{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T03:50:52Z","timestamp":1794282652343,"version":"4.9.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017596","name":"Natural Science Basic Research Program of Shaanxi Province","doi-asserted-by":"publisher","award":["2022JZ-14, 2023YBSF-449"],"award-info":[{"award-number":["2022JZ-14, 2023YBSF-449"]}],"id":[{"id":"10.13039\/501100017596","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072298, 82472310, 82002158, 82302555"],"award-info":[{"award-number":["82072298, 82472310, 82002158, 82302555"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Dysregulated T cell homeostasis leading to enhanced immune responses is a critical pathogenic mechanism in rheumatoid arthritis (RA). Programmed cell death protein 1 (PD-1) is a crucial immune checkpoint that modulates T cell activity. Soluble PD-1 (sPD-1) may contribute to the sustained activation of T cells. Investigating the mechanisms of sPD-1 production and its role in RA pathogenesis is essential for the development of alternative treatment strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A total of 122 patients with RA and 68 Health controls were enrolled in this study. We assessed PD-1 expression in T cells from patients with RA and measured sPD-1 levels in plasma, revealing a correlation between sPD-1 and disease activity progression in patients with RA. Furthermore, we examined the potential mechanisms underlying sPD-1 production in RA patients. Additionally, we evaluated the therapeutic effects of PD-L1-MSA, a fusion protein containing C-terminal PD-L1 and full-length MSA, in collagen-induced arthritis (CIA) mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Clinical analyses indicated that plasma sPD-1 levels positively correlated with indicators of disease activity. The generation of sPD-1 primarily resulted from matrix metalloproteinase-9 (MMP-9)-mediated shedding of surface PD-1 from activated T cells, with MMP-9 being derived from fibroblast-like synoviocytes (FLS). Additionally, therapeutic evaluation in collagen-induced arthritis (CIA) mice demonstrated that PD-L1-MSA, a fusion protein containing C-terminal PD-L1 and full-length mouse serum albumin (MSA), significantly mitigated pathological changes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These results indicate that plasma sPD-1 levels are positively associated with RA disease activity, supporting its potential as a complementary biomarker for monitoring disease activity (especially in combination with traditional indicators like CRP\/ESR), though its standalone diagnostic value requires further validation. Furthermore, targeting sPD-1, such as with PD-L1-MSA, represents a promising complementary therapeutic candidate for alleviating RA pathology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1665078","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T06:41:32Z","timestamp":1765348892000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Fibroblast-like synoviocytes mediate the generation of soluble PD-1 in an MMP-9-dependent manner: a novel target therapy for rheumatoid 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