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.
IgA-deficient humans exhibit gut microbiota dysbiosis despite secretion of compensatory IgM
