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Division of Rheumatology and Clinical Immunology, Teresa Scheu Rheumatoid Arthritis Research Laboratory, Department of Internal Medicine, University of Arkansas for Medical Sciences, and Veterans Administration Medical Center, Little Rock, AR 72205
In inflammatory arthritis, there is evidence indicating that the
affected tissues produce large amounts of oxygen-free radicals and NO.
Herein, we examine the biologic effects of exposure of IgG to
hypochlorous acid (HOCl) and peroxynitrite (ONOO). The concentrations
of IgG modified by chlorination and nitrosation were measured in
synovial fluids from inflammatory and noninflammatory arthritis. Human
IgG was exposed to increasing concentrations of HOCl and ONOO, and the
resulting products were tested for complement component binding;
binding to Fc
RI; activation of polymorphonuclear neutrophils; effect
on the Ab-combining site of Abs; and in vivo inflammatory activity in a
rabbit model of acute arthritis. Rheumatoid synovial fluids contained
significantly greater concentrations of nitrosated and chlorinated IgG
compared with ostearthritic specimens. In vitro exposure of human IgG
to HOCl and ONOO resulted in a concentration-dependent decrease in C3
and C1q fixation. The decrease in Fc domain-dependent biologic
functions was confirmed by competitive binding studies to the FcRI
of U937 cells. HOCl-treated IgG monomer was 10 times less effective in
competing for binding compared with native IgG, and ONOO-treated IgG
was 2.5 times less effective. The modified IgGs were also ineffective
in inducing synthesis of H2O2 by human PMN. The
Ag-binding domains of IgG also showed a concentration-dependent
decrease in binding to Ag. The ability of the modified IgGs to induce
acute inflammation in rabbit knees decreased 20-fold as gauged by the
intensity of the inflammatory cell exudates. These studies clarify the
modulating role of biological oxidants in inflammatory processes in
which Ag-autoantibody reactions and immune complex pathogenesis may
play an important role.
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