IgA deficiency destabilizes homeostasis toward intestinal microbes and increases systemic immune dysregulation

Abstract

The ability of most patients with selective immunoglobulin A (IgA) deficiency (SIgAD) 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 have 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 which microbes induce mucosal and systemic antibodies. We coupled this approach with high-dimensional immune profiling to study a cohort of pediatric patients with SIgAD and household control siblings. We found that mucosal and systemic antibody networks cooperate to maintain homeostasis by targeting a common subset of commensal microbes. In IgA-deficiency, we find increased translocation of specific bacterial taxa associated with elevated levels of systemic IgG targeting fecal microbiota. Associated features of immune system dysregulation in IgA-deficient mice and humans included elevated levels of inflammatory cytokines, enhanced follicular CD4 T helper cell frequency and activation, and an altered CD8 T cell activation state. Although SIgAD is clinically defined by the absence of serum IgA, the symptomatology and immune dysregulation were concentrated in the SIgAD participants 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 increase the likelihood of humoral and cellular immune dysregulation and symptomatic disease in patients with IgA deficiency.

Abstract

Mucosal IgA deficiency impairs immune homeostasis toward microbiota in children and mice, increasing the risk of immune dysregulation.

Editor’s summary

Although selective immunoglobin A (IgA) deficiency (SIgAD) is the most common primary human immunodeficiency, the apparently asymptomatic nature of SIgAD in many patients has prompted uncertainty about how necessary IgA is for homeostatic regulation of the commensal gut microbiota. Using a combination of bacterial flow cytometry and 16 S rRNA sequencing, Conrey et al . analyzed secretory and systemic antibody binding to fecal bacteria in a cohort of pediatric patients with SIgAD and their sibling controls. Patients with SIgAD lacking both serum and fecal IgA had higher concentrations of serum IgG reactive with gut bacteria than patients with SIgAD who retained some fecal IgA. These findings indicate that combined loss of systemic and secretory IgA amplifies systemic exposure to gut bacteria, leading to a higher incidence of systemic immune dysregulation. —Ifor R. Williams