Mast cells induce autoantibody-mediated vasculitis syndrome through tumor necrosis factor production upon triggering Fc gamma receptors

The generation of autoantibodies and deposition of immune complexes (ICs) i n tissue play a primary role in autoimmune diseases. However, the IC-trigge red response consists of complex mechanisms that make it difficult to ident ify the pathogenesis and develop specific therapy. We clarified here a sequ ential mechanism for the induction of hypersensitivity angiitis by analyzin g the responsible Fc receptor (FcR), effector cells, and mediators in an an imal model using FcR-deficient mice. In this model, rheumatoid factor-media ted skin vasculitis was induced in wild-type mice, whereas FcR gamma-defici ent mice did not develop the vasculitis. Adoptive transfer of various FcR() cells into FcR gamma-deficient mice showed that mast cells but not macrop hages derived from wild-type mice triggered skin vasculitis. Mast cells der ived from either Fc gamma RIII-deficient or tumor necrosis factor (TNF)-def icient mice did not possess the inducibility of skin vasculitis. These resu lts indicate that triggering of vascular inflammation was induced by mast c ells through IC binding on Fc gamma RIII. TNF produced by such activated ma st cells was mainly responsible for the pathogenesis of autoantibody-mediat ed vasculitis. These findings illustrate the clinical significance of mast cells, Fc gamma receptors, and TNF in IC-induced vasculitis syndrome. (C) 1 999 by The American Society of Hematology.