OP0188 PATHOGENICITY OF FUNCTIONAL AUTOANTIBODIES AGAINST AT1R IN A MOUSE MODEL OF SYSTEMIC SCLEROSIS

Background Systemic sclerosis (SSc) is an autoimmune connective tissue disease featured by autoimmunity, fibrosis and vasculopathy. Although many autoantibodies have been detected in the sera of patients with SSc, it is not clear whether they play a role in the pathogenesis of disease. It has been reported that autoantibodies against the angiotensin-II receptor type 1 (AT1R) are present in the sera of SSc patients and are associated with several clinical symptoms of the disease, suggesting that these autoantibodies may act as pathogenic drivers. Recently, our group has developed a novel mouse model for SSc by immunizing mice with human AT1R (hAT1R). From this model we were able to generate functional monoclonal antibodies agonizing AT1R. Objectives In the current study, we aim to clarify, whether B cells and antibodies directed against AT1R are involved in the pathogenesis of experimental SSc in vivo. Methods To investigate the role of B cells in the hAT1R-induced mouse model of SSc, we immunized B-cell deficient mice with hAT1R. Nine weeks after the first immunization, mice were sacrificed and sera and tissues were collected for further evaluation. To investigate the pathogenicity of anti-AT1R antibodies in the disease, monoclonal autoantibodies against hAT1R were applied to the ear of C57Bl/6 mice by single or repetitive injection. Mice were sacrificed 24 hours or 14 days after the first injection for single and repeated application, respectively, and ear and lung tissues were collected for further evaluation. Results Compared to the wild type C57Bl/6 mice, hAT1R-immunized B-cell deficient mice were resistant against experimental SSc with regard to autoantibody production, inflammation in the lung and skin, and skin fibrosis. Furthermore, both single and repetitive injection of monoclonal antibodies against hAT1R induced inflammation in ears of mice. Despite this local effect, repetitive injection of anti-AT1R monoclonal antibodies provoked also inflammation in the lung of mice. Conclusion Our data demonstrate that i) B cells are indispensable for the pathogenesis of the hAT1R-induced mouse model for SSc and ii) monoclonal antibodies against hAT1R can induce inflammation in mice. Therefore, our results support a role of autoantibodies against AT1R in the pathogenesis of SSc. References [1] Yannick Allanore, et al. Nat Rev Dis Primers2015. [2] Gabriela Riemekasten, et al. Ann Rheum Dis2011. [3] Mike O. Becker, et al. Am J Respir Crit Care Med2014. Disclosure of Interests Junping Yin: None declared, Xiaoqing Wang: None declared, Xiaoyang Yue: None declared, Gabriela Riemekasten Consultant for: Chugai, F. Hoffmann-La Roche, Speakers bureau: Chugai, F. Hoffmann-La Roche, Xinhua Yu: None declared, Frank Petersen: None declared