Absence of TNFRp55 influences virus-induced autoimmunity despite efficient lymphocytic infiltration

Tumor necrosis factor (TNF)-alpha is a multipotent cytokine associated withmany cellular functions, including inflammation and anti-viral defense.Many studies have implicated TNF-alpha in the pathogenesis of autoimmunediseases. TNF-alpha responses are mediated through binding to specific cellsurface receptors, TNFRp55 and TNFRp75. The objective of the present studywas to investigate the contribution of the TNFRp55 in the inflammatoryresponse associated with autoimmune diabetes development in a viraltransgenic model. In this model, the animals express lymphocyticchoriomeningitis virus (LCMV)-glycoprotein (gp) in the beta cells of thepancreas under the control of the rat insulin promoter (RIP-gp). Diabetesis induced following LCMV infection due to beta cell destruction byLCMV-specific CD8+ cytotoxic T lymphocytes. TNFRp55-deficient RIP-gpanimals were examined to assess the importance of the TNFRp55. The kineticsand onset of lymphocytic infiltration into the pancreatic islets andhyperglycemia was not altered in the absence of TNFRp55 after LCMVinfection. Animals were evaluated following recombinant LCMV-gp vacciniavirus infection to test whether properties of the infectious agentinfluence autoimmunity. Interestingly, the kinetics were accelerated andthe frequency of diabetes was increased in TNFRp55-deficient mice comparedwith control animals. This accelerated onset of diabetes is likely a resultof increased viral replication in the TNFRp55-deficient host. Thus, thesedata demonstrate that TNFRp55 is not essential for producing the localinflammatory effects which contribute to organ-specific autoimmunity inthis transgenic model. However, the absence of TNFRp55 altered the kineticsand incidence of the disease in a pathogen-dependent fashion.