IDENTIFICATION OF NOVEL CENTROMERE AUTOANTIGENS IN SJOGREN'S SYNDROME, SYSTEMIC SCLEROSIS AND PRIMARY BILIARY CHOLANGITIS

Background: Anti-centromere antibodies (ACA) are detected in the serum of patients with various autoimmune diseases including Sjogren’s syndrome (SjS), systemic sclerosis (SSc) and primary biliary cholangitis (PBC). ACA positivity is correlated with clinical manifestations such as Raynaud’s phenomenon and sclerodactyly and these features are commonly seen across diseases. Although CENPB is thought to be the major antigen against ACA, autoimmune features of other centromere proteins have not been fully evaluated. Objectives: The aim of this study is to elucidate centromere autoantigens comprehensively and clarify their association with pathogenesis of SjS, SSc and PBC. Methods: A centromere protein library was created by cloning 6 single proteins and 10 complexes consisting of 35 proteins belonging to human centromere region. The centromere antigens were immobilized on beads and incubated in the serum of patients with SjS (n = 86), SSc (n = 35), PBC (n = 10), patients with two or more diseases above (n = 44), and healthy volunteers (n = 68). Autoantibodies to each centromere protein were analyzed by flow cytometry. Results: Patients had a wide variety of antibodies against most of centromere antigens including 4 newly identified autoantigens. The hierarchical clustering of each antigen distinguished 2 antigen clusters. The reactivity of autoantibodies against a centromere protein of one cluster was mutually correlated regardless of disease types, indicating that these proteins/protein complexes might be the target of ACA. In addition, our method enabled us to detect sera reacted against multiple centromere antigens in some of the ACA-negative patients with existing methods. Conclusion: We identified 4 novel centromere autoantigens and our data suggested that the main target of ACA was the protein complex rather than a single specific antigen in SjS, SSc and PBC patients. Using the combination of centromere proteins may be useful to detect ACA with higher sensitivity. References: [1]Fritzler MJ, Rattner JB, Luft LM, Edworthy SM, Casiano CA, Peebles C, Mahler M. Historical perspectives on the discovery and elucidation of autoantibodies to centromere proteins (CENP) and the emerging importance of antibodies to CENP-F. Autoimmun Rev. 2011;10:194-200. Disclosure of Interests: Nobuhiko Kajio: None declared, Masaru Takeshita: None declared, Katsuya Suzuki: None declared, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd.