Karolinska Institutet and Karolinska University Hospital Stockholm, Sweden
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Sara Turcinov1, Charlotte de Vries2, Ravi Kumar Sharma2, Christina Gerstner2, Bruno Raposo2, Anatoly Dubnovitsky2, William Kwok3, Karine Chemin2, Vivianne Malmström4 and Aase Hensvold5, 1Division of Rheumatology, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet. Theme of Inflammation and Ageing, Medical Unit Gastro, Derma, Rheuma, Karolinska University Hospital, Stockholm, Sweden, 2Division of Rheumatology, Department of Medicine Solna, Center for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden, 3Benaroya Research Institute at Virginia Mason, Seattle, WA, 4Karolinska Institutet, Stockholm, Sweden, 5Division of Rheumatology, Department of Medicine Solna, Center for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet. Center for Rheumatology, Academic Specialist Center, Stockholm, Sweden
Background/Purpose: CD4+ T cells recognizing citrullinated epitopes are present in peripheral blood of anti-citrulline protein antibody (ACPA) positive rheumatoid arthritis (RA) patients at time of diagnosis and during the disease course. However, it has not priorly been known if these rare cells also can be found preceding disease onset. The aim of this study was thus to investigate the presence of such autoreactive CD4+ T cells, in the at-risk phase of RA, in combination with deep T cell phenotyping.
Methods: Twenty individuals from the Karolinska Risk-RA cohort carrying the genetic risk allele, HLA-DRB1*04:01, were included in the study. At baseline, all individuals had musculoskeletal symptoms, concomitant anti-CCP-positivity, but no clinical or ultrasound signs of synovitis. Ten of these individuals progressed to arthritis (over a median period of 13 months following inclusion) and were matched to individuals that had not progressed during a median follow-up period of 53 months. Peripheral blood mononuclear cells (PBMC), from up to three sample timepoints during one year of risk phase, were assessed using HLA-class II tetramers with twelve different citrullinated candidate autoantigens (originating from tenascin-C, α-enolase, fibrinogen-β, vimentin and cartilage intermediate layer protein) and a viral influenza peptide as positive control, combined with multiparameter phenotyping using a 20-color spectral flow-cytometry panel.
Results: Overall, the baseline CD4+ phenotype was similar in individuals who progressed to arthritis and those who did not when studying markers associated with Th1, Th17, T-peripheral helper and T-regulatory cells as well as with cell activation. The memory T cell compartment was predominantly of effector memory phenotype. When looking at antigen specific T cells, all individuals had similar levels of influenza specific CD4+ T cells irrespectively of disease progression status. CD4+ T cells recognizing pools of citrullinated antigens were also present in both groups but at significantly higher frequency in the non-progressors, particularly those with reactivity towards citrullinated fibrinogen-β/vimentin. Within the arthritis progressor group, CD4+ T cells specific for citrullinated tenascin-C were the most frequently observed, with their frequencies diminishing during follow-up time points leading up to arthritis onset. These cit-tenascin-C reactive CD4+ T cells displayed phenotypes of both activation and regulatory function.
Conclusion: Autoreactive CD4+ T cells recognizing citrullinated antigens are present in the circulation before disease onset in ACPA-positive individuals with arthralgia carrying HLA-DRB1*04:01. Lower frequency of circulating citrulline specific cells in arthritis progressor individuals may suggest an ongoing homing of these cells to the joints.
S. Turcinov: None; C. de Vries: None; R. Kumar Sharma: None; C. Gerstner: None; B. Raposo: None; A. Dubnovitsky: None; W. Kwok: None; K. Chemin: Janssen, 5; V. Malmström: Eli Lilly, 1, Janssen, 5, ONO, 1, Pfizer, 5; A. Hensvold: None.
