Inflammatory modalities shape the IgA repertoire via stochastic processes

Mucosal B cell immunity relies on the constant induction of immunoglobulin A (IgA) in the intestine. In spite of abundant homeostatic IgA, here we 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 auto-reactive IgA in individual colitic mice was indicative of stochastic selection of random B lineages in the inflammatory environment with potentially unforeseeable pathophysiological consequences.