The pathogenesis of type 1 diabetes mellitus - Type 1 diabetes mellitus is a chronic and prolonged autoimmune illness associated with the selective devastation of insulin-producing pancreatic β-cells (see the figure below). The onset of clinical sickness represents the end stage of β-cell damage leading to type 1 diabetes mellitus. Al Homsi and Lukic (1992) defined that several features and sign characterize type 1 diabetes mellitus as an autoimmune disease:
- Existence of accessory and immuno-competent cells in infiltrated pancreatic islets;
- Combination of susceptibility to illness with the class II (immune response) genes of the major histocompatibility complex (MHC; human leucocyte antigens HLA);
- Appearance of islet cell specific autoantibodies in the body.
- Modifications of T-cell-mediated immunoregulation, especially in CD4+ T cell compartment;
- The implication of monokines and TH1 cells producing interleukins in the sickness process;
- Response to immunotherapy, and;
- The frequent occurrence of another organ-specific autoimmune diseases in affected individuals or their family members.
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| pathogenesis of type 1 diabetes mellitus click to enlarge |
The pathogenesis of selective β-cell destruction within the islet in type 1 diabetes mellitus is hard to follow due to a clear heterogeneity of the pancreatic wounds and lesions. At the beginning of overt hyperglycemia, a mixture of pseudo atrophic islets with cells producing glycogen (a cells), pancreatic polypeptide (PP cells), somatostatin (d cells), normal islets, and islets conceiving both b-cells and infiltrating lymphocytes and monocytes may be visible. Lymphocytic penetration is found only in the islet containing residual β-cells and is likely that the chronicity with which type 1 diabetes mellitus develops mirrors this heterogeneity of islet lesions.
In contrast to this chronicity in the natural history of the disease, β-cells are rapidly damaged when the pancreas is transplanted from identical twin donors into their long-term diabetic twin mates in the nothingness of immunosuppression. In these cases, massive insulitis generates rapidly with infiltrating T lymphocytes indicating an anamnestic autoimmune reaction. Also, this observation also shows that the chronic time course in type 1 diabetes mellitus (but not in a transplanted pancreas) is a consequence of down regulatory phenomena taking part in the immunopathogenesis of the disease.
Activation of islet antigen - specific CD4+ T cells appear to be a decisive prerequisite for the development of diabetes in all animal models of type 1 diabetes mellitus. CD4+ islet-specific T-cell clones derived from diabetic NOD mice, when injected into prediabetic or non-diabetes-prone Fl mice, induce insulitis and diabetes. It was also informed that CD4+ T cells are enough to induce insulitis while CD8+ T cells provide the severity of the destruction. These findings together with the proof that insulitis in chronic graft versus host disease may happen in the lack of CD8+ T cells suggest that CD4+ T cells may be the only immuno-competent cells required in the illness process. However, it looks that only one subset of CD4+ T cells is responsible for disease induction.
CD4+ T cell bearing allo-antigen RT6 are absent in diabetes-prone BB rats and appear to protect AO rats from MLD-STZ induced diabetes. Down-regulation of diabetogenic autoimmune response by the spleen cells derived from animals treated with adjuvants could also be clarified by CD4+ T cell subsets interplay. High level of THI type cytokines IL-2 and interferon g are found to correlate Or/and to increase induction of autoimmune diabetes mellitus in experimental forms or models. The TH-1 type cells, and especially their product IFN-g, activate macrophages. In animal, models of type 1 diabetes mellitus electron microscopic studies of pancreata indicated that macrophages are the first cell type penetrating the islets. In vitro studies and studies on perfused pancreas prompt that Interleukin 1 (IL-1) and tumor necrosis factor (TNFa), two cytokines mainly generated by macrophages, induce structural changes of β-cells and suppression of their insulin releasing capacity.
However, it looks that IL-1 and TNF do not contribute appreciably to the cytotoxic activity of macrophages. Interferon g is also a potent activator of macrophages for nitric oxide synthesis. Recently, proof has been provided indicating that NO synthase action is involved in diabetes development. These data showed, for the first time, that nitric oxide may be a pathogenic element in auto-immunity and suggested a possibility that a new class of immuno-pharmacological agents, capable of modulating nitric oxide production may be tested in the prevention of type 1 diabetes mellitus development.
The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus by Ozougwu, J. C., Obimba, K. C., Belonwu, C. D., and Unakalamba, C. B.
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