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

Objective. The role of Fcgamma receptors (FcgammaR) in type I cryoglobulinemia was investigated to characterize novel mechanisms of neutrophil activation in the pathogenesis of leukocytoclastic vasculitis. Methods. Neutrophils from healthy donors were incubated with purified monoclonal IgG1kappa cryoglobulin complexes in vitro. Changes in surface antigen expression and mechanisms of intracellular hydrogen peroxide production 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 (Cd16), and LAM-1 were down-regulated. Using solubilized and complexed cryoglobulins, it was demonstrated that complex formation is necessary to induce intracellular H2O2 production and calcium release from intracellular stores. Both H2O2 generation and calcium mobilization could be inhibited by pretreatment with F(ab')2 fragments of monoclonal antibodies (MAb) against FcgammaRIII. In contrast, Fab fragments of anti-FcgammaRII MAb failed to block these activations. Neither the cryoglobulin complex-induced production of H2O2 nor the increase in cytoplasmic calcium was affected by treatment with pertussis toxin, which suggests that pertussis toxin-sensitive G proteins are not involved in signal transduction. Conclusion. These results indicate that FcgammaRIII plays a major role in the pathogenesis of leukocytoclastic vasculitis.