Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis

Inamo, J.; Keegan, J.; Griffith, A.; Ghosh, T.; Horisberger, A.; Howard, K.; Pulford, J.; Murzin, E.; Hancock, B.; Jonsson, A. H.; Seifert, J.; Feser, M. L.; Norris, J. M.; Cao, Y.; Apruzzese, W.; Bridges, S. L.; Bykerk, V.; Goodman, S.; Donlin, L.; Firestein, G. S.; Perlman, H.; Bathon, J. M.; Hughes, L. B.; Tabechian, D.; Filer, A.; Pitzalis, C.; H. Anolik, J.; Moreland, L.; Guthridge, J. M.; James, J. A.; Brenner, M. B.; Raychaudhuri, S.; Sparks, J. A.; The Accelerating Medicines Partnership RA/SLE Network,; Holers, V. M.; Deane, K. D.; Lederer, J. A.; Rao, D. A.; Zhang, F.

doi:10.1101/2023.07.03.547507

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bioRxiv · 10.1101/2023.07.03.547507

Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis

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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 naive 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.

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Inamo, J., Keegan, J., Griffith, A., Ghosh, T., Horisberger, A., Howard, K., Pulford, J., Murzin, E., Hancock, B., Jonsson, A. H., Seifert, J., Feser, M. L., Norris, J. M., Cao, Y., Apruzzese, W., Bridges, S. L., Bykerk, V., Goodman, S., Donlin, L., Firestein, G. S., Perlman, H., Bathon, J. M., Hughes, L. B., Tabechian, D., Filer, A., Pitzalis, C., H. Anolik, J., Moreland, L., Guthridge, J. M., James, J. A., Brenner, M. B., Raychaudhuri, S., Sparks, J. A., The Accelerating Medicines Partnership RA/SLE Network,, Holers, V. M., Deane, K. D., Lederer, J. A., Rao, D. A., Zhang, F.. 2023-07-04. Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis. https://doi.org/10.1101/2023.07.03.547507

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