Cellular and Molecular Pathogenic Mechanisms of Type I Diabetes

Abstract

Cumulative evidence suggests that Type Ⅰ Diabetes (Insulin-dependent diabetes mellitus: IDDM) results from progressive destruction of insulin producing pancreatic β-cells. Genetic susceptibility appears to be a prerequisite for the development of IDDM but, as the concordance rate for IDDM between identical twins approaches only 40%, environmental factors must also be involved in the clinical expression of the disease. Humoral autoimmunity precedes the onset of IDDM; however, it appears that the islet cell autoantibodies detected in the sera of patients with IDDM are a secondary phenomenon, generated by autoantigens released from damaged β-cells. The presence of these autoantibodies is valuable for the prediction and diagonosis of IDDM. Indications of the involvement of cell-mediated autoimmune responses in the pathogenesis of IDDM have come from autopsies performed on patients who have died from acute onset diabetes. Their pancreata show CD8+-rich lymphocytic infiltrates, which also contain macrophages, CD4+ T-cells, and natural killer cells. In animal models for IDDM, such as the BioBreeding (BB) rat and the non-obese diabetic (NOD) mouse, macrophages and CD4 + and CD8 + T-cells appear to be involved in the destruction of pancreatic β-cells. Macrophages play an important role in the initiation of insulitis, as evidenced by the prevention of further autoimmune precesses when they are inactivated. Several β-cell autoantigens, including a 64 kD protein (glutamic acid decarboxylase (GAD)), 37 kD/40 kD tryptic fragments of 64 kD protein, a 38 kD protein, a 52 kD protein, and a 69 kD heat shock protein, have been identified, although the precise roles of these β-cell autoantigens in the pathogenesis of IDDM have not been elucidated. It has been hypothesized that presentation of β-cell autoantigens, released during spontaneous turnover of β-cells, through antigen presenting cells, such as macrophages and dendritic cells, to CD4+ T helper cells, in conjuntion with MHC class D molecules, might be the initial step in the development of autoimmune IDDM. Activated CD4+ helper T-cells can secrete cytokines, such as interleudin-2. While this process is taking place, β-cell autoantigen-specific CD8+ precytotoxic T-cells may be recruited to the islets and differentiated into effector cells by the interleukin-2 and other cytokines released by CD4 + T helper cells. The autoantigen-specific CD8+ cytotoxic T-cells, as final effectors, may recognize the antigens expressed on the many unaffected β-cells, in conjuntion with MHC class I molecules. Free radicals and cytokines, such as interleukin-1, released by macrophages may act synergistically with the CD8+ effector T-cells, leading to the destruction of pancreatic β-cells. Development of autoimmune IDDM can be prevented by either induction of immunological tolerance using β-cell autoantigens or by induction of suppressor T-cells by microbial agents or bacterial products. In addition, T-cell receptor diversity in the pathogenesis of IDDM, use of transgenic mice for studies on diabetes, and induction of immunological tolerance will also be discussed in this chapter.