{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T16:46:32Z","timestamp":1772642792164,"version":"3.50.1"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T00:00:00Z","timestamp":1753401600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Primary Sj\u00f6gren\u2019s syndrome (pSS) is a systemic autoimmune disorder characterized by lymphocytic infiltration of exocrine glands, leading to sicca symptoms and systemic complications. CD226, a co-stimulatory receptor implicated in the pathogenesis of multiple autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis(RA), and pSS, regulates immune cell activation. However, the specific role of CD226+ B cells in pSS pathogenesis remains unclear. This study aims to elucidate the functional contribution of CD226<jats:sup>+<\/jats:sup> B cells to pSS development and their clinical relevance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The percentages of CD226 on T cells, B cells, CD56<jats:sup>+<\/jats:sup> NK cells and CD14<jats:sup>+<\/jats:sup> monocytes in the peripheral blood(PB) of pSS patients and healthy controls (HCs) were detected by flow cytometry.Multicolor flow cytometry was employed to examine the distribution of CD226 in B cell subsets of pSS patients, as well as the expression levels of co-stimulatory molecules, activation and proliferation markers, immunoglobulins, and pro-inflammatory cytokines on both CD226<jats:sup>+<\/jats:sup> B cells and CD226<jats:sup>-<\/jats:sup> B cells. Multicolor immunofluorescence staining was applied to detect the co-expression of B cells and CD226 in the salivary gland of pSS patients.Microarray analysis was conducted to analyze the transcriptomic profiles of sorted CD226<jats:sup>+<\/jats:sup> CD19<jats:sup>+<\/jats:sup> B cells and CD226<jats:sup>-<\/jats:sup> CD19<jats:sup>+<\/jats:sup> B cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CD226 expression in the peripheral blood of pSS patients was significantly increased on T cells, CD19<jats:sup>+<\/jats:sup> B cells and CD14<jats:sup>+<\/jats:sup> monocytes, but significantly decreased on CD56<jats:sup>+<\/jats:sup> NK cells.We identified a distinct CD226<jats:sup>+<\/jats:sup>CD19<jats:sup>+<\/jats:sup> B cell subset that exhibited pathogenic features in pSS. CD226 was significantly upregulated on B cells in the peripheral blood and salivary glands of pSS patients.CD226<jats:sup>+<\/jats:sup> CD19<jats:sup>+<\/jats:sup> B cell showed a stronger correlation with clinical features, disease activity, and prognosis in pSS patients.The ROC curve demonstrated that CD226<jats:sup>+<\/jats:sup> CD19<jats:sup>+<\/jats:sup> B cell exhibited significant diagnostic capability to distinguish pSS patients from healthy controls and to differentiate disease activity.This subset also exhibited heightened activation and pro-inflammatory phenotypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>CD226<jats:sup>+<\/jats:sup> B cells are expanded in pSS, strongly correlating with clinical manifestations and disease activity. These cells display enhanced effector profiles (activation, cytokine\/immunoglobulin production) and demonstrate diagnostic utility. Our findings identify CD226<jats:sup>+<\/jats:sup> B cell as a pathogenic driver in pSS, positioning CD226 as a promising novel therapeutic target and biomarker.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1623774","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T06:17:40Z","timestamp":1753424260000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["CD226+ B cells in primary Sj\u00f6gren\u2019s syndrome: a key player in clinical manifestations and disease 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