OP0281 ELEVATED EXPRESSION OF BAFF-RECEPTOR IN PERIPHERAL MONOCYTES PROMOTES B CELL ACTIVATION AND CORRELATES WITH CLINICAL MANIFESTATIONS OF PRIMARY SJÖGREN’S SYNDROME
Authors: Keiko Yoshimoto, Katsuya Suzuki, Yumi Ikeda, Eriko Takei, Tsutomu Takeuchi
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Primary Sjögren's syndrome (pSS) is an idiopathic autoimmune disease whose major clinical manifestations are xerostomia and keratoconjunctive sicca, and is often accompanied with hypergammaglobulinemia. Several lines of evidence suggest that a focal lymphocytic infiltrate of the exocrine glands is responsible for lesion formation, IgG production and subsequent dysfunction of the glands. It is well known that B cell activating factor (BAFF) and its receptor, BR3, are deeply involved in the pathogenesis of pSS, and hence BAFF and BR3 are promising targets to treat the disease. We have reported that the abnormally elevated expression of BR3 in monocytes is associated with overproduction of inflammatory cytokines, such as IL-6, by monocytes of pSS patients. Our in vitro experiments suggest that BAFF-stimulated monocytes contribute to IgG overproduction by pSS B cells. We also found that the population of a specific subset of B cells overexpressing BR3 was abnormally increased in pSS patients and that the proportion of the subset was positively and significantly correlated with serum levels of autoantibodies and total IgG as well as ESSDAI, one of the indicators of disease activity of pSS. Our results collectively suggest that the elevated expression of BR3 in pSS monocytes results in B cell activation and subsequent overproduction of IgG. However, the relationship between the abnormalities of peripheral cells and clinical manifestations of pSS has not been fully understood. <h3>Objectives</h3> To elucidate possible roles of abnormal monocytes in the development of clinical manifestations of pSS. <h3>Methods</h3> The expression level of BR3 in peripheral monocytes of patients with pSS (n = 65) and healthy controls (HC: n = 38) was analyzed by FACS. Peripheral B cells were cultured with BAFF-stimulated monocytes in the presence or absence of an anti-IL-6 receptor antibody, and the proportion of CD38<sup>high</sup>IgD<sup>low</sup> cells among CD19<sup>+</sup> cells, and IgG production were analyzed by FACS and ELISA, respectively. The serological data and focus scores by lip biopsy of the patients were collected by clinical records. <h3>Results</h3> FACS analysis revealed that the expression level of BR3 in pSS monocytes was significantly higher than that of HC (p &lt; 0.001). Moreover, the expression level of BR3 in peripheral monocytes was positively and significantly correlated with serum levels of IgG (p = 0.01) and IgM (p = 0.02) of the patients. Notably, BR3 expression in monocytes from focus score-positive pSS patients was significantly higher than that from negative patients (p = 0.006). In addition, BR3 expression in pSS monocytes was elevated in anti-SS-A and/or anti-SS-B positive patients as compared to negative patients. When B cells prepared from pSS patients were mixed with autologous monocytes and co-cultured in vitro in the presence of BAFF, 1) the proportion of CD38<sup>high</sup>IgD<sup>low</sup> cells, which are plasmablasts and/or plasma cells, among CD19 positive cells and 2) the amounts of IgG produced by the cells were drastically enhanced by BAFF-stimulation, whereas the stimulation showed only marginal effects when B cells were solely cultured in vitro. In addition, an anti-human sIL-6R antibody significantly inhibited the proportion of CD38<sup>high</sup>IgD<sup>low</sup> cells and IgG production. These data strongly suggest that IL-6 produced by BAFF-stimulated monocyte plays a pivotal role in B cell differentiation and the IgG overproduction in pSS patients. <h3>Conclusion</h3> Our data strongly suggest that accelerated signal transduction through a BAFF-BR3 axis in monocytes is involved in the pathogenesis of pSS and associates with clinical manifestations of the disease. These results also suggest that BAFF and the BAFF signaling pathways through BR3 are the possible therapeutic targets for pSS. <h3>Disclosure of Interests</h3> Keiko Yoshimoto: None declared, Katsuya Suzuki: None declared, Yumi Ikeda: None declared, Eriko Takei: None declared, Tsutomu Takeuchi Grant/research support from: Astellas Pharma Inc, Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., AbbVie GK, Asahikasei Pharma Corp., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Eisai Co., Ltd., AYUMI Pharmaceutical Corporation, Nipponkayaku Co. Ltd., Novartis Pharma K.K., Grant/research support from: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Grant/research support from: Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Janssen Pharmaceutical K.K., Celltrion Inc., Nipponkayaku Co. Ltd., and UCB Japan, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Abbivie GK, Nipponkayaku Co.Ltd, Janssen Pharmaceutical K.K., Astellas Pharma Inc., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd., GlaxoSmithKline K.K., UCB Japan Co. Ltd., Consultant for: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Asahi Kasei Medical K.K., AbbVie GK, Daiichi Sankyo Co., Ltd., Bristol Myers Squibb, and Nipponkayaku Co. Ltd., Speakers bureau: Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Janssen Pharmaceutical K.K., Celltrion Inc., Nipponkayaku Co. Ltd., and UCB Japan, Speakers bureau: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Astellas Pharma Inc, Diaichi Sankyo Co. Ltd., Eisai Co. Ltd., Sanofi K.K., Teijin Pharma Ltd., Takeda Pharmaceutical Co. Ltd., Novartis Pharma K.K.&nbsp;