Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease with currently no universally highly effective prevention strategies. Identifying pathogenic immune phenotypes in ‘At-Risk’ populations prior to clinical disease onset is crucial to establishing effective prevention strategies. Here, we applied mass cytometry to deeply characterize the immunophenotypes in blood from At-Risk individuals identified through the presence of serum antibodies to citrullinated protein antigens (ACPA) and/or first-degree relative (FDR) status (n=52), as compared to established RA (n=67), and healthy controls (n=48). We identified significant cell expansions in At-Risk individuals compared with controls, including CCR2+CD4+ T cells, T peripheral helper (Tph) cells, type 1 T helper cells, and CXCR5+CD8+ T cells. We also found that CD15+ classical monocytes were specifically expanded in ACPA-negative FDRs, and an activated PAX5low naïve B cell population was expanded in ACPA-positive FDRs. Further, we developed an “RA immunophenotype score” classification method based on the degree of enrichment of cell states relevant to established RA patients. This score significantly distinguished At-Risk individuals from controls. In all, we systematically identified activated lymphocyte phenotypes in At-Risk individuals, along with immunophenotypic differences among both ACPA+ and ACPA-FDR At-Risk subpopulations. Our classification model provides a promising approach for understanding RA pathogenesis with the goal to further improve prevention strategies and identify novel therapeutic targets.
Competing Interest Statement
A.H.J. reports research support from Amgen, outside the submitted work. A.F. reports personal fees from AbbVie, Roche, Janssen, and Sonoma and grant support from BMS, Roche, UCB, Nascient, Mestag, GSK and Janssen. J.A.S. has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, and ReCor unrelated to this work. M.B.B. is a founder for Mestag Therapeutics and a consultant for GlaxoSmithKline, 4FO Ventures, and Scailyte AG. S.R. is a founder for Mestag Therapeutics, a scientific advisor for Janssen and Pfizer, and a consultant for Gilead and Rheos Medicines. V.M.H. is a co-founder of Q32 Bio and has previously received sponsored research from Janssen and been a consultant for Celgene and BMS, outside the submitted work. D.A.R. reports personal fees from Pfizer, Janssen, Merck, Scipher Medicine, GlaxoSmithKline, and Bristol-Myers Squibb and grant support from Janssen and Bristol-Myers Squibb, outside the submitted work. In addition, D.A.R. is a co-inventor on a patent submitted on T peripheral helper cells.
Footnotes
↵* co-senior authors
