1. Activating STAT3 mutations in CD8+ T-cells correlate to serological positivity in rheumatoid arthritis.
- Author
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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., and Loughran Jr, Thomas P.
- Abstract
Objectives: Large granular lymphocyte (LGL) leukemia is a rare hematologic malignancy characterized by clonal expansion of cytotoxic T-cells frequent somatic activating STAT3 mutations. Based on the disease overlap between LGL leukemia rheumatoid arthritis (RA)a putative role for CD8+ T-cells in RA we hypothesized that STAT3 mutations may be detected in RA patient CD8+ Tcells 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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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