Modulating IL-21-driven B cell responses in idiopathic inflammatory myopathies via inhibition of the JAK/STAT pathway
Abstract Background 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...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-04-01
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| Series: | Arthritis Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13075-025-03547-2 |
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| Summary: | Abstract Background 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. Methods 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. Results 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. Conclusions 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. |
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| ISSN: | 1478-6362 |