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Requirement for Vav Proteins in Post-Recruitment Neutrophil Cytotoxicity in IgG but Not Complement C3-Dependent Injury¹

Ahmad Utomo^2,*, Junichi Hirahashi^2,*, Divya Mekala^2,*, Kenichi Asano^*, Michael Glogauer, Xavier Cullere^* and Tanya N. Mayadas^3,*

^* Department of Pathology, Center of Excellence in Vascular Biology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada

The signals linking neutrophil opsonic receptors, FcRs and complement receptor 3 (Mac-1) to cellular cytotoxic responses are poorly understood. Furthermore, because a deficiency in activating FcRs reduces both IgG-mediated neutrophil recruitment and tissue injury, the role of FcRs specifically in mediating neutrophil cytotoxicity in vivo remains unclear. In this study, we demonstrate that neutrophil Vav 1 and 3, guanine exchange factors for Rac GTPases, are required for IgG/FcR-mediated hemorrhage and edema in the reverse passive Arthus in the lung and skin. Rac GTPases are also required for development of the reverse passive Arthus reaction. A deficiency in Vav 1 and 3 does not affect neutrophil accumulation at the site of immune complex deposition, thus uncoupling neutrophil recruitment and tissue injury. Surprisingly, Vav and Rac proteins are dispensable for the development of the local Shwartzman reaction in vivo and phagocytosis of complement-opsonized RBC in vitro, processes strictly dependent on Mac-1 and complement C3. Thus, FcR signaling through the Vav and Rac proteins in neutrophils is critical for stimulating immune complex disease while Vav- and Rac-independent pathways promote Mac-1/complement C3-dependent functions.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by an American Lung Association Senior Research Fellowship (to A.U.), National Institutes of Health Grants R01 HL065095 and AR050800 (to T.N.M.), and Canadian Institutes of Health Research New Investigator award (to M.G.).

² A.U., J.H., and D.M. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Tanya N. Mayadas, Brigham and Women’s Hospital, Vascular Research Division, 77 Avenue Louis Pasteur, New Research Building 752O, Boston, MA 02115. E-mail address: tmayadas{at}rics.bwh.harvard.edu

⁴ Abbreviations used in this paper: IC, immune complex; RPA, reverse passive Arthus; LSR, local Shwartzman reaction; BMN, none marrow mouse neutrophil; BAL, bronchoalveolar lavage; RT, room temperature; PMN, polymorphonuclear neutrophil.