以NR4A核受体表达为特征的类风湿性关节炎滑膜中异位淋巴B细胞激活和高突变的动态图谱。

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

作者信息

Meednu Nida, Rangel-Moreno Javier, Zhang Fan, Escalera-Rivera Katherine, Corsiero Elisa, Prediletto Edoardo, DiCarlo Edward, Goodman Susan, Donlin Laura T, Raychauduri Soumya, Bombardieri Michele, Pitzalis Costantino, Orange Dana E, McDavid Andrew, Anolik Jennifer H

机构信息

Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.

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.

出版信息

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

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.

异位淋巴样结构（ELS）可在类风湿关节炎（RA）滑膜组织中形成，但B细胞激活和选择的确切途径尚不清楚。在此，我们鉴定出一类滑膜B细胞群体，其特征是共同表达一组孤儿核受体（NR4A1 - 3），该群体在RA滑膜组织中高度富集。NR4A滑膜B细胞的转录组图谱与生发中心亮区B细胞显著重叠，且体细胞超突变的积累与幼稚B细胞状态的丧失相关。NR4A B细胞共同表达淋巴毒素α和β以及IL - 6，支持其在促进ELS形成中的功能。滑膜NR4A B细胞与浆细胞之间扩增并共享的克隆以及BCR刺激后的快速上调表明其原位分化。总之，我们确定了RA滑膜ELS中B细胞激活的动态过程，其中NR4A转录因子在局部适应性免疫反应中起重要作用。