Inflammatory modalities shape the IgA repertoire via stochastic processes

Mucosal B-cell immunity relies on the constant induction of IgA in the intestine. In spite of abundant homeostatic IgA, we here present further amplification of IgA plasma cells during intestinal inflammation that was linked to massive clonal expansion of dominant B lineages. We characterized the inducible B cell response during colitis and show the properties of intestinal IgA produced by adaptive and innate B cell subsets. Fab-dependent specific recognition of individual commensal taxa by inflammation-induced IgA was associated with signs of affinity maturation and cross-reactivity to cellular autoantigens. However, despite the principal ability of mucosal B cells to specifically induce microbiota-targeting IgA, the vast majority of inflammation-induced intestinal IgA was microbiota-non-reactive, generated upon clonal burst of germline-encoded bystanders. Unpredictable variation in the prevalence of microbiota- and autoreactive IgA in individual colitic mice was indicative for stochastic selection of random B lineages in the inflammatory environment with potentially unforeseeable pathophysiological consequences.

黏膜B细胞免疫（mucosal B-cell immunity）依赖于肠道内免疫球蛋白A（Immunoglobulin A，IgA）的持续诱导合成。尽管机体内存在大量稳态状态下的IgA，本研究仍揭示了肠道炎症进程中IgA浆细胞的进一步扩增现象，该过程与优势B细胞谱系的大规模克隆扩增紧密关联。我们对结肠炎（colitis）发生过程中的诱导性B细胞应答开展了系统性表征，并阐明了适应性及先天B细胞亚群所产生的肠道IgA的分子特性。炎症诱导产生的IgA通过Fab段依赖性特异性识别单一共生类群（commensal taxa）的现象，与亲和力成熟（affinity maturation）特征以及对细胞自身抗原（autoantigens）的交叉反应性密切相关。然而，尽管黏膜B细胞在理论上能够特异性诱导靶向微生物群（microbiota）的IgA产生，但绝大多数炎症诱导产生的肠道IgA并不与微生物群发生反应，此类IgA由种系编码的旁观者B细胞发生克隆爆发所生成。个体结肠炎小鼠体内靶向微生物群与自身反应性IgA的丰度存在不可预测的差异，这提示炎症微环境中随机B细胞谱系的随机选择可能引发难以预见的病理生理后果。