As with most autoimmune diseases, the pathogenesis of type 1 diabetes involves genetic susceptibility and environmental factors. Genome-wide association studies have identified over 20 susceptibility loci for type 1 diabetes. Of these, the strongest association is with class II MHC (HLA-DR) genes. Between 90% and 95% of white patients with type 1 diabetes have HLA-DR3, or DR4, or both, in contrast with about 40% of normal subjects, and 40% to 50% of patients are DR3/DR4 heterozygotes, in contrast with 5% of normal subjects. Of note, however, most individuals who inherit these HLA alleles do not develop diabetes, indicating that these genes contribute to the disease but do not, by themselves, cause it. Several non-HLA genes also increase susceptibility to type 1 diabetes, including polymorphisms within the gene encoding (?) Precipitating event Genetic Overt loss of release insulin release
Fig.20.22Stagesinthedevelopmentoftype1diabetesmellitus.Thestagesarelistedfromlefttoright,andhypotheticalβ cellmassisplottedagainstage.(From Eisenbarth GE: Type 1 diabetes—a chronic autoimmune disease. NEnglJMed314:1360, 1986.) insulin itself, as well as CTLA4 and PTPN22. As discussed in Chapter 5, CTLA-4 is an inhibitory receptor of T cells, and PTPN-22 is a protein tyrosine phosphatase; both are thought to inhibit T-cell responses, so polymorphisms that interfere with their functional activity are expected to set the stage for excessive T-cell activation. Polymorphisms in the insulin gene may reduce its expression in the thymus, thus reducing the elimination of T cells reactive with this self protein (Chapter 5).
Additional evidence suggests that environmental factors, especially infections, are involved in type 1 diabetes. It has been proposed that certain viruses (mumps, rubella, and coxsackie B viruses, in particular) may be initiating triggers, perhaps because some viral antigens mimic beta cell antigens, leading to bystander damage to the islets, but this idea is not conclusively established. More recent advances in elucidating environmental contributions to the pathogenesis of type 1 diabetes have come from studies of the human microbiome. Studies in diabetic children have shown evidence for “intestinal dysbiosis” (change in composition of usual commensal flora), with reduction in diversity of the microbiome, and reduced abundance of certain bacterial species during progression of subclinical to clinical stages of the disease. Whether this is a cause or consequence of hyperglycemia remains unclear.
The fundamental immune abnormality in type 1 diabetes is a failure of self-tolerance in T cells specific for beta cell antigens. This failure of tolerance may result from some combination of defective clonal deletion of self-reactive T cells in the thymus and abnormalities of regulatory T cells (Tregs) that normally dampen effector T-cell responses (Chapter 5). One consequence of loss of self tolerance is the production of autoantibodies against a variety of beta cell antigens, including insulin and the beta cell enzyme glutamic acid decarboxylase, which are detected in the blood of 70% to 80% of patients. In the rare cases in which the pancreatic lesions have been examined http://ebooksmedicine.net