Merino-Vico Ana, Kocyigit Merve, Frazzei Giulia, Landman Lisa, Boon Louis, van Leeuwen Ester M, Lundberg Ingrid E, van der Kooi Anneke J, Raaphorst Joost, van Hamburg Jan Piet, Tas Sander W
Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Department of Experimental Immunology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Arthritis Res Ther. 2025 Apr 1;27(1):76. doi: 10.1186/s13075-025-03547-2.
Idiopathic inflammatory myopathies (IIM) are autoimmune disorders characterized by muscle inflammation and autoreactive B cell responses. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway is essential for B cell functions, making it a promising therapeutic target. This study explores the potential of tofacitinib, a JAK1/JAK3 inhibitor, to modulate B cell activity in IIM.
Peripheral B cell populations from dermatomyositis (DM), anti-synthetase syndrome (ASyS) and overlap myositis (OM) patients were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMC) or sorted memory B cells were cultured with tofacitinib and stimulated with combinations of CD40, IL-21, IL-2, BAFF and CpG. B cell proliferation, differentiation and (auto)antibody, cytokine/chemokine production were assessed by flow cytometry, Luminex, and ELISA/ELiA assays.
The IIM peripheral B cell compartment had elevated transitional and naive B cells, with reduced Bmem frequencies compared to healthy donors. Tofacitinib significantly inhibited CD40/IL-21-induced B cell proliferation, plasmablast formation and function in PBMC and B cell-only cultures across all IIM subgroups, predominantly affecting the IL-21-induced differentiation and antibody production. Remarkably, tofacitinib reduced the levels of anti-Jo1 autoantibodies, as well as of CXCL10 and CXCL13 in ASyS memory B cell cultures.
These findings highlight the B cell involvement in IIM, evidenced by altered peripheral B cell composition in active disease and the effective inhibition of essential B cell responses, including proliferation, differentiation, and (auto)antibody production, by tofacitinib in vitro. This positions the JAK/STAT pathway as a promising new therapeutic target to modulate B cell activity in IIM.
特发性炎性肌病（IIM）是一种自身免疫性疾病，其特征为肌肉炎症和自身反应性B细胞应答。Janus激酶（JAK）-信号转导子和转录激活子（STAT）信号通路对B细胞功能至关重要，使其成为一个有前景的治疗靶点。本研究探讨JAK1/JAK3抑制剂托法替布调节IIM中B细胞活性的潜力。
通过流式细胞术分析皮肌炎（DM）、抗合成酶综合征（ASyS）和重叠性肌炎（OM）患者的外周B细胞群体。将外周血单核细胞（PBMC）或分选的记忆B细胞与托法替布一起培养，并用CD40、IL-21、IL-2、BAFF和CpG的组合进行刺激。通过流式细胞术、Luminex以及ELISA/ELiA检测评估B细胞增殖、分化以及（自身）抗体、细胞因子/趋化因子的产生。
与健康供者相比，IIM外周B细胞区室中的过渡性和幼稚B细胞增多，记忆B细胞频率降低。托法替布在所有IIM亚组的PBMC和仅B细胞培养物中均显著抑制CD40/IL-21诱导的B细胞增殖、浆母细胞形成和功能，主要影响IL-21诱导的分化和抗体产生。值得注意的是，托法替布降低了ASyS记忆B细胞培养物中抗Jo1自身抗体以及CXCL10和CXCL13的水平。
这些发现突出了B细胞在IIM中的参与，这在活动性疾病中外周B细胞组成的改变以及托法替布在体外有效抑制包括增殖、分化和（自身）抗体产生在内的关键B细胞应答中得到了证实。这使JAK/STAT通路成为调节IIM中B细胞活性的一个有前景的新治疗靶点。
