title: Impaired Fas signaling pathway is involved in defective T cell apoptosis in autoimmune murine arthritis.
abstract: Proteoglycan (PG)-induced arthritis (PGIA) is a novel autoimmune murine model for rheumatoid arthritis induced by immunization with cartilage PG in susceptible BALB/c mice. In this model, hyperproliferation of peripheral CD4(+) T cells has been observed in vitro with Ag stimulation, suggesting the breakdown of peripheral tolerance. Activation-induced cell death (AICD) is a major mechanism for peripheral T cell tolerance. A defect in AICD may result in autoimmunity. We report in this study that although CD4(+) T cells from both BALB/c and B6 mice, identically immunized with human cartilage PG or OVA, express equally high levels of Fas at the cell surface, CD4(+) T cells from human cartilage PG-immunized BALB/c mice, which develop arthritis, fail to undergo AICD. This defect in AICD in PGIA may lead to the accumulation of autoreactive Th1 cells in the periphery. The impaired AICD in PGIA might be ascribed to an aberrant expression of Fas-like IL-1beta-converting enzyme-inhibitory protein, which precludes caspase-8 activation at the death-inducing signaling complex, and subsequently suppresses the caspase cascade initiated by Fas-Fas ligand interaction. Moreover, this aberrant expression of Fas-like IL-1beta-converting enzyme-inhibitory protein may also mediate TCR-induced hyperproliferation of CD4(+) T cells from arthritic BALB/c mice. Our data provide the first insight into the molecular mechanism(s) of defective AICD in autoimmune arthritis.
authors: Section of Biochemistry and Molecular Biology, Department of Orthopedic Surgery, Rush Medical College at Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA. jzhang1@rush.edu
authors: J
authors: J
authors: Zhang
authors: T
authors: T
authors: Bárdos
authors: K
authors: K
authors: Mikecz
authors: A
authors: A
authors: Finnegan
authors: T T
authors: TT
authors: Glant
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology; D002358:Cartilage, Articular / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D007274:Injections, Intraperitoneal; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011509:Proteoglycans / Q000008:administration & dosage / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; C506387:Cflar protein, mouse; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D019014:fas Receptor