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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1466276

Activating STAT3 Mutations in CD8+ T-Cells Correlate to Serological Positivity in Rheumatoid Arthritis

Provisionally accepted
Katharine B. Moosic Katharine B. Moosic 1,2,3Thomas L. Olson Thomas L. Olson 1,2*Mark Freijat Mark Freijat 4*Samara Khalique Samara Khalique 4*Cait E. Hamele Cait E. Hamele 1,2*Bryna Shemo Bryna Shemo 1,2*Jesse Boodoo Jesse Boodoo 4*William Baker William Baker 4*Gitanjali Khurana Gitanjali Khurana 4*Matthew Schmachtenberg Matthew Schmachtenberg 1,2*Tristin Duffy Tristin Duffy 1,2*Aakrosh Ratan Aakrosh Ratan 1,5,6*Erika Darrah Erika Darrah 7Felipe Andrade Felipe Andrade 7Marieke Jones Marieke Jones 6*Kristine C. Olson Kristine C. Olson 1,2*David J. Feith David J. Feith 1,2Donald L. Kimpel Donald L. Kimpel 4*Thomas P. Loughran Jr Thomas P. Loughran Jr 1,2*
  • 1 University of Virginia Cancer Center, Charlottesville, Virginia, United States
  • 2 Division of Hematology/Oncology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, United States
  • 3 Department of Pathology, School of Medicine, University of Virginia, Charlottesville, Virginia, United States
  • 4 Division of Rheumatology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, United States
  • 5 Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville, Virginia, United States
  • 6 Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, Virginia, United States
  • 7 Division of Rheumatology, The Johns Hopkins School of Medicine, Baltimore, United States

The final, formatted version of the article will be published soon.

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

    Keywords: Rheumatoid arthritis, Large granular lymphocytic leukemia, Anti-citrullinated protein antibodies, CD8-Positive T-Lymphocytes, Rheumatoid Factor, stat3, JAK/STAT

    Received: 17 Jul 2024; Accepted: 06 Sep 2024.

    Copyright: © 2024 Moosic, Olson, Freijat, Khalique, Hamele, Shemo, Boodoo, Baker, Khurana, Schmachtenberg, Duffy, Ratan, Darrah, Andrade, Jones, Olson, Feith, Kimpel and Loughran Jr. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Thomas L. Olson, University of Virginia Cancer Center, Charlottesville, 22903, Virginia, United States
    Mark Freijat, Division of Rheumatology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, United States
    Samara Khalique, Division of Rheumatology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, United States
    Cait E. Hamele, University of Virginia Cancer Center, Charlottesville, 22903, Virginia, United States
    Bryna Shemo, University of Virginia Cancer Center, Charlottesville, 22903, Virginia, United States
    Jesse Boodoo, Division of Rheumatology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, United States
    William Baker, Division of Rheumatology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, United States
    Gitanjali Khurana, Division of Rheumatology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, United States
    Matthew Schmachtenberg, University of Virginia Cancer Center, Charlottesville, 22903, Virginia, United States
    Tristin Duffy, University of Virginia Cancer Center, Charlottesville, 22903, Virginia, United States
    Aakrosh Ratan, University of Virginia Cancer Center, Charlottesville, 22903, Virginia, United States
    Marieke Jones, Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, 22908, Virginia, United States
    Kristine C. Olson, University of Virginia Cancer Center, Charlottesville, 22903, Virginia, United States
    Donald L. Kimpel, Division of Rheumatology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, United States
    Thomas P. Loughran Jr, University of Virginia Cancer Center, Charlottesville, 22903, Virginia, United States

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