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 sub set 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 pro duction 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 1):
• Insulin autoantibodies (IAAs)
• Glutamic acid decarboxylase (GAD) autoantibodies
• Islet cell antigen-2 (IA-2)
Box1. Autoantibody Assays to Differentiate Type 1 Diabetes*
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 auto immune 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 com ponents 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 dis order that causes a rapid decline in pituitary function. This dis order 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.
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