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,
,
Section of Biochemistry and Molecular Biology, Departments of
*
Orthopedic Surgery,
Immunology/Microbiology,
Biochemistry, and
Medicine, Rush Medical College at Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL 60612
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
-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-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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