T Cell–Dependent Affinity Maturation and Innate Immune Pathways Differentially Drive Autoreactive B Cell Responses in Rheumatoid Arthritis

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Abstract
Objective: Rheumatoid arthritis (RA) is characterized by the activation of B cells that produce anti–citrullinated protein antibodies (ACPAs) and rheumatoid factors (RFs), but the mechanisms by which tolerance is broken in these B cells remain incompletely understood. We undertook this study to investigate whether ACPA+ and RF+ B cells break tolerance through distinct molecular mechanisms.Methods: We developed antigen–tetramers to isolate ACPA+ and RF+ B cells and performed single‐cell RNA sequencing on 2,349 B cells from 6 RA patients and 1 healthy donor to analyze their immunoglobulin repertoires and transcriptional programs. Prominent immunoglobulins were expressed as monoclonal antibodies and tested for autoantigen reactivity.Results: ACPA+ and RF+ B cells were enriched in the peripheral blood of RA patients relative to healthy controls. Characterization of patient‐derived monoclonal antibodies confirmed ACPA and RF targeting of tetramer‐specific B cells at both antigen‐inexperienced and affinity‐matured B cell stages. ACPA+ B cells used more class‐switched isotypes and exhibited more somatic hypermutations relative to RF+ B cells, and these differences were accompanied by down‐regulation of CD72 and up‐regulation of genes that promote class‐switching and T cell–dependent responses. In contrast, RF+ B cells expressed transcriptional programs that stimulate rapid memory reactivation through multiple innate immune pathways. Coexpression analysis revealed that ACPA+ and RF+ B cell–enriched genes belong to distinct transcriptional regulatory networks.Conclusion: Our findings suggest that ACPA+ and RF+ B cells are imprinted with distinct transcriptional programs, which suggests that these autoantibodies associated with increased inflammation in RA arise from 2 different molecular mechanisms.
Funding Information
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR-063676, U01-AI-101981, U19-AI-11049103, UH2-AR-067676)

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