (Box 28-1). Autoimmune disorders exhibit a full spectrum of tissue reactivity (Fig. 28-1). At one extreme are organ-specific disorders such as Hashimoto’s disease of the thyroid; at the other extreme are disorders that manifest as organ-nonspecific diseases, such as systemic lupus erythematosus (SLE; see Chapter 29) and rheumatoid arthritis (RA; see Chapter 30; Table 28-2).

Differences Organ-Specific Organ-Nonspecific Antibodies and lesions are organ-specific. Antibodies and lesions are organ nonspecific. Clinical and serologic overlap (e.g., thyroid, stomach, adrenal glands, kidney). Overlap of SLE, RA, and other connective tissue disorders. Antigens only available to lymphoid system in low concentrations. Antigens accessible at higher concentrations. Antigens evoke organ-specific antibodies in normal animals with complete Freund’s adjuvant. No antibodies produced in animals with comparable stimulation. Familial tendency to develop organ-specific autoimmunity. Familial tendency to develop connective tissue disease.
Questionable abnormalities in immunoglobulin synthesis in relatives. Lymphoid invasion, parenchymal destruction by questionable cell-mediated hypersensitivity or antibodies. Lesions caused by deposition of antigen-antibody (immune) complexes. Tendency to develop cancer in the organ. Tendency to develop lymphoreticular neoplasia.

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Figure 28-1 Autoimmune disorders.

In organ-specific disorders, both the lesions produced by tissue damage and the autoantibodies are directed at a single target organ (e.g., the thyroid). Midspectrum disorders are characterized by localized lesions in a single organ and by organ-nonspecific autoantibodies. For example, in primary biliary cirrhosis, the small bile duct is the main target of inflammatory cell infiltration, but the serum autoantibodies are mainly mitochondrial antibodies and are not liver-specific.

Organ-nonspecific disorders are characterized by the presence of both lesions and autoantibodies not confined to any one organ.

Factors Influencing Development of Autoimmunity

Autoimmunity begins with an abnormal interaction of T and B lymphocytes with autoantigens. No single theory or mechanism has been identified as a cause. The potential for autoimmunity, if given appropriate circumstances, is constantly present in every immunocompetent individual because lymphocytes that are potentially reactive with self antigens exist in the body. Antibody expression appears to be regulated by a complex set of interacting factors; these influences include genetic factors, patient age, and exogenous factors.

Immunopathogenic Mechanisms

Autoimmune disorders are usually prevented by the normal functioning of immunologic regulatory mechanisms. When these controls dysfunction, antibodies to self antigens may be produced and bind to antigens in the circulation to form circulating immune complexes or to antigens deposited in specific tissue sites.

The mechanisms governing the deposition in one organ or another are unknown; however, several mechanisms may be operative in a single disease. Wherever antigen-antibody complexes accumulate, complement can be activated, with the subsequent release of mediators of inflammation. These mediators increase vascular permeability, attract phagocytic cells to the reaction site, and cause local tissue damage. Alternatively, cytotoxic T cells can directly attack body cells bearing the target antigen, which releases mediators that amplify the inflammatory reaction. Autoantibody and complement fragments coat cells bearing the target antigen, which leads to destruction by phagocytes or antibody-seeking K-type lymphocytes.

An individual may develop an autoimmune response to a variety of immunogenic stimuli (Table 28-3). These responses may be caused by the following:

Table 28-3

Antigens Implicated in Autoimmune Endocrine Diseases

Disorder Antigen
Hashimoto’s disease Thyroglobulin
Thyroid peroxidase
Thyrotropin receptor
Graves’ disease Thyrotropin receptor
Thyroid peroxidase
Thyroglobulin
64-kDa antigen
70-kDa heat shock protein
Type 1 diabetes Insulin/proinsulin
Insulin receptor
Glutamic acid decarboxylase
B cell release granule
Pancreatic cytokeratin
64-kDa antigen
Glucagon
65-kDa heat shock protein
Addison’s disease Adrenal cortical cells
55-kDa microsomal antigen
Idiopathic hypoparathyroidism 130- and 200-kDa antigens
Endothelial antigen
Mitochondrial antigen

• Antigens that do not normally circulate in the blood

The hidden antigen (sequestered antigen) theory is one of the earliest views of organ-specific antibodies. Antigens are sequestered within the organ and, because of the lack of contact with the mononuclear phagocyte system, they fail to establish immunologic tolerance. Any conditions producing a release of antigen would then provide an opportunity for autoantibody formation. This situation occurs when sperm cells or lens and heart tissues are released directly into the circulation, and autoantibodies are formed. Unmodified extracts of tissues involved in organ-specific autoimmune disorders, however, do not readily elicit antibody formation.

• Altered antigens that arise because of chemical, physical, or biological processes (e.g., hapten complexing, physical denaturation, mutation)

• A foreign antigen that is shared or cross-reactive with self antigens or tissue components

• Mutation of immunocompetent cells to acquire a response to self antigens

• Loss of the immunoregulatory function by T lymphocyte subsets

Understanding the mechanism of autoimmunity requires an understanding of the regulation of the immune response. The immune response involves interaction of cellular elements such as lymphocytes and macrophages, antigens, antibody, immune complexes, and complement.

Self-Recognition (Tolerance)

In the initial stage of some diseases, infiltration by T lymphocytes may induce inflammation and tissue damage, leading to alterations in self antigens and production of autoantibodies. In other diseases, only the production of autoantibodies is noted with tissue damage. These autoantibodies attack cell surface antigens or membrane receptors or combine with antigen to form immune complexes that are deposited in tissue, subsequently causing complement activation and inflammation.

An immune response requires presentation of a foreign antigen by an antigen-presenting cell (APC) and another signal from the appropriate major histocompatibility complex (MHC) molecule on the host’s cells. Both are needed for an immune response. Tolerance is the lack of immune response to self antigens and is initiated during fetal development (central tolerance) by the elimination of cells with the potential to react strongly with self antigens. Peripheral tolerance is a process involving mature lymphocytes and occurs in the circulation. Central tolerance develops in the thymus during fetal life. Self antigens are presented by dendritic cells to self-reactive T cells that are responsible for positive and negative selection of specific lymphocytes. The ultimate goal is to remove T lymphocytes that respond strongly to self antigens. As genes rearrange and code for antigen receptors, the T cell receptors (TCRs) produced may or may not be specific for the MHC expressed on that individual’s cells. Positive selection cells that have TCRs capable of responding with self antigens (low-level MHC affinity) are selected for continued growth.

Self-recognition (tolerance) is induced by at least two mechanisms involving contact between antigen and immunocompetent cells:

The normal immune response is modulated by antigen-specific and antigen-nonspecific suppressor cell activity.

Major Autoantibodies

Major autoantibodies can be detected in different disorders. Many diagnostic laboratory tests (Box 28-2) are based on detecting these autoimmune responses. Common autoantibodies include thyroid, gastric, adrenocortical, striated muscle, acetylcholine receptor, smooth muscle, salivary gland, mitochondrial, reticulin, myelin, islet cell, and skin. Antibodies to antinuclear antibodies (ANAs) include deoxyribonucleic acid (DNA), histone, and nonhistone protein antibodies.

Box 28-2   Major Autoantibodies

Acetylcholine receptor (AChR)–binding antibody Antireticulin antibody
Acetylcholine receptor (AChR)–blocking antibody Anti–rheumatoid arthritis nuclear antigen (anti-RANA; RA precipitin)
Antiadrenal antibody Antiribosome antibody
Anticardiolipin antibody Anti–nuclear ribonucleoprotein (anti-nRNP) antibody
Anticentriole antibody Anti-Scl antibody or anti–Scl-70 antibody
Anticentromere antibody Antiskin (dermal-epidermal) antibody
Antiskin (interepithelial) antibody
Anti-DNA antibody Anti-Sm antibody
Anti–glomerular basement membrane antibody Anti–smooth muscle antibody
Anti–intrinsic factor antibody Antisperm antibody
Anti–islet cell antibody Anti–SS-A (SS-A precipitin; anti-Ro) antibody
Anti–liver-kidney microsomal (anti-LKM) antibody Anti–SS-B (SS-B precipitin, anti-La) antibody
Antimitochondrial antibody Antistriational antibody
Antimyelin antibody Antithyroglobulin and antithyroid microsome antibody
Antimyocardial antibody Histone-reactive antinuclear antibody (HR-ANA)
Antineutrophil antibody Jo-1 antibody
Antinuclear antibody (ANA) Ku antibody
Anti–parietal cell antibody Mi-1 antibody
Antiplatelet antibody PM-1 antibody

Organ-Specific and Midspectrum Disorders

Cardiovascular Disorders

The primary immunologic diseases of the blood vessels are termed vasculitis; those of the heart are termed carditis.

Vasculitis

Deposition of circulating immune complexes is considered directly or indirectly responsible for many forms of vasculitis. The inflammatory lesions of blood vessels produce variable injury or necrosis of the blood vessel wall. This may result in narrowing, occlusion, or thrombosis of the lumen or aneurysm formation or rupture. Vasculitis occurs as a primary disease process or as a secondary manifestation of another disease (e.g., RA).

Vasculitis is characterized by inflammation within blood vessels, which often results in a compromise of the vessel lumen with ischemia. Ischemia causes the major manifestations of the vasculitic syndromes and determines the prognosis. Any size and type of blood vessel may be involved. Therefore, the vasculitic syndromes are a heterogeneous group of diseases (Box 28-3).

Antibodies specific to endothelial cells also contribute to immune vasculopathy. Antiendothelial antibodies are autoantibodies directed against antigens in the cytoplasmic membrane of endothelial cells.

Carditis

The heart shares a susceptibility to immune-mediated injury with other organs. Numerous cardiac diseases are characterized by the presence of inflammatory cells within the myocardium resulting from immune sensitization to endogenous or exogenous cardiac antigens. The consequent reaction of cardiac myocytes to immune injury can range from reversible modulation of their electrical and mechanical capabilities to cell death. Carditis can be caused by a variety of conditions, including acute rheumatic fever, Lyme disease, and cardiac transplant rejection.

Myocardial contractility can be impaired by cell-mediated injury or the local release of cytokines. The study of immune cardiac disease has entered a period of rapid expansion. Primary idiopathic myocarditis is an autoimmune disease characterized by infiltration of the heart by macrophages and lymphocytes. Studies involving the mechanisms whereby immune cells and factors localize in the myocardium, modulate myocyte function, and remodel myocardial architecture are under way.

A diagnosis of acute rheumatic fever requires differentiation from other immunologic and infectious diseases. The immunologic basis for rheumatic heart disease has long been suspected. Patients with rheumatic heart disease exhibit antimyocardial antibodies that bind in vitro to foci in the myocardium and heart valves. These antibodies may be responsible for the deposition of immunoglobulin and complement components found in the same area of rheumatic heart disease tissues at autopsy.

Antimyocardial antibodies appear to be strongly cross-reactive with streptococcal antigens, but they are not toxic to heart tissue unless the latter is damaged previously by some other cause. Because antimyocardial antibodies are often found in patients with a recent myocardial infarction or streptococcal infection without cardiac sequelae, detection of these antibodies has not been a particularly useful differential diagnostic test for cardiac injury. The presence of myocardial antibodies, however, is diagnostic of Dressler’s syndrome (cardiac injury) or rheumatic fever.

Collagen Vascular Disorders

Progressive Systemic Sclerosis (Scleroderma)

Scleroderma is a collagen vascular disease of unknown cause that assumes various forms. Eosinophilic fasciitis may be a variant of scleroderma.

The development of scleroderma has been associated with a number of occupations and with drugs such as bleomycin sulfate, tryptophan, and carbidopa. Occupational exposure to vinyl chloride, vibratory stimuli, and silicosis have been associated with the subsequent development of scleroderma.

Immunologic Manifestations

Idiopathic scleroderma is considered an autoimmune disease because of the associated autoantibodies and the overlapping syndromes of scleroderma-polymyositis and scleroderma-SLE.

Antinuclear antibodies are formed in 40% to 90% of patients to the following: (1) extractable nuclear antigens; (2) the nucleolus; (3) the centromere; and (4) Scl-70. The anticentromere antibody is sensitive and is specific for patients with a subset of scleroderma with CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia).

In addition, T cell hyperactivity correlates with disease activity. Activated T cells can result in both the vascular changes and increased collagen production in scleroderma. It is now thought that both the vascular disorder and fibrosis result from this cellular immune activation. Vascular injury could be mediated by cytokines or direct cell-cell interaction by activated lymphocytes and endothelial cells.

Endocrine Gland Disorders: Thyroid Disease

Numerous endocrine gland disorders are attributable to an autoimmune process. Several of the classic and more common disorders are discussed in this section.

The clinical spectrum of autoimmune thyroid disease is very broad. There are two major forms of autoimmune thyroid disease, chronic autoimmune thyroiditis and Graves’ disease.

Lymphoid (Hashimoto’s) chronic thyroiditis is a classic example of an organ-specific autoimmune disorder. Other autoimmune disorders affecting the thyroid gland include transient thyroiditis syndrome and idiopathic hypothyroidism.

Lymphoid (Hashimoto’s) Chronic Thyroiditis

Signs and Symptoms

Lymphoid thyroiditis is believed to be the most common cause of sporadic goiter. Characteristically, there is a firm, diffusely enlarged, nontender thyroid gland that may be lobulated. Hypothyroidism, however, is a common late sequela of lymphoid thyroiditis, and patients are usually euthyroid when first seen by a physician. Some individuals have clinical and pathologic evidence of the coexistence of Graves’ disease and lymphoid (Hashimoto’s) thyroiditis. Histologically, Hashimoto’s thyroiditis is characterized by diffuse lymphocytic infiltration (Fig. 28-2).

Immunologic Manifestations

Patients with lymphoid thyroiditis, as well as other autoimmune thyroid disorders, can demonstrate histologic and immunologic manifestations of the disease. Antibodies to thyroid constituents may be observed in these patients. Antibodies to the following constituents may be demonstrated serologically:

Thyroglobulin

Antithyroglobulin (TgAb) was the first antibody discovered against a thyroid protein, thyroglobulin. Immunofluorescent laboratory methods using fluorescein-labeled anti–human globulin can demonstrate the binding of antithyroglobulin antibody to thin sections of thyroid tissue in abnormal conditions or in approximately 4% of the normal population. The frequency of positive titers gradually increases in the female population with aging. The absence of antithyroglobulin antibodies, however, does not exclude the diagnosis of Hashimoto’s thyroiditis; conversely, the presence of antibodies does not establish the diagnosis because it can be positive in Graves’ disease and is occasionally positive in thyroid cancer and subacute thyroiditis. Testing for antibody may also be used to monitor patients with thyroid cancers.

Diagnostic Evaluation

Fine-needle aspiration biopsy of the thyroid is useful in conjunction with clinical evaluation and serologic studies for the diagnosis of lymphocytic thyroiditis.

Histologic examination of thyroid tissue demonstrates variable infiltration of the entire gland with lymphocytes. Germinal lymphoid centers are characteristic and destruction and distortion of normal thyroid follicles are apparent. The thyroid cells remain intact but are hypertrophied, although the usual heterogeneity of small, enlarged thyroid follicles, some containing flat epithelium, can also be seen. In advanced cases, there is almost complete destruction of normal thyroid tissue, with replacement by lymphocytes or fibrous tissue.

When the disease produces hypothyroidism, a slight increase in plasma thyroid-stimulating hormone (TSH) concentration can usually be demonstrated in the early phase, followed by a decrease in serum T4 and eventually by a decrease in serum T3 levels. Antithyroglobulin and/or antithyroid microsomal antibodies are found in moderate to high titers in more than 50% of patients, but the presence of antimicrosomal antibodies is considered to be more diagnostic.

Antibodies directed against thyroid microsomal antigen (thyroid peroxidase antibody [anti-TPO]) can be detected by various techniques (Table 28-4). Chemiluminescent immunoassay is typically performed to detect anti-TPO autoantibodies. TPO plays a significant role in the biosynthesis of thyroid hormones by catalyzing the iodination of tyrosyl residues in thyroglobulin and the coupling of iodotyrosyl residues to form T4 and T3. Autoantibodies produced against TPO are capable of inhibiting enzyme activity. They are also complement-fixing antibodies that can induce cytotoxic changes in cells and consequently cause thyroid dysfunction. More than 90% of patients with autoimmune thyroiditis (Hashimoto’s thyroiditis) have anti-TPO. Antibodies to TPO have also been found in most patients with idiopathic hypothyroidism (85%) and Graves’ disease (50%).

Table 28-4

Antithyroid Antibody Tests

Antigen Test to Identify Antibody
Thyroglobulin Indirect immunofluorescence on fixed thyroid tissues
Tanned RBC hemagglutination
Immunometric assays (IMAs) or sandwich methods
Radioimmunoassay (RIA)
Microsomal antigen Enzyme-linked immunosorbent assay (ELISA)
Second colloid antigen (CA2) Indirect immunofluorescence
Thyroid membrane receptors LATS
LATS-P
In vitro assays for thyroid-stimulating immunoglobulin (TSI) or TSH–binding inhibition (TBI)
Triiodothyronine (total T3) RIA using different separation methods
Electrophoresis with radioactive-labeled thyronines

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Pancreatic Disorders

The autoimmune forms of diabetes include type 1 diabetes (T1D), estimated at 5% to 10% of those with diabetes, and latent autoimmune diabetes in adults (LADA), estimated to be 5% to 10% of those diagnosed with type 2 diabetes (T2D). It is now believed that some overlap exists between T1D and T2D. A subset of adult patients diagnosed with T2D actually have LADA.

Insulin-Dependent Diabetes Mellitus

Etiology

Insulin-dependent diabetes mellitus (IDDM), or type 1 diabetes mellitus (T1D), is a disorder of deficient insulin production caused by immune destruction of the B cells of the pancreatic islets. The only definitively identified environmental factor causing T1D is congenital rubella infection. Reports of an association between diabetes and infection with coxsackievirus B and several other viruses have suggested other triggers for the disease.

Genetic susceptibility factors have been identified. T1D is associated with HLA-DR3, DR4, DQ2, and DQ8 antigens. About 90% of white patients with T1D have one or both DR antigens. The presence of both DR3 and DR4 antigens yields an even higher risk of disease development than the additive susceptibility from either antigen, suggesting that other MHC-related genes may be involved in its pathogenesis. Another HLA antigen, DR2, is found less frequently in people with diabetes than in the general population, indicating that this antigen is associated with some type of protective effect. HLA-DQw8 is associated with a twofold to sixfold increased risk for diabetes. Several lines of investigation have implicated the CD4+ T lymphocyte as central in the immune process that leads to the development of diabetes.

Immunologic Manifestations

T cells of the CD4+ type are responsible for initiating the immune response to the islets that results in islet cell autoantibodies and B cell destruction. Patients with T1D have the following types of autoantibodies (Box 28-4):

Box 28-4   Autoantibody Assays to Differentiate Type 1 Diabetes

Assay Characteristic
Insulin autoantibodies (IAA) Autoantibodies specific for beta cells of the pancreas; may aid in proband diagnosis or predict development of type 2 diabetes
Glutamic acid decarboxylase autoantibodies Aid in the diagnosis and confirmation of type 1 diabetes; may be found in patients who eventually develop type 1 diabetes
Islet antigen-2 autoantibodies Associated with type 1 diabetes; may be present in patients years before the onset of clinical symptoms

American Diabetic Association (2008):

United States Preventive Services Task Force (USPSTF; 2008):

Antibodies reacting with the cells of the pancreatic islets have been found in patients with diabetes accompanying autoimmune endocrine disorders. Autoantibodies to islet-related antigens precede the development of clinical T1D by a prolonged period, often several years. A higher incidence of these anti–islet cell antibodies, however, has been demonstrated in T1D patients.

An immunoglobulin in the sera of patients with insulin-resistant diabetes appears to bind to a tissue receptor for insulin, which prevents some of the biological effects of insulin. In addition, antibodies that bind to and possibly kill pancreatic islet cells have been found in most young patients with T1D.

A small subgroup of patients with T1D has demonstrated antireceptor antibody (InR), an IgG class of antibodies directed against the insulin receptor. Antibodies to InR may be directed to the binding site or to determinants away from the binding site for insulin. This condition is predominant in nonwhite females of all ages.

IA-2 is directed against a phosphatase-type transmembrane 37-kDa islet beta cell antigen (ICA512).

Autoimmune Pancreatitis

Autoimmune pancreatitis is a heterogeneous disease. This type of chronic pancreatitis is characterized by an autoimmune inflammatory process in which prominent lymphocyte infiltration with associated fibrosis of the pancreas causes organ dysfunction.

Adrenal Glands

Idiopathic adrenal atrophy is the primary cause of Addison’s disease. It is believed that many of these cases have an autoimmune cause. Women are afflicted twice as often as men. The disease usually presents in the third or fourth decade of life. Although a great potential exists for morbidity, it has a relatively low incidence. The adult form of Addison’s disease is associated with HLA class II antigens DR3 and DR4.

Idiopathic Addison’s disease is usually diagnosed in patients because of low serum cortisol levels in the presence of elevated levels of corticotropin. Approximately 80% of patients manifest serum antibodies against cortical elements, probably microsomal. Some patients demonstrate antibodies against adrenal cell surfaces. These antibodies generally bind to components in the adrenal cortex but affect only individual zones. Antibodies are generally low in titer and are not a direct reflection of adrenal cell damage. In women with premature ovarian failure, autoimmune destruction of the ovarian stroma has been observed.

Pituitary Gland

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