IgA deficiency Alters Systemic Immune Response to Commensal Gut Microbes

Selective IgA deficiency (sIgAD) is the most common primary immune deficiency. Symptomatic patients can experience increased atopy, recurrent infections or autoimmunity, though patients are frequently asymptomatic. However, we lack prognostic markers. Since IgA promotes homeostasis with commensal microbes, we investigated whether sIgAD impaired commensal microbe compartmentalization and altered systemic immune responses Blood and fecal samples were collected from 15 pairs of pediatric sIgAD patients and IgA sufficient siblings. Deep immunoprofiling using flow cytometry, CyTOF, cytokine analysis and ELISAs for Ig binding to fecal microbes was combined with metagenomic analysis of fecal microbiomes and microbial flow cytometry (mFLOW) of the IgA, IgG and IgM bound fecal microbiomes. mFLOW was performed by applying patient’s serum antibodies to their fecal microbes, assessing binding of immunoglobulin isotypes and metagenomic sequencing of Ig-bound microbiomes. Higher frequency of fecal microbes targeted by serum IgG (24.3% vs. 14.3%) and elevated serum sCD14 in sIgAD, indicating enhanced systemic immune response against commensals. We identified microbes enriched in sIgAD patients and microbes that selectively induce a systemic IgG response in sIgAD. Unexpectedly, 15% of sIgAD patients had normal stool IgA, and those deficient in serum and stool IgA had fewer IgA+ memory B cells. We built a controlled pediatric cohort to investigate the effect of sIgAD on systemic immune responses to commensal organisms and used systems immunology strategies to analyze this multimodal dataset. sIgAD has significant impacts on immunophenotype and access of the systemic immune response to commensal gut microbes. These findings provide novel strategies for developing prognostic markers.