Broad Institute of MIT and Harvard , Cambridge, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School , Boston, MA, USA.
J Exp Med. 2023 Apr 3;220(4). doi: 10.1084/jem.20220538. Epub 2023 Feb 8.
Plasma cells (PCs) constitute a significant fraction of colonic mucosal cells and contribute to inflammatory infiltrates in ulcerative colitis (UC). While gut PCs secrete bacteria-targeting IgA antibodies, their role in UC pathogenesis is unknown. We performed single-cell V(D)J- and RNA-seq on sorted B cells from the colon of healthy individuals and patients with UC. A large fraction of B cell clones is shared between different colon regions, but inflammation in UC broadly disrupts this landscape, causing transcriptomic changes characterized by an increase in the unfolded protein response (UPR) and antigen presentation genes, clonal expansion, and isotype skewing from IgA1 and IgA2 to IgG1. We also directly expressed and assessed the specificity of 152 mAbs from expanded PC clones. These mAbs show low polyreactivity and autoreactivity and instead target both shared bacterial antigens and specific bacterial strains. Altogether, our results characterize the microbiome-specific colon PC response and how its disruption might contribute to inflammation in UC.
浆细胞（PCs）构成结肠黏膜细胞的重要部分，并有助于溃疡性结肠炎（UC）的炎症浸润。虽然肠道 PCs 分泌针对细菌的 IgA 抗体，但它们在 UC 发病机制中的作用尚不清楚。我们对来自健康个体和 UC 患者结肠的分选 B 细胞进行了单细胞 V(D)J-和 RNA-seq 分析。很大一部分 B 细胞克隆存在于不同的结肠区域之间，但 UC 中的炎症广泛破坏了这种景观，导致转录组发生变化，其特征是未折叠蛋白反应（UPR）和抗原呈递基因的增加、克隆扩展以及同种型从 IgA1 和 IgA2 向 IgG1 的倾斜。我们还直接表达和评估了来自扩增的 PC 克隆的 152 种 mAb 的特异性。这些 mAb 显示出低的多反应性和自身反应性，而是针对共享的细菌抗原和特定的细菌菌株。总之，我们的研究结果描述了微生物组特异性结肠 PC 反应，以及其破坏如何导致 UC 中的炎症。
