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Activation of the G_i Heterotrimeric G Protein by ANCA IgG F(ab')₂ Fragments Is Necessary but not Sufficient to Stimulate the Recruitment of Those Downstream Mediators Used by Intact ANCA IgG

Julie M. Williams^*, Anne Ben-Smith^*, Peter Hewins^*, Stephen K. Dove, Philip Hughes, Robert McEwan, Michael J.O. Wakelam and Caroline O.S. Savage^*

*Renal Immunobiology, Department of Biochemistry, and Institute for Cancer Studies, MRC Centre for Immune Regulation, The Medical School, University of Birmingham, Birmingham, UK

Correspondence to Professor C.O.S. Savage, Renal Immunobiology, MRC Centre for Immune Regulation, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK. Phone: 44-121-414-7042; Fax: 44-121-414-6840;

ABSTRACT. Anti-neutrophil cytoplasm autoantibodies (ANCA) are implicated in the pathogenesis of systemic vasculitis. Intact ANCA IgG activate superoxide generation in cytokine-primed neutrophils after binding their antigens and co-engaging Fc receptors (FcR). The contribution of antigen binding via ANCA F(ab')₂ fragments to signaling has been unclear. This study shows that both ANCA IgG and F(ab')₂ fragments of ANCA IgG induce significant GTPase activity, which could be blocked with pertussis toxin and anti-G_i protein antibodies. Pertussis toxin inhibited ANCA IgG-induced superoxide generation but was without effect on superoxide production after conventional FcR ligation. ANCA F(ab')₂ fragments did not induce superoxide generation. ANCA IgG activated PI 3-kinase–generating PIP₃, activated protein kinase B (PKB), and p21^ras; activation of each mediator was inhibited with pertussis toxin, but PI3K and PKB were not activated by ANCA IgG F(ab')₂ fragments. Intact ANCA IgG induced tyrosine phosphorylation, whereas F(ab')₂ fragments did not, and ANCA IgG-mediated superoxide generation was inhibited with genistein. Both genistein and pertussis toxin together completely abrogated the ANCA-induced oxidative burst. Genistein also inhibited ANCA IgG-induced PIP₃ generation and p21^ras activation. These data implicate a novel ANCA IgG stimulated signaling pathway that involves both F(ab')₂-mediated antigen binding and Fc-mediated FcR ligation in cooperative interactions between G_i proteins and tyrosine kinases that facilitates activation of downstream mediators. E-mail: C.O.S.Savage@bham.ac.uk.

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