Selective IgA deficiency alters systemic immune response to commensal gut microbiome

Abstract

Immunoglobulin A (IgA) is a fundamental component of mucosal immunity, but only ∼1/3 of patients with selective IgA deficiency (SIgAD) are symptomatic with increased rates of allergy, infection and/or autoimmunity. We cannot yet explain or predict the variability in the clinical phenotype so we sought to investigate whether IgA impacts access of gut microbes to the systemic immune compartment and immune function. We recruited a cohort of pediatric SIgAD patients, with unaffected sibling controls and collected blood and stool. We performed immune profiling (flow cytometry and CyTOF) and microbial flow cytometry (mFlow) and metagenomic sequencing. In mFlow, patient’s serum is added to their stool microbes and Ig binding to these microbes is measured by flow cytometry (to measure anti-commensal responses). Stool microbes can then be sorted based on whether bound IgA, IgM and/or IgG and sequenced (in addition to bulk stool metagenomic sequencing). Patients who were deficient in both serum and stool IgA had fewer IgA+ memory B cells and IgG+ B cells. Serum cytokine analysis demonstrated a broad increase in inflammatory cytokines in SIgAD patients. SIgAD patients lack IgA bound microbes and have higher frequency of IgG bound microbes. SIgAD has significant impacts on immune phenotype (B cell differentiation, inflammatory cytokine profile and T cell activation) and the access of commensal gut microbes to the systemic immune compartment. We are currently linking these alterations to the diverse phenotypes of IgA deficiency in humans and mice.