Fcγ receptor activation of neutrophils in cryoglobulin‐induced leukocytoclastic vasculitis

Abstract

Objective. The role of Fcγ receptors (FcγR) 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 IgG1k 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 FcγRI (CD64), CD66, and CD67 was up‐regulated; FcγRII (CDw32), FcγRIII (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 FcγRIII. In contrast, Fab fragments of anti‐FcγRII 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 FcγRIII plays a major role in the pathogenesis of leukocytoclastic vasculitis.

The IgG Fc receptor family

“…Cryoglobulin-induced activation of neutrophils triggered by hFcgRIIIb plays a contributory role in the pathogenesis of leukocytoclastic vasculitis [86], the dominant lesion of type-I cryoglobulinemia in human beings [130]. Clinical symptoms of type-I cryoglobulinemia include cold urticaria, Raynaud's phenomenon, cutaneous ulcers, and gangrene of the fingers and toes upon exposure to cold [131].…”

“…Cooperation of hFcgRIIIb with hFcgRIIa and CR3 is necessary for efficient phagocytosis, ADCC, and degranulation [6,84,85]. In an in vitro model of immune vasculitis hFcgRIIIb-mediated activation of neutrophils appeared to be critical for the pathogenesis of cryoglobulin-induced leukocytoclastic vasculitis [86]. mFcgRIII was first classified as an mFcgRII protein because it reacted with the same anti-FcgRII/III mAb 2.4G2 and shared with mFcgRII identical binding characteristics, interacting with mIgG1, mIgG2b, and mIgG2a in the form of immune complexes [87].…”

Evaluation of neutrophilic activity in patients submitted to kidney transplantation

“…18 Lazzarin et al 19 studied patients with hepatitis A, B, and acute non-A and non-B hepatitis: circulating immune complexes were found in the serum of these patients with inhibitory effect upon the phagocytic activity of neutrophils. The Fcg receptors are important for phagocytic activity, and Hundt et al 20 demonstrated that, besides the cytokines, immune complexes can induce the expression of FcgRI and significantly reduced FcgRII and FcgRIII expression in the synovial fluid of rheumatoid arthritis patients. In this study, during the evaluation of the phagocytosis digestion phase by PMNs through the NBT test, a significant difference was not demonstrated among the different patients groups analyzed.…”