Epidemiology

Scleroderma occurs in all races and is three times more frequent in women than men.

Signs and Symptoms

Scleroderma is characterized by fibrosis in the skin and internal organs and by arterial occlusions with a distinct proliferative pattern. Initial symptoms usually appear in the third decade of life. Raynaud’s phenomenon is the most frequent manifestation. The disease is slowly progressive and chronically disabling, but can be rapidly progressive and fatal.

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.

Signs and Symptoms

Systemic sclerosis is a chronic multisystem disorder that causes thickening of the skin (scleroderma) and involves other organ systems.

In more than 50% of patients, Raynaud’s phenomenon occurs before the onset of other manifestations. Skin manifestations can proceed through the stages of pitting edema, a sclerotic hidebound stage, and a final stage of atrophy or softening and a return toward normal. Articular complaints are common. Hypomotility of the gastrointestinal tract is the second most common clinical feature.

Eosinophilia-Myalgia Syndrome

Many people exposed to the agent causing eosinophilia-myalgia syndrome (EMS) may develop illness. Patients develop severe myalgia. More than 50% of patients with EMS develop scleroderma-like manifestations.

The most important predictor of EMS is the ingestion of contaminated l-tryptophan. The association of ingestion of l-tryptophan with a systemic disease now called EMS was first observed in 1989. Some patients have died from the l-tryptophan.

l-Tryptophan was widely used after it was introduced in 1974 as an over-the-counter nostrum for various ailments (e.g., insomnia, premenstrual syndrome, anxiety). Medical professionals also recommended its use for neuropsychiatric or fibromyalgia disorders.

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:

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%).

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.

Insulin-Dependent Diabetes Mellitus

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.

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

Sheehan’s syndrome, lymphocytic adenohypophysitis, is a disorder that causes a rapid decline in pituitary function. This disorder is most frequently seen in postpartum women. Antibodies against pituitary cells are observed in some patients. The disorder is distinguished by a mononuclear infiltrate of the pituitary gland and hypophysis.

Parathyroid Gland

Idiopathic hypoparathyroidism occurs as a childhood disorder in type I polyglandular syndrome and, less often, as an isolated disorder in adults. It is associated with complement-mediated cytotoxicity of parathyroid cells, indicating a specific immune response to the parathyroid. Several antigens have been associated with this disorder, including endothelial cell proteins and mitochondria.

Polyglandular Syndromes

Three syndromes of associated endocrinopathies have been defined as the polyglandular syndromes. Type I polyglandular syndrome involves mucocutaneous candidiasis and associated endocrinopathies that begin in early childhood. Patients initially develop candidiasis and hypoparathyroidism, but more than 50% also develop Addison’s disease. Gonadal failure, alopecia, and chronic hepatitis are also seen. Patients have organ-specific autoantibodies and poorly defined defects in cell-mediated immunity.

Type II polyglandular syndrome involves the combined occurrence of IDDM or autoimmune thyroid disease with Addison’s disease. It is also called Schmidt’s syndrome. This type of disorder is seen primarily in women in the second or third decade of life. Most cases are familial, but the mode of inheritance is unknown. There is a strong association with HLA-DR3.

Type III polyglandular syndrome is defined as autoimmune thyroid disease occurring with two other autoimmune disorders, including IDDM, pernicious anemia, and a nonendocrine, organ-specific autoimmune disorder, such as myasthenia gravis. These patients do not have Addison’s disease. The HLA-DR3 allele is present in more than 50% of cases. Patients in this category are overwhelmingly female.

Etiology

Sjögren’s syndrome is a chronic inflammatory disease of unknown cause that affects lacrimal, salivary, and other excretory glands. It results in keratoconjunctivitis sicca and xerostomia.

As with RA and SLE, causative factors include infection, abnormalities of immune regulation, and genetic factors. Development of Sjögren’s syndrome is strongly associated with HLA-B8 and HLA-DR3. An infectious origin has been suggested. Clear evidence for excessive B cell activity has been demonstrated, but it is not known whether this is caused by B or T cell abnormalities.

Epidemiology

A primary form is not associated with other diseases; a secondary form is associated with RA and other connective tissue diseases. About 90% of patients are women. A 44-fold increased incidence of lymphoma has been noted in patients with Sjögren’s syndrome.

Signs and Symptoms

The main clinical manifestations of Sjögren’s syndrome are dry eyes, dry mouth, and recurrent salivary gland pain and swelling (Table 28-5). Hoarseness, chronic cough, and increased incidence of infection have been observed. Dryness of the vagina leads to dyspareunia and itching. Dysphagia and atrophic gastritis can also be present. Extraglandular involvement results in interstitial pneumonitis and fibrosis. Renal tubular acidosis and vasculitis involving the peripheral nerves and central nervous system (CNS) can also result from Sjögren’s syndrome.

Immunologic Manifestations

The immunologic characteristics of Sjögren’s syndrome include hypergammaglobulinemia, ANAs, rheumatoid factor, autoantibodies to salivary duct and other antigens, and lymphocyte and plasma cell infiltration of involved tissue. Antibodies are usually polyclonal and may result in the hyperviscosity syndrome and hypergammaglobulinemic purpura. Speckled or homogeneous ANA patterns are present in 65% of patients and occur more frequently in primary Sjögren’s syndrome. Antibodies to Sjögren’s syndrome A antigen have been associated with vasculitis in primary Sjögren’s syndrome. Antibodies to Sjögren’s syndrome B antigen are almost always found in association with Sjögren’s syndrome A antigen and only occur in SLE and Sjögren’s syndrome. Rheumatoid factor is found in 90% of cases. A rather new autoantibody, anti–α-fodrin, has been found in the sera of most patients with primary Sjögren’s syndrome. This antibody may be pathophysiologically associated with some extraglandular manifestations characteristically seen in patients with Sjögren’s syndrome.

Autoantibodies to salivary duct antigens are frequently detected in patients with secondary Sjögren’s syndrome. They are also common in 25% of patients with RA without Sjögren’s syndrome. Mitochondrial antibodies are detected in 10% of patients with primary Sjögren’s syndrome and rarely in patients with secondary Sjögren’s syndrome and RA. Patients with primary Sjögren’s syndrome also have higher levels of antibodies to the thyroid gland, gastric parietal cells, pancreatic epithelial cells, and smooth muscle. Lymphocytic infiltration of the exocrine glands of the eyes, mouth, nose, lower respiratory tract, gastrointestinal (GI) tract, and vagina occurs. The infiltrate is composed of B and T cells. In tissue culture, these cells produce large amounts of IgM and IgG. T cells are predominantly helper cells.

Immunologic Findings

Antibodies against a lipoprotein cytoplasmic component of gastric parietal cells can be detected by immunofluorescence in up to 90% of PA patients and in about 60% of patients with atrophic gastritis without hematologic abnormalities. These antibodies may also be demonstrated in patients with other autoimmune diseases, such as thyroiditis. In addition, antibodies can be found in asymptomatic patients and in those older than 60 years.

Histologic Findings

Atrophic gastritis, which almost always accompanies PA, is characterized by destruction of the gastric mucosa, with lymphocytic infiltration and the absence of parietal and chief cells. The lesions are associated with decreased synthesis of gastric acid and intrinsic factor. Intrinsic factor normally binds ingested vitamin B₁₂ at one site and binds to receptors in the distal ileum at another site. Therefore, vitamin B₁₂ transport across the ileum is affected.

Vitamin B₁₂ (Cobalamin) Transport

Cobalamin transport is mediated by three different binding proteins capable of binding the vitamin at its required physiologic concentrations—intrinsic factor, transcobalamin II, and the R proteins (Table 28-6).

Intrinsic factor (IF), a glycoprotein, is synthesized and secreted by the parietal cells of the mucosa in the fundus region of the stomach in several mammalian species, including human beings. In a healthy state, the amounts of IF secreted by the stomach greatly exceed the quantities required to bind ingested cobalamin in its coenzyme forms. At a very acidic pH, cobalamin splits from dietary protein and combines with IF to form a vitamin-IF complex. Binding by IF is extraordinarily specific and is lost with even slight changes in the cobalamin molecule. This complex is stable and remains unabsorbed until it reaches the ileum. In the ileum, the vitamin-IF complex attaches to specific receptor sites present only on the outer surface of microvillous membranes of ileal enterocytes.

The release of this complex from the mucosal cells, with subsequent transport to the tissues, depends on transcobalamin II (TCII). TCII is a plasma polypeptide synthesized by the liver and probably by several other tissues. TCII, which turns over very rapidly in plasma, acts as the acceptor and principal carrier of the vitamin to the liver and other tissues, as with IF. Receptors for TCII are observed on the plasma membranes of a wide variety of cells. TCII is also capable of binding a few unusual cobalamin analogues. TCII also stimulates cobalamin uptake by reticulocytes.

The R proteins compose an antigenically cross-reactive group of cobalamin-binding glycoproteins. The R proteins bind cobalamin and various cobalamin analogues. Their function is unknown, but they appear to serve as storage sites and as a means of eliminating excess cobalamin and unwanted analogues from the blood circulation through receptor sites on liver cells. R proteins are produced by leukocytes and perhaps other tissues. They are present in plasma as transcobalamin I and transcobalamin III, as well as in saliva, milk, and other body fluids. Transcobalamin I probably serves only as a backup transport system for endogenous cobalamin. Endogenous vitamin is synthesized in the human GI tract by bacterial action, but none is adsorbed.

Autoimmune Liver Disease

Autoimmune processes are believed to be the possible cause of chronic liver disease. Hypergammaglobulinemia, prominent lymphocyte and plasma cell inflammation of the liver, and the presence of one or more circulating tissue antibodies are typically manifested. These manifestations suggest an organ-localized autoimmune pathogenesis.

Autoimmune hepatitis (AIH), formerly known as chronic active hepatitis is an inflammatory condition most common in young women. It is characterized by prominent lymphocyte and plasma cell inflammatory changes, which start in the portal tracts. In some patients, this condition results from a chronic viral infection or inflammation, but in others a number of immunologic abnormalities are present to varying degrees in addition to hypergammaglobulinemia and an elevated erythrocyte sedimentation rate (ESR). A defect in immunoregulation is often demonstrated, which may lead to unrestrained immunoglobulin production.

Antinuclear autoantibody using HEp-2 cells will have differing levels of reactivity depending on factors such as the disease activity or multiple ANA specificities. A homogeneous staining pattern (see Color Plate 13) is the most frequent pattern particularly in active AIH. The frequency of positive ANA tests is about 70% in AIH. In remission, the frequency of ANA positivity decreases and the ANA pattern is replaced by a speckled pattern in almost 40% of cases. Other significant antibodies can include an atypical perinuclear ANCA (pANCA) in one type of AIH with a frequency of 65% positivity. In addition, AIH is characterized by autoantibodies to cytoskeletal proteins that support cellular structure, contractility, and locomotion: microfilaments. These autoantibodies to cytoskeleton can be studied by immunofluorescent light (IFL) methodology.

These patients display ANAs and anti–smooth muscle antibodies. A high and persistent titer of antismooth antibodies is suggestive of the autoimmune form of chronic active hepatitis or viral disorders such as infectious mononucleosis.

In some cases this disease is referred to as lupoid hepatitis.Patients with aggressive chronic active hepatitis have a poor prognosis, and a significant rate of mortality is reported 5 years after diagnosis.

Idiopathic Biliary Cirrhosis

Idiopathic biliary cirrhosis is a slowly progressive disease that starts as an apparently noninfectious inflammation in the bile ducts of young to middle-aged women. An increased familial incidence has been noted.

Patients exhibit increased serum IgM, depression of cellular immunity, with prominent decreases in suppressor T cells common, and associated autoimmune disorders. It is believed that tissue damage results from an unmodulated attack against host tissue antigens. Antimitochondrial antibodies directed against the cellular ultrastructures, mitochondria, can be displayed. A high titer of antimicrobial antibody strongly suggests primary biliary cirrhosis (PBC); an absence of mitochondrial antibodies is strong evidence against PBC. Other forms of liver disease, however, frequently exhibit low mitochondrial antibody titers.

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is the collective name given to Crohn’s disease (CD) and ulcerative colitis (UC). A major gene has been identified in these disorders. The Centers for Disease Control and Prevention (CDC) estimates that IBD, which is more common among Ashkenazi Jews than other groups, affects more than 1 million Americans. When researchers examined more than 300,000 single nucleotide polymorphisms (SNPs), the variations that occur when a nucleotide (molecular subunit of DNA) is altered, it was discovered that the frequency of variations in the receptor gene for interleukin-23 (IL-23) is significantly different for those with IBD. A coding variant that apparently protects against IBD is found less frequently in patients with IBD than in healthy patients.

Many factors (e.g., genetic susceptibility, diet) affect the onset and development of IBD. The crux of the disease is an abnormal immune response to harmless bacteria in the gut that benefits the host by providing energy and nutrients. In IBD patients, these microorganisms become a target for attack by the immune system. The inflammation seen in IBD patients has been linked to the following:

Studies have suggested that one cytokine, IL-12, is a crucial mediator of this disease. IL-12 causes inflammation by activating a class of different immune cells, type 1 helper T (Th1) cells, which in turn secrete proinflammatory molecules such as interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). These pathways have been suggested as therapeutic targets for human IBD.

The discovery of IL-23 has led some to question the central role of IL-12 and Th1 cells in IBD. Newer studies have indicated that IL-12 and IL-23 are closely related molecules that share a common subunit known as p40. IL-23 has been associated with the activation of a new class of proinflammatory T cells called Th17. These cells secrete the proinflammatory cytokine IL-17, which mediates the inflammatory response in organs such as the brain and joints. Intestinal inflammation is still associated with large increases in IL-17 production in the intestines. Innate immune cells present in inflamed intestines (e.g., granulocytes, monocytes) have been found to contribute to the increased production of IL-17.

Celiac Disease

Celiac disease is a lifelong autoimmune intestinal disorder found in individuals who are genetically susceptible. There are also associated clinical disorders of an immune basis (Box 28-5). Damage to the mucosal surface of the small intestine is caused by an immunologically toxic reaction to the ingestion of gluten and interferes with the absorption of nutrients. Celiac disease is unique in that a specific food component, gluten, has been identified as the trigger. Gluten is the common name for the offending proteins in specific cereal grains that are harmful to those with celiac disease. These proteins are found in all forms of wheat (e.g., durum, semolina, spelt, kamut, einkorn, faro) and related grains (rye, barley, triticale) and must be eliminated.

In recent years, key laboratory diagnostic assays comprise testing for autoantibodies against tissue transglutaminase (anti-tTG) or endomysium (EmA) antibodies against deamidated gliadin peptides and the celiac disease (CD)-associated human leukocyte antigens (HLA) DQ2 and DQ8.

New European guidelines have results in two algorithms of testing: symptomatic patients versus asymptomatic patients. For symptomatic patients, the algorithm begins with determination of specific anti-TG antibodies of class IgA in parallel with total IgA or specific IgG measured in parallel testing. If the anti-tTG antibody titer is more than 10 above the upper normal limit,the endomysium (EmA) is positive, and compatible HLA results are found, it is not necessary to perform a small bowel biopsy as was done in the past. Diagnostic tests should be done on individuals on a gluten-containing diet. A biopsy is needed only if serologic and genetic findings are inconclusive. In asymptomatic patients with a high risk factor for CD, e.g., patients with diabetes type 1, Down’s syndrome, autoimmune thyroid or liver disease, Turner’s syndrome, Williams’ syndrome, or selective Ig A deficiency and patients with first-degree relatives of CD patients, HLA-DQ2/DQ8 determination is the first-line of analysis that can be followed up with specific antibody testing. Asymptomatic patients require a duodenal biopsy for a definite diagnosis of CD.

Other Gastrointestinal Tract Immunologic Disorders

Examples of other immunologic disorders related to the GI and hepatobiliary tracts include GI allergy, Whipple’s disease, immunoproliferative intestinal disease (alpha heavy-chain disease), and infectious hepatitis (see Chapter 23). Allergy of the GI tract is an IgE-mediated hypersensitivity to food substances that involves the GI tract and, in some cases, the skin and lungs. Examples of systemic autoimmune disease caused by mucosal immune abnormalities are IgA nephropathy (Berger’s disease), Henoch-Schönlein purpura, and diseases associated with circulating IgA complexes in the kidney and vasculature. Immunoproliferative intestinal disease is characterized by monoclonal B cells that produce an aberrant alpha heavy chain.

Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia can be classified into the following four groups:

Idiopathic Thrombocytopenic Purpura

Idiopathic thrombocytopenic purpura is now also known as immunologic thrombocytopenic purpura (ITP). Patients with ITP usually demonstrate petechiae, bruising, menorrhagia, and bleeding after minor trauma. ITP may be acute or chronic. Children are most often affected with the acute type, whereas adults predominantly experience the chronic type. This common disorder may complicate other antibody-associated disorders such as SLE.

Thrombocytopenia, a condition of absent or severely decreased platelets (<10-20 × 10⁹/L), may result from a wide variety of conditions, such as after extracorporeal circulation in cardiac bypass surgery or from alcoholic liver disease. However, most thrombocytopenic conditions can be classified into the following three major categories:

Decreased platelet production may result from invasion of the bone marrow by neoplastic cells and is usually not associated with an immunologic cause. Disorders of platelet distribution are associated with a sequestering of platelets in the spleen for various nonimmunologic reasons. Increased destruction or use of platelets, however, is associated with immunologic mechanisms. These mechanisms of destruction are caused by antigens, antibodies, or complement.

Drugs or foreign substances that can cause platelet destruction include quinidine, sulfonamide derivatives, heroin, morphine, and snake venom. Sulfonamide derivative reactions involve the interaction of platelet antigens with drug antibodies. Morphine reactions involve the activation of complement.

Bacterial sepsis causes increased destruction of platelets resulting from the attachment of platelets to bacterial antigen-antibody immune complexes. Certain microbial antigens may initially attach to platelets, followed by specific antibodies to the microorganism. This mechanism has been reported to cause the thrombocytopenia that frequently complicates Plasmodium falciparum malaria.

Antibodies of autoimmune or isoimmune origin may cause increased destruction of platelets. Examples of thrombocytopenias of isoimmune origin include posttransfusion purpura and isoimmune neonatal thrombocytopenia. Neonatal autoimmune thrombocytopenia is a condition caused by immunization of a pregnant female by a fetal platelet antigen and by transplacental passage of maternal IgG platelet antibodies. The antigen is inherited by the fetus from the father and is absent on maternal platelets. Posttransfusion purpura is a rare form of isoimmune thrombocytopenia.

Pernicious Anemia

Pernicious anemia is a megaloblastic anemia characterized by a variety of hematologic and chemical manifestations (Table 28-9). PA is caused by a deficiency of vitamin B₁₂ that results from the patient’s inability to secrete intrinsic factor. In autoimmune cases of PA, anti-IF or antiparietal antibodies have been reported. Demonstration of these antibodies supports the theory that PA is an autoimmune disorder. Nutritional disorders (e.g., vegan diet, gastric bypass surgery, AIDS, small bowel disorders, and competition for vitamin B₁₂) can be nonimmunological causes of PA.

Assays for anti-IF measure antibodies to IF. The presence of IF–blocking antibodies is diagnostic of PA. Antibodies can be demonstrated in about 60% of cases. Antiparietal cell assays measure antibodies to parietal cells (large cells on the margins of the peptic glands of the stomach). Most patients with PA (80%) have parietal cell antibodies. In the presence of these antibodies, gastric biopsy almost always demonstrates gastritis. Low antibody titers to parietal cells are often found with no clinical evidence of PA or atrophic gastritis and are sometimes seen in older patients.

Amyotrophic Lateral Sclerosis

Along with Alzheimer’s disease and Parkinson’s disease, ALS is one of the so-called degenerative diseases of the aging nervous system. The immune system has been implicated in ALS. Monoclonal paraproteinemia seems to be disproportionately frequent in patients with ALS. It has also been suggested that ALS patients have a higher incidence of lymphoproliferative disease—lymphoma, Waldenström’s macroglobulinemia, and myeloma. There also seems to be an increased frequency of antibodies to a neuronal ganglioside, GM-1.

Inflammatory Polyneuropathies

This group of idiopathic disorders, which includes the acute disorder Guillain-Barré syndrome (GBS), is characterized clinically by the subacute onset of generally symmetric weakness, ranging from modest lower extremity weakness to total, life-threatening involvement of motor and even cranial nerves. Sensory symptoms are less prominent. Unstable blood pressure and potentially fatal arrhythmias have also been observed. Progression of GBS can be rapid; however, most patients do recover.

The cause of GBS is unknown, but it is likely that an abnormal immune response against the peripheral nervous system (PNS) is involved. This may be triggered by an antecedent viral infection. There is infiltration of the PNS with lymphocytes and macrophages and patchy myelin destruction. Some patients display deposition of IgG, IgM, and IgA in PNS tissues. Greatly elevated immunoglobulin levels in the cerebrospinal fluid (CSF), sometimes with oligoclonal bands, suggests locally altered immunoregulation. The antigenic targets of these immunoglobulins remain unknown.

Myasthenia Gravis

Myasthenia gravis is a disorder of the neuromuscular junction characterized by neurophysiologic and immunologic abnormalities (Box 28-6). A postsynaptic defect is caused by a decrease in receptors for acetylcholine and frequently an anatomic defect in the neuromuscular junction plate. Acetylcholine receptor (AChR)–binding antibody is directed against acetylcholine receptors at neuromuscular junctions of skeletal muscle and AChR-blocking antibodies. The ligand bungarotoxin or acetylcholine is important in producing a neuromuscular block. About one third of patients with myasthenia gravis demonstrate AChR-blocking antibodies.

The role of these antibodies in producing disease is unclear. Complement-mediated, antibody-determined damage may be an important mechanism in myasthenia gravis because IgG, C3, and C9 can be demonstrated at the neuromuscular junction and the motor endplate is often abnormal. This suggests that antibody to AChR is capable of increasing the normal rate of degradation, resulting in fewer available receptors.

Multiple Sclerosis

Multiple sclerosis (MS) is the most common demyelinating disorder of the CNS related to abnormalities of the immune system. It is characterized by regions of demyelinization of varying size and age scattered throughout the white matter of the CNS. Demyelinization plaques have a propensity to form in the cerebrum, optic nerves, brainstem, spinal cord, and cerebellum.

Renal Disease Associated With Circulating Immune Complexes

Renal diseases associated with circulating immune complexes are caused by nonrenal antigens and their corresponding antibodies. These complexes are deposited in one or more of several loci in the glomerulus. Deposition may depend on the size and other characteristics of the complex. Studies have suggested that potentially damaging immune complexes may be formed in situ and involve antigens already present or fixed in the glomerulus. In addition, immune complex activation of complement in the glomerular basement membrane may be augmented by the presence of cells with receptors for C3 located in that area. Activation probably releases biologically active products such as chemotactic substances and causes an inflammatory type of tissue injury. A renal complication of this type can be manifested in SLE.

Membranoproliferative Glomerulonephritis

Another type of glomerular disease, membranoproliferative glomerulonephritis, is believed to be caused by nonimmunologically activated complement. Activation is thought to be analogous to the alternate pathway activation of C3 by certain bacterial products and polysaccharides.

Renal Disease Associated With Anti–Glomerular Basement Membrane Antibody

Anti–glomerular basement membrane (GBM) antibodies are directed against GBM of the glomerulus of the kidney (Fig. 28-3). These antibodies are induced in vivo against the basement membrane of the glomerulus and possibly that of the renal tubule or lung. The factors that stimulate antibody production are not well defined, but it appears likely that binding of drugs (e.g., methicillin), certain infectious agents, or renal damage caused by other immune mechanisms may lead to an immune antibody response. The end result may be direct damage to the bone marrow, with or without complement activation. Production of anti–bone marrow antibodies, however, appears to be self-limited and lasts for several weeks to months after removal of the inciting agent (i.e., by the kidney).

High antibody titers of anti-GMB are suggestive of Goodpasture’s disease, early SLE, or anti-GBM nephritis. The absence of antibodies, however, does not rule out Goodpasture’s disease. This type of renal disease represents less than 5% of glomerular disorders.

Tubulointerstitial Nephritis

Tubulointerstitial nephritis involving the renal tubules has been associated with a variety of causes, including immune complex–mediated disease. Precipitating factors can include drugs and possibly infection, as well as the involvement of transplanted kidneys.