title: Complement anaphylatoxin receptors C3aR and C5aR are required in the pathogenesis of experimental autoimmune uveitis.
abstract: Recent studies have suggested that reagents inhibiting complement activation could be effective in treating T cell mediated autoimmune diseases such as autoimmune uveitis. However, the precise role of the complement anaphylatoxin receptors (C3a and C5a receptors) in the pathogenesis of autoimmune uveitis remains elusive and controversial. We induced experimental autoimmune uveitis in mice deficient or sufficient in both C3a and C5a receptors and rigorously compared their retinal phenotype using various imaging techniques, including indirect ophthalmoscopy, confocal scanning laser ophthalmoscopy, spectral domain optical coherence tomography, topical endoscopic fundus imaging, and histopathological analysis. We also assessed retinal function using electroretinography. Moreover, we performed Ag-specific T cell recall assays and T cell adoptive transfer experiments to compare pathogenic T cell activity between wild-type and knockout mice with experimental autoimmune uveitis. These experiments showed that C3a receptor/C5a receptor-deficient mice developed much less severe uveitis than did control mice using all retinal examination methods and that these mice had reduced pathogenic T cell responses. Our data demonstrate that both complement anaphylatoxin receptors are important for the development of experimental autoimmune uveitis, suggesting that targeting these receptors could be a valid approach for treating patients with autoimmune uveitis.
authors.affiliation: *Eye Research Institute, Tianjin Medical University Eye Center, Tianjin, China; Department of Immunology, Lerner Research Institute, Department of Ophthalmic Research, Cole Eye Institute, and Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA; and Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Lingjun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: *Eye Research Institute, Tianjin Medical University Eye Center, Tianjin, China; Department of Immunology, Lerner Research Institute, Department of Ophthalmic Research, Cole Eye Institute, and Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA; and Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Bell
authors.affiliation: *Eye Research Institute, Tianjin Medical University Eye Center, Tianjin, China; Department of Immunology, Lerner Research Institute, Department of Ophthalmic Research, Cole Eye Institute, and Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA; and Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Minzhong
authors.initials: M
authors.lastname: Yu
authors.affiliation: *Eye Research Institute, Tianjin Medical University Eye Center, Tianjin, China; Department of Immunology, Lerner Research Institute, Department of Ophthalmic Research, Cole Eye Institute, and Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA; and Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
authors.affiliation: *Eye Research Institute, Tianjin Medical University Eye Center, Tianjin, China; Department of Immunology, Lerner Research Institute, Department of Ophthalmic Research, Cole Eye Institute, and Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA; and Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Neal S
authors.initials: NS
authors.lastname: Peachey
authors.affiliation: *Eye Research Institute, Tianjin Medical University Eye Center, Tianjin, China; Department of Immunology, Lerner Research Institute, Department of Ophthalmic Research, Cole Eye Institute, and Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA; and Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: John
authors.initials: J
authors.lastname: Fung
authors.affiliation: *Eye Research Institute, Tianjin Medical University Eye Center, Tianjin, China; Department of Immunology, Lerner Research Institute, Department of Ophthalmic Research, Cole Eye Institute, and Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA; and Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA linf2@ccf.org xzhang08@tmu.edu.cn.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhang
authors.affiliation: *Eye Research Institute, Tianjin Medical University Eye Center, Tianjin, China; Department of Immunology, Lerner Research Institute, Department of Ophthalmic Research, Cole Eye Institute, and Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA; and Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Caspi
authors.affiliation: *Eye Research Institute, Tianjin Medical University Eye Center, Tianjin, China; Department of Immunology, Lerner Research Institute, Department of Ophthalmic Research, Cole Eye Institute, and Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA; and Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA linf2@ccf.org xzhang08@tmu.edu.cn.
authors.forename: Feng
authors.initials: F
authors.lastname: Lin
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology*; D004596:Electroretinography; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044087:Receptor, Anaphylatoxin C5a / Q000502:physiology*; D011951:Receptors, Complement / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D014605:Uveitis / Q000209:etiology*
chemical_list: C000591759:C5ar1 protein, mouse; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; C085567:complement C3a receptor
keywords: T cell; innate immunity; mouse model; regulation; retinal inflammation