title: Inhibition of the alternative pathway of complement activation reduces inflammation in experimental autoimmune uveoretinitis.
abstract: We have shown previously that complement factor H (CFH) and complement factor B (CFB) are constitutively expressed by retinal pigment epithelial cells and their production is regulated by inflammatory cytokines, suggesting that the alternative pathway (AP) of complement activation might play a role in retinal inflammation. In this study, we further investigated the role of the AP in retinal inflammation using experimental autoimmune uveoretinitis (EAU) as a model. Mice with EAU show increased levels of C3d deposition and CFB expression in the retina. Retinal inflammation was suppressed clinically and histologically by blocking AP-mediated complement activation with a complement receptor of the Ig superfamily fusion protein (CRIg-Fc). In line with reduced inflammation, C3d deposition and CFB expression were markedly decreased by CRIg-Fc treatment. Treatment with CRIg-Fc also led to reduced T-cell proliferation and IFN-γ, TNF-α, IL-17, and IL-6 cytokine production by T cells, and reduced nitric oxide production in BM-derived macrophages. Our results suggest that AP-mediated complement activation contributes significantly to retinal inflammation in EAU. CRIg-Fc suppressed retinal inflammation in EAU by blocking AP-mediated complement activation with probable direct effects on C3/C5 activation of macrophages, thus leading to reduced nitric oxide production by infiltrating CRIg(-) macrophages.
authors.affiliation: Centre for Vision and Vascular Science, Queen's University Belfast, Belfast, UK.
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Muckersie
authors.forename: Chang
authors.initials: C
authors.lastname: Luo
authors.forename: John V
authors.initials: JV
authors.lastname: Forrester
authors.forename: Heping
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D003167:Complement Activation / Q000276:immunology*; D003179:Complement C3b / Q000276:immunology*; D011415:Complement Factor B / Q000235:genetics / Q000276:immunology*; D003170:Complement Pathway, Alternative / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D011951:Receptors, Complement / Q000276:immunology*; D012173:Retinitis / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D016207:Cytokines; D011951:Receptors, Complement; C509992:VSIG4 protein, mouse; D012313:RNA; D003179:Complement C3b; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011415:Complement Factor B