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

Abstract

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.

Secretory IgM (sIgM) is an ancient master regulator of microbiota homeostasis and metabolism

“…Here we show that a large portion of the trout gut microbiota is double-coated by sIgT and sIgM, while the largest proportion is sIgT single coated, being the smallest percentage single sIgM coated. Interestingly, two reports have shown that the human gut microbiota follows a similar pattern of coating with sIgA and sIgM double-coated microbiota being the most prevalent coating mode (5,18), while in another human study they reported different proportions of sIgA/sIgM coating (19). Among many other possibilities, it is likely that such differences in gut sIg microbiota coating in humans are due to methodological methods in the assessment of sIg coating, or the use of different human cohorts with very different genetic backgrounds.…”

“…Our follow-up studies on fish sIgT demonstrated that control of microbiota homeostasis by sIgs is a primordial function of specialized mucosal sIgs already found in early vertebrates such as teleosts ( 10 ). However, the current dogma that sIg-dependent microbiota homeostasis is mediated by sIgA or sIgT in vertebrates, has recently been challenged by several studies showing that significant proportions of human and fish microbiota are coated by sIgM in the gut and other mucosal surfaces ( 5, 18, 19 ). Because sIgM does not coat the microbiota of mice under either specific-pathogen-free (SPF) or non-SPF conditions ( 5, 7 ), laboratory mouse models to study the potential role of sIgM in host-microbiome interactions are not suitable to address this question.…”

Suppression of epithelial proliferation and tumourigenesis by immunoglobulin A

“…IgA is known to control mucosal pathogens 12–14 , but the impact of IgA on inflammatory diseases and malignancy remains unclear. Recent studies have indicated that IgA deficiency is associated with changes in microbiota and systemic inflammation 4,6,7,15 , which may be more pronounced in patients with undetectable IgA 8 . A compensatory increase in the other major secreted antibody isotype, IgM, is insufficient to rescue these effects 4 .…”

Exploring Immunome and Microbiome Interplay in Reproductive Health: Current Knowledge, Challenges, and Novel Diagnostic Tools

“…IgA prevents microbial translocation and related immune dysregulation, leading to milder symptoms in SIgAD patients. 190 Furthermore, a study underscores commensal bacteria's impact on serum IgA levels, emphasizing T cell-dependent systemic responses. It links microbiota composition to serum IgA concentrations and identifies protective roles against sepsis when using mFLOW-Seq for microbiota analysis.…”