Pujol-Borrell, Ricardo; (1990) Modulation of HLA antigen expression in the endocrine cells of the human pancreas. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

HLA Class II molecules are surface glycoproteins which are essential in the initiation of immune responses to specific antigens. Work on thyroid autoimmune disease has suggested that the induction of Class II expression in epithelial cells such as endocrine cells, which are normally Class II negative, may contribute to the development of autoimmunity. In recent onset Type 1 diabetes, islet β cells, the target of the autoimmune process, selectively express Class II antigens. The regulation of Class II expression by β cells is therefore of great potential interest for understanding the pathogenesis of Type 1 diabetes. Given the inaccessibility of the endocrine islets in the diabetic pancreas, the approach adopted here has been to search for those mediators capable of inducing Class II in the human β cells in vitro and then, on the basis of their characteristics, surmise whether these mediators could correspond to those acting in vivo. Initially, considerable work was carried out to establish a culture system in which the expression of HLA by human islet cells (adult and foetal) could be studied with simultaneous identification of the cell type. As an internal control exocrine/ductal cells were also characterized and monitored. In contrast to most other cell types, islet β cells were not stimulated to express Class II by IFN-γ and thus the conditions under which this occurs have been elusive. Many other mediators tested were also unable to induce Class II expression by islet cells. Finally, it was found that IFN-γ in combination with either TNF-α or TNF-β induced islet cell Class II expression (DR, DP and DQ) in a dose related manner. As it has been shown that in the pancreata of newly diagnosed Type 1 diabetes patients the four types of islet cells strongly hyperexpress HLA Class I, the regulation of Class I expression was also studied. The in vitro experiments showed that all three types of IFNs, i.e. α, β and γ, have the capability of enhancing Class I expression in the islet cells. These findings strengthen the previous histopathological observations on the pancreas of diabetic individuals and also point to a possible sequence of events leading to this phenomenon in vivo.

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