T Cell-Dependent Affinity Maturation and Innate Immune Pathways Differentially Drive Autoreactive B Cell Responses in Rheumatoid Arthritis.
T Cell-Dependent Affinity Maturation and Innate Immune Pathways Differentially Drive Autoreactive B Cell Responses in Rheumatoid Arthritis.
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DOI：
10.1002/art.40578
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发表时间：
2018-11
期刊：
影响因子：
--
通讯作者：
Robinson WH
中科院分区：
文献类型：
--
作者：
Lu DR;McDavid AN;Kongpachith S;Lingampalli N;Glanville J;Ju CH;Gottardo R;Robinson WH
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. 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. 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. 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.
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