FC-GAMMA RECEPTOR ACTIVATION OF NEUTROPHILS IN CRYOGLOBULIN-INDUCED LEUKOCYTOCLASTIC VASCULITIS

Objective. The role of Fcgamma receptors (FcgammaR) in type I cryoglob ulinemia was investigated to characterize novel mechanisms of neutroph il activation in the pathogenesis of leukocytoclastic vasculitis. Meth ods. Neutrophils from healthy donors were incubated with purified mono clonal IgG1kappa cryoglobulin complexes in vitro. Changes in surface a ntigen expression and mechanisms of intracellular hydrogen peroxide pr oduction and calcium release were measured by flow cytometry. Results. After incubation for 2 hours, surface expression of FcgammaRI (CD64), CD66, and CD67 was up-regulated; FcgammaRII (CDw32), FcgammaRIII (Cd1 6), and LAM-1 were down-regulated. Using solubilized and complexed cry oglobulins, it was demonstrated that complex formation is necessary to induce intracellular H2O2 production and calcium release from intrace llular stores. Both H2O2 generation and calcium mobilization could be inhibited by pretreatment with F(ab')2 fragments of monoclonal antibod ies (MAb) against FcgammaRIII. In contrast, Fab fragments of anti-Fcga mmaRII MAb failed to block these activations. Neither the cryoglobulin complex-induced production of H2O2 nor the increase in cytoplasmic ca lcium was affected by treatment with pertussis toxin, which suggests t hat pertussis toxin-sensitive G proteins are not involved in signal tr ansduction. Conclusion. These results indicate that FcgammaRIII plays a major role in the pathogenesis of leukocytoclastic vasculitis.