T cell-dependent affinity maturation and innate immune pathways differentially drive autoreactive B cell responses in rheumatoid arthritis. Arthritis & rheumatology (Hoboken, N.J.) Lu, D. R., McDavid, A. N., Kongpachith, S., Lingampalli, N., Glanville, J., Ju, C., Gottardo, R., Robinson, W. H. 2018


OBJECTIVE: Rheumatoid arthritis (RA) is characterized by the activation of B cells that produce anti-citrullinated protein antibodies (ACPA) and rheumatoid factors (RF), but the mechanisms by which tolerance is broken in these B cells remain incompletely understood. Here we investigate whether ACPA and RF B cells break tolerance through distinct molecular mechanisms.METHOD: We developed antigen-tetramers to isolate ACPA- and RF-producing B cells and performed single-cell RNA-sequencing on 2,349 B cells from six RA patients 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 utilized more class-switched isotypes and exhibited more somatic hypermutations relative to RF B cells, and these differences were accompanied by the downregulation of CD72 and upregulation 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, suggesting that these autoantibodies associated with increased inflammation in RA arise from two different molecular mechanisms. This article is protected by copyright. All rights reserved.

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