Impaired Fas signaling pathway is involved in defective T cell apoptosis in autoimmune murine arthritis

被引:60
作者
Zhang, J
Bárdos, T
Mikecz, K
Finnegan, A
Glant, TT
机构
[1] Rush Presbyterian St Lukes Med Ctr, Rush Med Coll, Sect Biochem & Mol Biol, Dept Orthoped Surg, Chicago, IL 60612 USA
[2] Rush Presbyterian St Lukes Med Ctr, Rush Med Coll, Sect Biochem & Mol Biol, Dept Microbiol Immunol, Chicago, IL 60612 USA
[3] Rush Presbyterian St Lukes Med Ctr, Rush Med Coll, Sect Biochem & Mol Biol, Dept Biochem, Chicago, IL 60612 USA
[4] Rush Presbyterian St Lukes Med Ctr, Rush Med Coll, Sect Biochem & Mol Biol, Dept Med, Chicago, IL 60612 USA
关键词
D O I
10.4049/jimmunol.166.8.4981
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-1 beta -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-1 beta -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.
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页码:4981 / 4986
页数:6
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