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A Protective Role for C5a in the Development of Allergic Asthma Associated with Altered Levels of B7-H1 and B7-DC on Plasmacytoid Dendritic Cells ¹

Xun Zhang^*, Ian P. Lewkowich, Gabriele Köhl^*, Jennifer R. Clark, Marsha Wills-Karp and Jörg Köhl^2,*,

^* Division of Molecular Immunology and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229; and Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany

The role of complement in the development of maladaptive immunity in experimental allergic asthma is unclear. In this study, we show that C3a receptor (C3aR)-deficient mice are protected from the development of Th2 immunity in a model of house dust mite-induced asthma. C5a receptor (C5aR)-targeting of C3aR-deficient mice during allergen sensitization not only reversed the protective effect but enhanced Th2 cytokine production, airway inflammation, and airway responsiveness, suggesting that the reduced allergic phenotype in C3aR-deficient mice results from protective C5aR signaling. In support of this view, C5aR expression in C3aR-deficient pulmonary dendritic cells (DCs) was increased when compared with wild-type DCs. Moreover, C5aR targeting regulated the frequency of pulmonary plasmacytoid DCs expressing costimulatory molecules B7-H1 and B7-DC. Ex vivo targeting of B7-H1 and B7-DC increased Th2 cytokine production from T cells of wild-type but not of C5aR-targeted mice, suggesting a protective role for C5a through regulation of B7 molecule expression on plasmacytoid DCs.

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 funded by National Institutes of Health Grant AI057839 (to J. K.).

² Address correspondence and reprint requests to Dr. Jörg Köhl, Division of Molecular Immunology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, 45229. E-mail address: joerg.koehl{at}cchmc.org or joerg.koehl{at}uk-sh.de

³ Abbreviations used in this paper: AHR, airway hyperresponsiveness; AT, anaphylatoxin; BAL, bronchoalveolar lavage; C3aR, C3a receptor; C5aR, C5a receptor; C3aRKO, C3aR-deficient mice; C5aRKO, C5aR-deficient mice; DC, dendritic cell; HDM, house dust mite; i.t., intratracheal; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; WT, wild type.

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