Fas/CD95 is required for gastric mucosal damage in autoimmune gastritis.
OBJECTIVE
Experimental autoimmune gastritis (EAG), characterized by a gastric mononuclear cell infiltrate, mucosal cell damage, and autoantibodies to parietal cell-associated H(+)/K(+) adenosine triphosphatase, is a model for human autoimmune gastritis that leads to pernicious anemia. Previous in vitro studies have implicated Fas/CD95 in initiating damage to gastric mucosal cells in humans and an animal model of autoimmune gastritis. Here we used 2 in vivo animal models to examine the role of Fas in the development of mucosal cell damage in autoimmune gastritis.


METHODS
We initiated EAG in BALB/cCrSlc mice by neonatal thymectomy and examined for Fas expression in the gastric mucosa by immunohistochemistry. To address the in vivo relevance of Fas in mucosal injury, we examined the stomachs and sera of BALB/cCrSlc lpr/lpr mice subjected to neonatal thymectomy and BALB/cCrSlc nu/nu lpr/lpr mice transferred with lymphocytes from gastritic BALB/cCrSlc mice.


RESULTS
Fas expression was up-reguiated in parietal cells of mice with EAG. Neonatally thymectomized lpr/lpr mice were resistant to developing destructive gastritis compared with heterozygous and wild-type littermates. Nu/nu Fas-sufficient mice transferred with lymphocytes from thymectomized lpr/lpr mice developed destructive gastritis. Nu/nu lpr/lpr mice transferred with lymphocytes from gastritic mice developed a nondestructive gastritis.


CONCLUSIONS
The observations that Fas is up-regulated 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.
Department of Pathology and Immunology, Monash University Medical School, Monash University, Prahran, Victoria, Australia.
Aiden C j
AC
Marshall
Frank
F
Alderuccio
Ban-Hock
BH
Toh
D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004198:Disease Susceptibility; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology*; D005756:Gastritis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020022:Genetic Predisposition to Disease; D017710:Lymphocyte Transfusion; D008214:Lymphocytes / Q000378:metabolism; D008661:Metabolism, Inborn Errors / Q000150:complications; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013934:Thymectomy; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism*
D015375:Receptors, Interleukin-2; D019014:fas Receptor