AUTHOR=Moosic Katharine B. , Olson Thomas L. , Freijat Mark , Khalique Samara , Hamele Cait E. , Shemo Bryna , Boodoo Jesse , Baker William , Khurana Gitanjali , Schmachtenberg Matthew , Duffy Tristin , Ratan Aakrosh , Darrah Erika , Andrade Felipe , Jones Marieke , Olson Kristine C. , Feith David J. , Kimpel Donald L. , Loughran Thomas P. 

TITLE=Activating STAT3 mutations in CD8+ T-cells correlate to serological positivity in rheumatoid arthritis

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1466276

DOI=10.3389/fimmu.2024.1466276

ISSN=1664-3224

ABSTRACT=<sec><title>Objectives</title><p>Large granular lymphocyte (LGL) leukemia is a rare hematologic malignancy characterized by clonal expansion of cytotoxic T-cells frequent somatic activating <italic>STAT3</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 <italic>STAT3</italic> mutations may be detected in RA patient CD8+ T-cells correlate with clinical characteristics.</p></sec><sec><title>Methods</title><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 <italic>STAT3</italic> mutations common in LGL leukemia: Y640F, D661Y, and the S614 to G618 region. <italic>STAT3</italic> data from 99 HCs from a public dataset supplemented our 9 HCs.</p></sec><sec><title>Results</title><p>RA patients had significantly increased presence of <italic>STAT3</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 <italic>STAT3</italic> mutation at a VAF &gt;5% compared to 0/108 controls. Serological markers, RF and anti-CCP positivity, were more frequently positive in RA patients with <italic>STAT3</italic> mutation relative to those without (88% vs 59% RF, p=0.047; 92% vs 58% anti-CCP, p=0.031, respectively).</p></sec><sec><title>Conclusions</title><p><italic>STAT3</italic> activating mutations were detected in RA patient CD8+ cells and associated with seropositivity. Thus, <italic>STAT3</italic> activating mutations may play a role in disease pathogenesis in a subset of RA patients.</p></sec>