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.

Mincle Activation and the Syk/Card9 Signaling Axis Are Central to the Development of Autoimmune Disease of the Eye

“…For example, Ccl5 was regulated in a Card9-dependent fashion within the retina and CCL5 (RANTES) has been found to activate CCR5 on T cells to promote EAU (31). The anaphylaxins C3a and C5a, whose induction was also regulated by Card9, were recently shown to contribute to EAU through promotion of the Th17 response (32). Taken together, these data identify an important role for Card9 in induction of genetic responses and pathways relevant to the Th17 cell response, which is an underlying mechanism of EAU.…”

Notch signalling suppresses regulatory T‐cell function in murine experimental autoimmune uveitis

“…EAU induction was conducted following the established method. 10,17,18 Briefly, mice were immunized with an emulsion of complete Freund's adjuvant with 2 mg/ml desiccated Mycobacterium tuberculosis (Sigma-Aldrich, St Louis, MO, USA) and 300 lg human interphotoreceptor retinoidbinding protein (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). The mice received a subcutaneous injection of the emulsion (200 ll) into three sites on the lower back, followed by an intraperitoneal injection of 0Á3 lg pertussis toxin.…”

Retinal endothelial cell phenotypic modifications during experimental autoimmune uveitis: a transcriptomic approach

“…A few studies have already reported involvement of the complement cascade in uveitis development [53][54][55], as well as in EAE pathogenesis [56].…”