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IFN- and IL-17 Production in Experimental Autoimmune Encephalomyelitis Depends on Local APC–T Cell Complement Production¹

Jinbo Liu^*, Feng Lin^*, Michael G. Strainic^*, Fengqi An^*, Robert H. Miller, Cengiz Z. Altuntas, Peter S. Heeger, Vincent K. Tuohy and M. Edward Medof^2,*

^* Institute of Pathology, Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106; Department of Immunology, Cleveland Clinic, Cleveland, OH 44106; and Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029

IFN-- and IL-17-producing T cells autoreactive across myelin components are central to the pathogenesis of multiple sclerosis. Using direct in vivo, adoptive transfer, and in vitro systems, we show in this study that the generation of these effectors in myelin oligodendrocyte glycoprotein_35–55-induced experimental autoimmune encephalomyelitis depends on interactions of locally produced C3a/C5a with APC and T cell C3aR/C5aR. In the absence of the cell surface C3/C5 convertase inhibitor decay-accelerating factor (DAF), but not the combined absence of DAF and C5aR and/or C3aR on APC and T cells, a heightened local autoimmune response occurs in which myelin destruction is markedly augmented in concert with markedly more IFN-⁺ and IL-17⁺ T cell generation. The augmented T cell response is due to increased IL-12 and IL-23 elaboration by APCs together with increased T cell expression of the receptors for each cytokine. The results apply to initial generation of the IL-17 phenotype because naive CD62L^high Daf1^–/– T cells produce 3-fold more IL-17 in response to TGF-β and IL-6, whereas CD62L^high Daf1^–/–C5aR^–/–C3aR^–/– T cells produce 4-fold less.

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 National Institutes of Health Grants AI23598 and EY-11288 (to M.E.M.), AI-51837 and DC-006422 (to V.K.T.), RG3664-A-1 and NS052471 (to F.L.), and N536674 (to R.H.M.), AI 43578 (to P.S.H.), and E. Pearlman director, core facility EY015476.

² Address correspondence and reprint requests to Dr. M. Edward Medof, Institute of Pathology, Case Western Reserve University, School of Medicine, 2085 Adelbert Road, Room 301, Cleveland, OH 44106. E-mail address: mxm16{at}case.edu

³ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; DAF, decay-accelerating factor; DC, dendritic cell; fD, factor D; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; PLP, proteolipid protein; WT, wild type.