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* Institute of Medical Microbiology and
Department of Clinical Immunology, Medical School Hannover, Hannover, Germany;
Division of Molecular Immunology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229;
Department of Immunology, Georg August University Goettingen, Goettingen, Germany;
¶ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands;
|| Austin Research Institute, Austin and Repatriation Medical Center, Heidelberg, Victoria, Australia;
# Ina Sue Perlmutter Laboratory, Children’s Hospital, Harvard Medical School, Boston, MA 02115; and
** Department of Cell Biology and Immunology, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands
Immune complex (IC)-induced inflammation is integral to the pathogenesis of several autoimmune diseases. ICs activate the complement system and interact with IgG Fc
R. In this study, we demonstrate that activation of the complement system, specifically generation of C5a, initiates the neutrophilic inflammation in IC peritonitis. We show that ablation of C5a receptor signaling abrogates neutrophil recruitment in wild-type mice and prevents the enhancement of neutrophil migration seen in FcRIIB–/– mice, suggesting that C5aR signaling is the crucial initial event upstream of FcR signaling. We also provide evidence that C5a initiates the inflammatory cascade both directly, through C5aR-mediated effector functions on infiltrating and resident peritoneal cells, and indirectly, through shifting the balance between activating and inhibitory FcRs on resident cells toward an inflammatory phenotype. We conclude that complement activation and C5a generation are prerequisites for IC-induced inflammation through activating FcR, which amplifies complement-induced inflammation in autoimmunity.
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