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Immunol."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>Large granular lymphocyte (LGL) leukemia is a rare hematologic malignancy characterized by clonal expansion of cytotoxic T-cells frequent somatic activating <jats:italic>STAT3<\/jats:italic> mutations. Based on the disease overlap between LGL leukemia rheumatoid arthritis (RA)a putative role for CD8+ T-cells in RA we hypothesized that <jats:italic>STAT3<\/jats:italic> mutations may be detected in RA patient CD8+ T-cells correlate with clinical characteristics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Blood samples, clinical parameters, and demographics were collected from 98 RA patients and 9 healthy controls (HCs). CD8+ cell DNA was isolated and analyzed via droplet digital (dd)PCR to detect <jats:italic>STAT3<\/jats:italic> mutations common in LGL leukemia: Y640F, D661Y, and the S614 to G618 region. <jats:italic>STAT3<\/jats:italic> data from 99 HCs from a public dataset supplemented our 9 HCs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>RA patients had significantly increased presence of <jats:italic>STAT3<\/jats:italic> mutations compared to controls (Y640F p=0.0005, D661Y p=0.0005). The majority of these were low variant allele frequency (VAF) (0.008-0.05%) mutations detected in a higher proportion of the RA population (31\/98 Y640F, 17\/98 D661Y) vs. HCs (0\/108 Y640F, 0\/108 D661Y). In addition, 3\/98 RA patients had a <jats:italic>STAT3<\/jats:italic> mutation at a VAF &amp;gt;5% compared to 0\/108 controls. Serological markers, RF and anti-CCP positivity, were more frequently positive in RA patients with <jats:italic>STAT3<\/jats:italic> mutation relative to those without (88% vs 59% RF, p=0.047; 92% vs 58% anti-CCP, p=0.031, respectively).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:italic>STAT3<\/jats:italic> activating mutations were detected in RA patient CD8+ cells and associated with seropositivity. Thus, <jats:italic>STAT3<\/jats:italic> activating mutations may play a role in disease pathogenesis in a subset of RA patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1466276","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T04:39:42Z","timestamp":1729485582000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Activating STAT3 mutations in CD8+ T-cells correlate to serological positivity in rheumatoid arthritis"],"prefix":"10.3389","volume":"15","author":[{"given":"Katharine B.","family":"Moosic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas 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