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Fcγ receptors complement interaction: new aspects in pathogenesis and treatment of vasculititis

For a long time, detailed mechanisms of immune-complex-mediated vasculitis have been unknown. The advent of gene knockout technology and the characterization of the various Fc and complement receptors as well as cytokines now allows the various pathogenetic elements in vasculitic inflammation to be distinguished.

Using various murine knockout models, in particular Fcγ-receptor-deficient animals, mast-cell-defective animals, and complement-deficient animals in recent years, we have shown that FcγRIII and C5a receptor are critical for induction of immune-complex-mediated vasculitis. In several studies, it became clear that mast cells have a critical role in the initiation of the inflammatory process. On these mast cells, again the FcγRIII is a critical activating receptor used by immune complexes. When examining the effects of immune complexes in glomerular mesangial cells and GBM nephritis, we showed that IgG immune complexes had opposing regulatory effects on FcγRII and FcγRIII receptors in glomerular mesangial cells. Whereas activation by TNF-α/IL-1β induces substantial FcγRII expression, IFN-γ showed a complete down-regulation of FcγRII. At the same time, IFN-γ induced the Fc receptor γ-chain as well as the low-affinity IgG receptor FcγRIII. Triggering of FcγRIII again induced chemoattractant protein 1, MCP-1, MCP-5 and RANTES.

Examining the regulatory role in the cooperation of Fcγ receptors and complement, we showed that C5a is critical in amplifying the inflammatory response to IgG. C5a is important on the one hand in down-regulating FcγRII, and on the other hand in inducing the activating FcγRIII.

Altogether, distinguishing the various components of vasculitis pathogenesis allows for new strategies to intervene in this inflammatory process.

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Schmidt, R. Fcγ receptors complement interaction: new aspects in pathogenesis and treatment of vasculititis. Arthritis Res Ther 5 (Suppl 1), 26 (2003).

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