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.

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).

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:

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.

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

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

Etiology

The exact causative mechanism is unknown but is believed to be related to an autoimmune process in which the development of circulating cytotoxic antibodies eventually destroys the thyroid gland, producing hypothyroidism. This disorder is associated with the presence of human leukocyte antigen (HLA)–DR4 and HLA-DR5. However, these associations are not consistent in different races and ethnic groups.

Epidemiology

Lymphoid thyroiditis can occur at any age but is first diagnosed most often in the third to fifth decades of life; it is much more common in women than in men. The fibrous variant of the disease is more often present in middle-aged and older patients.

The mode of inheritance is unknown. However, a genetic tendency to inherit the trait for the development of antibodies against the thyroid gland is highly possible. It is common to have multiple members of a family develop the same disease (e.g., Graves’ disease, lymphoid 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

• Thyroid microsome

• Second colloid antigen (CA2 antigen)

• Thyroid membrane receptors

• Thyronine (T₄) and triiodothyronine (T₃)

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.

Thyroid Microsomes

Antibodies directed against thyroid microsomes, antithyroid microsomal antibodies, or antithyroperoxidase antibodies (TPO Abs) can be detected in about 7% of the population, with titers ranging from 1:100 to 1:1600. Even a low titer of antithyroid antibodies correlates with a degree of thyroid involvement by an autoimmune process. The absence of antibodies has been documented in diagnosed cases of autoimmune thyroiditis, which may be explained by special characteristics of the antibody, or because it forms complexes with thyroglobulins in the circulation and escapes detection. The presence of these circulating complexes has been documented in patients with thyroid autoimmune disorders.

Second Colloid Antigen

CA2 antigen is directed against a colloid protein and can be detected by immunofluorescent examination. Antibody to CA2 is present in about 50% of patients who have subacute thyroiditis, and it is detectable in some patients with Hashimoto’s thyroiditis whose sera show no other evidence of abnormal antibodies.

Thyroid Membrane Receptors

The thyroid membrane receptors are a group of immunoglobulin G (IgG) antibodies that interact with receptors on thyroid membranes. They often produce hyperthyroidism that manifests itself clinically, chemically, and histologically. At present, classification of these IgG antibodies is operational, based on their method of detection. Long-acting thyroid stimulator (LATS) and long-acting thyroid stimulator protector (LATS-P) assays are of importance.

Thyronine and Triiodothyronine

Antibodies to T₄ and T₃ have been found in several patients, most of whom had evidence of a thyroid autoimmune process such as goiter or hypothyroidism. In these cases, the underlying autoimmune process is most likely responsible for the hypothyroidism rather than hormone binding by the circulating antithyronine antibodies.

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

Graves’ Disease

Graves’ disease is a form of hyperthyroidism. This disease is most likely if a patient has signs and symptoms of hyperthyroidism. Laboratory chemistry assays usually demonstrate low TSH and elevated free T₄ levels. Of patients with Graves’ disease, 50% exhibit thyroid peroxidase antibody (anti-TPO). TSH receptor antibody (TRAb) can discriminate between Graves’ disease and toxic nodular goiter. In addition, thyroid-stimulating immunoglobulin can detect thyroid antibodies for diagnosing Graves’ disease.

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.

Epidemiology

T1D was previously called juvenile-onset diabetes because of when it often presents; 10% of people with diabetes have T1D and approximately 10,000 new cases are diagnosed each year. Most patients develop T1D in childhood or early adolescence, but it may occur at any age. Approximately 95% of patients who develop clinical diabetes before age 30 years have T1D.

Signs and Symptoms

The central clinical feature is the requirement for exogenous insulin to maintain euglycemia.

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):

^•Type 1 diabetes results typically have antibodies and low C-peptide levels.

^•Absence of antibodies or normal C-peptide levels does not rule out type 1, but likelihood of type 1 diabetes is low.

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

^•C-peptide testing—use to confirm lack of insulin production, suggesting type 1 diabetes.

^•Use of C-peptide levels or insulin levels to diagnose type 1 diabetes is not recommended.

• Insulin autoantibodies (IAAs)

• Glutamic acid decarboxylase (GAD) autoantibodies

• Islet cell antigen-2 (IA-2)

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).

Latent Autoimmune Diabetes in Adults

LADA is now recognized as a slowly developing form of autoimmune diabetes found in patients who are older than 35 years of age. LADA is frequently misdiagnosed as type 2 diabetes. LADA patients progress more rapidly to insulin dependence (T1D) than the typical T2D patient.

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.

Etiology

Although the cause of the disorder is unknown, it is thought to be a systemic autoimmune disorder. It is frequently associated with other autoimmune disorders (e.g., RA).

Epidemiology

Autoimmune pancreatitis is rare, but an increasing number of cases has been reported since 2000. Although this condition can occur in both genders, it is at least twice as common in men as women. Most patients are older than 50 years at diagnosis.

Signs and Symptoms

Symptoms are variable. Many patients have jaundice; some have abdominal pain. Histologic examination of pancreatic tissue reveals a collar-like periductal infiltrate composed of lymphocytes and plasma cells. Computed tomography (CT) typically reveals a diffuse enlargement of the pancreas, with a halo around its peripheral rim. Various findings on imaging radiography are correlated with serologic and histologic analyses. It is important to diagnose autoimmune pancreatitis correctly on the basis of imaging, histology, and serology because it can mimic pancreatic cancer.

Immunologic Manifestations

In the Japanese population, an association between HLA haplotype DRB1∗0405-DQB1∗0401 has been observed. Immunologic abnormalities include the following:

• Hypergammaglobulinemia (elevated serum IgG or gamma globulin level) in patients with enhanced peripheral rim halo of the pancreas on CT

• Elevated serum IgG4 concentrations in patients with a diffusely enlarged pancreas

• Autoantibodies against carbonic anhydrase II (ACA II), lactoferrin (antilactoferrin antibody [ALA]), anti–smooth muscle antibody (ASMA), or ANA

• Increased number of CD4+ T lymphocytes in peripheral blood

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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