Year: 2026
Type: article
Study design: Observational Study
Abstract: OBJECTIVES: We aimed to study the serologic, genetic, and immunologic underpinnings associated with cytotoxic T lymphocytes (CTLs) in rheumatoid arthritis (RA), using T-large granular lymphocytic leukaemia with comorbid RA (T-LGLL/RA) as a model of CTL-linked RA. METHODS: We used blood samples and paired clinical data from patients with RA, T-LGLL/RA, T-LGLL and healthy controls. Serological characterisation was performed using anti-cyclic citrullinated peptide 3.1 (anti-CCP3.1) enzyme-linked immunosorbent assay, multiplex RA autoantigen array, and radiolabelled peptidylarginine deiminase type III and IV (PAD4) immunoprecipitations. Genetic characterisation was performed using PADI4 single nucleotide polymorphism TaqMan genotyping assays and droplet digital polymerase chain reaction for signal transducer and activator of transcription 3 (STAT3) mutations. Multiparameter flow cytometry and pentamer binding assays were performed to immunophenotype CTLs and characterise PAD4-specific CTLs, respectively. RESULTS: Patients with T-LGLL/RA had enhanced anticitrullinated protein antibody responses compared with RA, and a strikingly higher frequency of anti-PAD4 antibodies (60% vs 27%, P < .0001). Among patients with T-LGLL, PADI4 single nucleotide polymorphisms were associated with anti-PAD4-positive RA (20% vs 3%, P = .02), and anti-PAD4 antibody levels were inversely correlated with absolute neutrophil count (Spearman's rho = -0.236; P = .02). Activating STAT3 mutations were associated with anti-PAD4 antibodies in both T-LGLL/RA (90% vs 74%, P = .047) and RA (39% vs 9%, P = .002). Flow cytometric characterisation of CTLs showed that anti-PAD4-positive RA was enriched for CD57+, CD7 low, T effector memory cells re-expressing CD45RA (TEMRA) CTLs. Furthermore, PAD4-specific CTLs were detected in anti-PAD4+ patients with RA and expressed elevated levels of CD69, CD57, and KLRG1, and a TEMRA phenotype. CONCLUSIONS: These data demonstrate a mechanistic link between autoimmunity to PAD4 and CTL-associated disease in RA.
Source: Annals of the Rheumatic Diseases
Authors: Kusuma Ananth, Katharine B Moosic, Eduardo Gomez-Banuelos, Hong Wang, Isabel Trejo-Zambrano, Ramona Johnson, Jessica Marie Kirschmann, Tess Deddens, Omar Elghawy, Bryna Shemo, William H Robinson, Donald Kimpel, Clifton O Bingham, David J Feith, Brendan Antiochos, Felipe Andrade, Thomas P Loughran, Erika Darrah
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,870
Funders: Patient-Centered Outcomes Research Institute, Johns Hopkins University, Jerome L. Greene Foundation, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases
Awards: G1610190245, G1849506536, G1938938305, Core Center, G465951118, G723705234, G9000066787, Insights into the origin of ACPAs in RA, Genomic Architecture of LGL Leukemia, Johns Hopkins Rheumatic Diseases Resource-based Core Center (Johns Hopkins RDRCC), Regional Oncology Research Center, The role of cytotoxic T cells in rheumatoid arthritis pathogenesis
OpenAlex ID: W7161000259