Since Yoon et al. (131) isolated coxsackie B4 virus from the pancreas of a patient with type 1 diabetes, various viruses have been studied to examine their diabetogenic potential and to what extent viruses represent an environmental factor that contributes to the disease. The viral infection seems to be able to indirectly activate autoreactive T-cells that, in turn, can generate initial pancreatic tissue damage. Damaged P-cells release previously ignored self antigens that may activate an autoimmune process, rapidly promoting the generation of insulitis and, eventually, overt diabetes by immune-mediated P-cell killing. Viral infections could trigger type 1 diabetes through several mechanisms; for example, (1) sequence similarities between islet-cell GAD65 and coxsackie virus could cause immune attack against coxsackie virus to also target the beta cells, (2) enteroviral infections could sustain autoimmunity until a final "hit" results in P-cell destruction following lysis of the cells, (3) acute or chronic enteroviral infections of peri-insular tissue could lead to P-cell destruction from an abundance of free radicals (132), or (4) rapid replication of virus in P-cells may cause P-cell lysis, clearance of debris by lymphatic drainage to pancreatic lymph nodes where antigen presentation takes place, resulting in an autoimmune reaction to beta cell antigens (133). The relationship between coxsackie B virus infection and GAD65 autoimmunity has recently received the most attention. The sequence homology of an amino acid peptide between human GAD65 and the coxsackie virus p2-C protein provides the support of specific molecular mimicry (10,134). IA-2 is another molecular target of pancreatic islet autoimmunity in immune-mediated type 1 diabetes. The epitope spanning 805-820 amino acid was found to have 56% identity and 100% similarity over 9 amino acid with a sequence in VP7, a major immunogenic protein of human rotavirus (51,52). The role of virus antigen molecular mimicry in disease association and in the generation of insulitis remains to be clarified. It is also not clarified whether infection by one of the many viruses implicated in type 1 diabetes initiates or enhances the disease process.
Antigen-specific T-cell activation results in the differentiation of naive CD4+ Th cells into Th1 and Th2 clones based on their pattern of cytokine production and effector functions. Th1 cells produce IL-2 and IFN-y and promote cell-mediated responses and delayed-type hypersensitivity reactions. Th2 cells produce IL-4, IL-5, IL-10, and IL-13 and stimulate humoral immunity. It is speculated that the progression of type 1 diabetes from insulitis to overt diabetes may be controlled by Th1 rather than Th2 cells because human islets are primarily infiltrated by CD8+ T-cells. It has, therefore, been suggested that Th1 cytokines promote, whereas Th2 cytokines protect from the onset and progression of type 1 diabetes. However, this appear to be a serious oversimplification because in some cases Th2 cells and their cytokines may accelerate P-cell destruction. Although nothing is known in humans, the Th2-induced component of anti-P-cell immunity appeared to be mediated by local production of IL-10, but not IL-4, and accelerated the autoimmune destruction of P islets (135). Th2 cytokines, in particular IL-10, may promote necrosis through occlusion of the microvasculature, thereby reducing the viability of the larger islets. Th2 cytokines promote peri-insulitis and frank insulitis by enhancing major histocompatibility complex class II expression, thereby stimulating the accumulation of macrophages and B-cells (136).
It is evident that Th1 cells are not the sole mediators of islet P-cell destruction, that Th2 cells are not inhibitory or benign, as was previously suggested, because they are capable of inducing islet P-cell destruction, and that both Th1 and Th2 cytokines appear to cooperate in driving P-cell destruction. Th1-driven attacks are more rapid and aggressive and are sustained for a longer time period. This suggested that Th2-mediated attacks are responsible for an early phase of type 1 diabetes, whereas Th1-driven responses are responsible for the persistent and sustained attacks. Th1 lesions comprised focally confined insulitis consisting primarily of CD8+ and CD4+ T-cells, and islet P-cells die by apoptosis, thereby sparing surrounding exocrine tissue. In contrast, Th2 lesions were more dispersed and consisted primarily of macrophages, with a notable scarcity of T-cells and P-cells die by necrosis. Also, there is an accumulation of fibroblasts and the generation of extensive extracellular matrix and adipose tissue in Th2 lesions, which subsequently leads to tissue necrosis (137). The above represents speculations primarly based on animal studies. Studies in humans are required to dissect the mechanisms by which T-cells may kill P-cells. It is hypothesized that future immunotherapy must take into consideration the delicate balance between Th1 and Th2 cells during distinct phases of insulitis and type 1 diabetes development.
Mediators of P-cell destruction include factors secreted from CD8 T-cell granules (e.g., perforin and granzymes), T-cell surface molecules (e.g., Fas-L, TNF, and other TNF family members), as well as secreted cytokines (e.g., TNF, IFN-y). All of these mediators are known to induce DNA fragmentation and the morphological changes of apoptosis through complex signaling cascades that involve the activation of cystein proteases or caspases (138). It was investigated whether or not the Fas-FasL system was involved in insulitis. Pancreas biopsy specimens showed insulitis in 6/13 of recent-onset patients. In these six patients, Fas was expressed in both the islets and infiltrating cells but not in either cell type in the seven other patients without insulitis. Double immuno-staining revealed that FasL-positive cells was primarily CD8+ but could also be found on macrophages and CD4+ cells. It was speculated that Fas on P-cells may interact with FasL on infiltrating cells to trigger apoptotic P-cell death in inflamed islets (139).
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