IgA deficiency destabilizes immunological homeostasis towards intestinal microbiota and increases the risk of systemic immune dysregulation

Mammals produce large quantities of mucosal and systemic antibodies that maintain the intestinal barrier, shape the intestinal microbiome and promote lifelong mutualism with commensal microbes. Here, we developed an integrated host-commensal approach combining microbial flow cytometry and 16s rRNA gene sequencing to define the core microbes that induce mucosal and systemic antibodies in pediatric selective Immunoglobulin A (IgA) deficient and household control siblings with CyTOF analysis to determine the impacts of IgA deficiency on host cellular immune phenotype. In healthy controls, mucosal secretory IgA and IgM antibodies coat an overlapping subset of microbes, predominantly Firmicutes and Proteobacteria. Serum IgG antibodies target a similar consortium of fecal microbes, revealing connections between mucosal and systemic antibody networks. Unexpectedly, IgM provides limited compensation for IgA in children lacking intestinal IgA. Furthermore, we find broad systemic immune dysregulation in a subset of children and mice lacking IgA, including enhanced IgG targeting of fecal microbiota, elevated levels of inflammatory and allergic cytokines and alterations in T cell activation state. Thus, IgA tunes systemic interactions between the host and commensal microbiota. Understanding how IgA tunes baseline immune tone has implications for predicting and preventing autoimmune, inflammatory and allergic diseases broadly, as well as providing improved prognostic guidance to patients with IgA deficiency. One Sentence SummaryIgA deficiency impairs immune homeostasis toward microbiota in children, increasing the risk of immune dysregulation.