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.
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.
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