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MECHANISMS OF MUCOSAL CELL DEATH IN EXPERIMENTAL AUTOIMMUNE GASTRITIS

Marshall ACJ, Alderuccio F and Toh BH.

Department of Pathology and Immunology, Monash University Medical School, Melbourne, Victoria, 3181

Aiden.marshall@med.monash.edu.au

Experimental autoimmune gastritis (EAG), induced by day 3 thymectomy, has proven to be an excellent model for autoimmune gastritis; the underlying basis of pernicious anaemia. While immunopathology is characterised by tissue destruction, the mechanisms of cellular destruction are not well understood. Here we used the neonatal thymectomy model to explore the role of the Fas (CD95) pathway in pathology associated with EAG. By immunohistochemistry, Fas was upregulated on parietal cells of gastritic mice compared to non-gastritic mice. Fas expression on parietal cells was observed in conjunction with upregulation of MHC class II on the epithelium and infiltrating CD4 T cells in the gastric mucosa. Fas deficient lpr/lpr mice backcrossed 8 times to the gastritis-susceptible BALB/cCrSlc background were resistant to thymectomy induced EAG (0/10), lack parietal cell autoantibodies and tissue destruction. In contrast, 80% (12/15) wild type and 61% (11/18) heterozygous mice developed EAG (p<0.05 compared to lpr/lpr group). Nu/nu Fas-sufficient mice transferred with lymphocytes from thymectomised lpr/lpr mice developed destructive gastritis, indicating that pathogenic cells were present in the lpr/lpr mice. To further address the need for Fas expression in tissue destruction, nu/nu mice lacking Fas expression were generated (nu/nu-lpr/lpr). Transfer of splenocytes from gastritic mice resulted in a destructive EAG in wild type nu/nu mice but a non-destructive gastritis in nu/nu-lpr/wt and nu/nu-lpr/lpr mice. The observations that Fas is upregulated in gastric parietal cells of mice with EAG and that Fas-deficient mice are resistant to development of destructive gastritis provide compelling evidence that Fas is required in vivo for development of gastric mucosal cell damage in autoimmune gastritis.