Dynamic spectrum of ectopic lymphoid B cell activation and hypermutation in the RA synovium characterized by NR4A nuclear receptor expression

Nida Meednu; Javier Rangel-Moreno; Fan Zhang; Katherine Escalera-Rivera; Elisa Corsiero; Edoardo Prediletto; Edward DiCarlo; Susan Goodman; Laura T Donlin; Soumya Raychauduri; Michele Bombardieri; Costantino Pitzalis; Dana E Orange; Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium; Andrew McDavid; Jennifer H Anolik

doi:10.1016/j.celrep.2022.110766

Dynamic spectrum of ectopic lymphoid B cell activation and hypermutation in the RA synovium characterized by NR4A nuclear receptor expression

Cell Rep. 2022 May 3;39(5):110766. doi: 10.1016/j.celrep.2022.110766.

Authors

Nida Meednu¹, Javier Rangel-Moreno¹, Fan Zhang², Katherine Escalera-Rivera³, Elisa Corsiero⁴, Edoardo Prediletto⁴, Edward DiCarlo⁵, Susan Goodman⁶, Laura T Donlin⁶, Soumya Raychauduri⁷, Michele Bombardieri⁴, Costantino Pitzalis⁴, Dana E Orange⁸; Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium; Andrew McDavid⁹, Jennifer H Anolik¹⁰

Affiliations

¹ Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
² Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA 02115, USA.
³ Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA.
⁴ Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute, Queen Mary University of London, EC1M 6BQ, London, UK.
⁵ Department of Pathology and Laboratory Medicine, Hospital for Special Surgery, New York, NY 10021, USA.
⁶ Hospital for Special Surgery, New York, NY 10021, USA; Weill Cornell Medicine, New York, NY, USA.
⁷ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA 02115, USA; Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
⁸ Hospital for Special Surgery, New York, NY 10021, USA; Rockefeller University, New York, NY 10028, USA.
⁹ Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY 14642, USA.
¹⁰ Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA; Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: jennifer_anolik@urmc.rochester.edu.

Abstract

Ectopic lymphoid structures (ELS) can develop in rheumatoid arthritis (RA) synovial tissue, but the precise pathways of B cell activation and selection are not well understood. Here, we identify a synovial B cell population characterized by co-expression of a family of orphan nuclear receptors (NR4A1-3), which is highly enriched in RA synovial tissue. A transcriptomic profile of NR4A synovial B cells significantly overlaps with germinal center light zone B cells and an accrual of somatic hypermutation that correlates with loss of naive B cell state. NR4A B cells co-express lymphotoxins α and β and IL-6, supporting functions in ELS promotion. Expanded and shared clones between synovial NR4A B cells and plasma cells and the rapid upregulation with BCR stimulation point to in situ differentiation. Together, we identify a dynamic progression of B cell activation in RA synovial ELS, with NR4A transcription factors having an important role in local adaptive immune responses.

Keywords: B cells; CP: Immunology; ectopic lymphoid structure; rheumatoid arthritis; single-cell RNA-seq; synovial tissue.

MeSH terms

Arthritis, Rheumatoid*
B-Lymphocytes
Humans
Plasma Cells / metabolism
Receptors, Cytoplasmic and Nuclear / metabolism
Synovial Membrane* / metabolism

Substances

Receptors, Cytoplasmic and Nuclear

Abstract

MeSH terms

Substances

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