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リウマチ Vol.40 No2 indexに戻る
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リウマチ Vol.40 No.2 |
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「Mechanism of Cartilage Degeneration
in Rheumatoid Arthritis」 |
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| Hugo E. Jasin |
| University of Arkansas for Medical Sciences,
Little Rock, AR 72205, USA |
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| 特別講演-１
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Loss of joint function in rheumatoid arthritis
is the result of the irreversible damage to the articular cartilage
as a direct
consequence of the sustained chronic inflammatory process. The
mechanisms operative in cartilage damage in rheumatoid arthritis
are not completeley understood. It is likely, however, that the
inability of chondrocytes to maintain tissue integrity as a result
of cell death and metabolic abnormalities induced by factors secreted
by cells in inflamed synovium, invasive pannus, and synovial fluid,
plays a major role in the process of cartilage destruction. In
a recent review of the subject (Arthritis and Allied Conditions,
W. Koopman, editor), as many as 100 different factors were found
to play a possible role in cartilage damage. In this lecture we
will review the pathogenic roles of oxygen radicals and nitric
oxide (NO) as mediators of damage or as protective factors. Activation
of phagocytic cells by immune complexes or cytokines within the
inflamed joint gives rise to large amounts of highly reactive oxygen-derived
products that in conjunction with cell peroxidases, free divalent
metals, halide ions, and other substrates play a major role in
the generation of tissue injury in acute and chronic inflammatory
reactions. We have previously shown that activation of inflammatory
cells resulting in the production of hypochlorous acid (HOCl),
the end product of superoxide ion, mediates covalent cross-linking
of IgG in vitro. The modified IgG aggregates were shown to have
characteristics similar to true immune complexes in that they interacted
with rheumatoid factor and C1q. Moreover, further work showed that
inflammatory synovial fluids contained IgG aggregates exhibiting
evidence of oxidative modification. We and others have shown that
the superficial chondrocytes secrete large amounts of nitric oxide,
which can react with oxygen radicals derived from inflammatory
cells and chondrocytes at the cartilage surface, to form peroxynitrite
and other reactive molecules able to nitrate and aggregate IgG.
Although the modified IgG may be aggregated, its capacity to induce
inflammation compared to similar “native" immune complexes
is not known. We now show that exposure of IgG and immune complexes
to peroxinitrite or HOCl results in a significant decrease in the
proinflammatory properties of these molecules. Our studies clarify
the modulating role of biological oxidants in inflammatory processes
in which antigen-autoantibody reactions and immune complex pathogenesis
may play an important role. |
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