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,
Andrew McDavid,
Jennifer H. Anolik
Affiliations
Nida Meednu
Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
Javier Rangel-Moreno
Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
Fan Zhang
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
Katherine Escalera-Rivera
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
Elisa Corsiero
Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute, Queen Mary University of London, EC1M 6BQ, London, UK
Edoardo Prediletto
Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute, Queen Mary University of London, EC1M 6BQ, London, UK
Edward DiCarlo
Department of Pathology and Laboratory Medicine, Hospital for Special Surgery, New York, NY 10021, USA
Susan Goodman
Hospital for Special Surgery, New York, NY 10021, USA; Weill Cornell Medicine, New York, NY, USA
Laura T. Donlin
Hospital for Special Surgery, New York, NY 10021, USA; Weill Cornell Medicine, New York, NY, USA
Soumya Raychauduri
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
Michele Bombardieri
Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute, Queen Mary University of London, EC1M 6BQ, London, UK
Costantino Pitzalis
Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute, Queen Mary University of London, EC1M 6BQ, London, UK
Dana E. Orange
Hospital for Special Surgery, New York, NY 10021, USA; Rockefeller University, New York, NY 10028, USA
Andrew McDavid
Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY 14642, USA
Jennifer H. Anolik
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; Corresponding author
Summary: 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.
