title: Absence of TNFRp55 influences virus-induced autoimmunity despite efficient lymphocytic infiltration.
abstract: Tumor necrosis factor (TNF)-alpha is a multipotent cytokine associated with many cellular functions, including inflammation and anti-viral defense. Many studies have implicated TNF-alpha in the pathogenesis of autoimmune diseases. TNF-alpha responses are mediated through binding to specific cell surface receptors, TNFRp55 and TNFRp75. The objective of the present study was to investigate the contribution of the TNFRp55 in the inflammatory response associated with autoimmune diabetes development in a viral transgenic model. In this model, the animals express lymphocytic choriomeningitis virus (LCMV)-glycoprotein (gp) in the beta cells of the pancreas under the control of the rat insulin promoter (RIP-gp). Diabetes is induced following LCMV infection due to beta cell destruction by LCMV-specific CD8+ cytotoxic T lymphocytes. TNFRp55-deficient RIP-gp animals were examined to assess the importance of the TNFRp55. The kinetics and onset of lymphocytic infiltration into the pancreatic islets and hyperglycemia was not altered in the absence of TNFRp55 after LCMV infection. Animals were evaluated following recombinant LCMV-gp vaccinia virus infection to test whether properties of the infectious agent influence autoimmunity. Interestingly, the kinetics were accelerated and the frequency of diabetes was increased in TNFRp55-deficient mice compared with control animals. This accelerated onset of diabetes is likely a result of increased viral replication in the TNFRp55-deficient host. Thus, these data demonstrate that TNFRp55 is not essential for producing the local inflammatory effects which contribute to organ-specific autoimmunity in this transgenic model. However, the absence of TNFRp55 altered the kinetics and incidence of the disease in a pathogen-dependent fashion.
authors.affiliation: Ontario Cancer Institute, Department of Immunology and Medical Biophysics, University of Toronto, Canada.
authors.forename: K J
authors.initials: KJ
authors.lastname: McKall-Faienza
authors.forename: K
authors.initials: K
authors.lastname: Kawai
authors.forename: T M
authors.initials: TM
authors.lastname: Kündig
authors.forename: B
authors.initials: B
authors.lastname: Odermatt
authors.forename: M F
authors.initials: MF
authors.lastname: Bachmann
authors.forename: A
authors.initials: A
authors.lastname: Zakarian
authors.forename: T W
authors.initials: TW
authors.lastname: Mak
authors.forename: P S
authors.initials: PS
authors.lastname: Ohashi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology*; D004195:Disease Models, Animal; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology / Q000821:virology; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000473:pathology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D011506:Proteins / Q000235:genetics / Q000276:immunology; D051381:Rats; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014616:Vaccinia virus / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D015703:Antigens, CD; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse