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

The ability of most selective IgA deficient (SIgAD) patients to remain apparently healthy has been a persistent clinical conundrum. Compensatory mechanisms, including IgM, have been proposed, yet it remains unclear how secretory IgA and IgM work together in the mucosal system, and on a larger scale, whether the systemic and mucosal anti-commensal responses are redundant or possess unique features. To address this gap in knowledge, we developed an integrated host-commensal approach combining microbial flow cytometry and metagenomic sequencing (mFLOW-Seq) to comprehensively define the population of microbes that induce mucosal and systemic antibodies. We coupled this innovative approach with high dimensional profiling of the peripheral immune system to study a cohort of pediatric SIgAD patients and household control siblings. We find that mucosal and systemic antibody networks cooperate to maintain homeostasis by targeting a common subset of commensal microbes. In IgA deficient mice and humans, we find dysregulated immune system characterized by elevated levels of inflammatory cytokines, enhanced follicular CD4 T helper cell frequency and activation, altered CD8 T cell activation state and increased translocation of specific bacterial taxa associated with elevated levels of systemic IgG targeting of fecal microbiota. While SIgAD is clinically defined by absence of serum IgA, the symptomatology and immune dysregulation were concentrated in the subjects who were also fecal IgA deficient. These findings reveal that mucosal IgA deficiency leads to aberrant systemic exposures and immune responses to commensal microbes which drive an increase in the likelihood of humoral and cellular immune dysregulation and symptomatic disease in IgA deficient patients.