{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T07:02:34Z","timestamp":1779778954838,"version":"3.53.1"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82174285"],"award-info":[{"award-number":["82174285"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012829","name":"Guangdong Provincial Hospital of Traditional Chinese Medicine","doi-asserted-by":"publisher","award":["YN2023HL03, YN2023ZH06"],"award-info":[{"award-number":["YN2023HL03, YN2023ZH06"]}],"id":[{"id":"10.13039\/100012829","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>Background<\/jats:title>\n                    <jats:p>Gouty arthritis (GA) has long been considered a disease primarily driven by innate immune activation, whereas the contribution of adaptive immune remodeling remains incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we integrated bidirectional Mendelian randomization (MR), CyTOF immune profiling, single-cell transcriptomic analysis, plasma proteomics, and prospective clinical follow-up analyses to investigate immune-associated features and recurrence-related inflammatory signatures in acute GA. Bidirectional two-sample MR analyses were performed using publicly available European ancestry GWAS datasets to evaluate genetic association patterns between 731 immune cell phenotypes and gout. Peripheral immune remodeling was subsequently characterized in Chinese cohorts using CyTOF analysis of PBMC samples from GA-A (n = 25), GA-R (n = 22), and healthy controls (n = 9), together with re-analysis of a public PBMC-derived single-cell RNA-seq dataset. Cell-cell communication, pathway enrichment, and differential expression analyses were performed to explore inflammatory programs associated with acute flares. Plasma inflammatory proteins were quantified using the Olink platform in independent training (n = 40) and validation (n = 64) cohorts, followed by exploratory recurrence risk stratification analyses incorporating independent validation, calibration analysis, and decision curve analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Mendelian randomization analysis suggested associations between several immune traits and gout risk, including CD127\u207a CD4\u207a T cells and CD4\u207a\/CD8\u207a double-negative T cells. Mass cytometry of peripheral blood revealed expansion and functional remodeling of CD4\u207a na\u00efve T cells during acute flares. Re-analysis of public single-cell RNA-seq data further showed that scRNA-seq-defined CD4\u207a na\u00efve T cells exhibited inflammatory transcriptional features, including upregulation of S100A8\/S100A9, and predicted interactions with granulocyte-like myeloid cells through MIF\u2013CXCR2 and ANXA1\u2013FPR1 signaling. Granulocyte-like myeloid cells displayed enhanced inflammatory and chemotactic signatures during acute GA. Plasma proteomic analysis identified elevated MMP1 and S100A12 levels during acute flares, both of which were associated with systemic inflammatory markers. Exploratory mediation analyses suggested that MMP1 may serve as a statistical mediator linking serum uric acid, systemic inflammation, and peripheral CD4\u207a na\u00efve T cell abundance. In exploratory recurrence risk analyses, MMP1 showed exploratory potential for 12-week recurrence risk stratification, particularly within the GA-A subgroup (AUC = 0.8533).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Together, these findings suggest that peripheral CD4\u207a na\u00efve T cell remodeling and MMP1-associated inflammatory signatures may represent relevant features of acute GA and recurrence risk, while their mechanistic roles require further functional validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1828679","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T06:04:47Z","timestamp":1779775487000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Peripheral CD4+ na\u00efve T cell remodeling and MMP1-associated inflammatory 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