Synergistic convergence of microbiota-specific systemic IgG and secretory IgA

Abstract

Background: Besides intestinal barrier function, the host tolerates gut commensals through both innate and adaptive immune mechanisms. It is now clear that gut commensals induce local immunoglobulin A (IgA) responses, but it remains unclear whether anti-microbiota responses remain confined to the gut. Objective: The aim of this study was to investigate systemic and intestinal responses against the whole microbiota under homeostatic conditions, and in the absence of IgA. Methods: We analyzed blood and feces from healthy donors, patients with selective IgA deficiency (SIgAd) and common variable immunodeficiency (CVID). Immunoglobulincoated bacterial repertoires were analyzed by combined bacterial fluorescence-activated cell sorting and 16S rRNA sequencing, and bacterial lysates were probed by western blot analysis with healthy donors serums. Results: Although absent from the healthy gut, serum anti-microbiota IgG are present in healthy individuals, and increased in SIgAd patients. IgG converge with non-overlapping secretory IgA repertoires to target the same bacteria. Each individual targets a diverse, microbiota repertoire whose proportion inversely correlates with systemic inflammation. Finally, Intravenous Immunoglobulin preparations (IVIG) target much less efficiently CVID gut microbiota than healthy microbiota. Conclusion: Secretory IgA is pivotal for induction of tolerance to gut microbiota. SIgAdassociated inflammation is inversely correlated with systemic anti-commensal IgG responses, which may thus serve as a second line of defense. We speculate that SIgAd patients could benefit from oral IgA supplementation. Our data also suggest that IVIG preparations might be supplemented with IgG from IgA deficient patients pools in order to offer a better protection against gut bacterial translocations in CVID. Key Messages:-Systemic IgG and secretory IgA bind a common spectrum of commensals.-Increased proportions of IgG+ microbiota and inflammatory markers in SIgAd.-IVIG poorly target CVID and SIgAd gut microbiota.

Lack of Gut Secretory Immunoglobulin A in Memory B-Cell Dysfunction-Associated Disorders: A Possible Gut-Spleen Axis

“…In the lamina propria, B cells may also switch into IgA in a T cell-independent way (21). The T cell-independent generation of SIgA by B cells may represent a mechanism to generate IgA expressing a wide repertoire of Ig genes, useful to face the thousands of different bacterial species of the microbiota (23,24,42), and to control host-microbiota mutualism, reducing the risk of bacterial translocation and immune activation (43)(44)(45). IgM memory B cells have been shown to home to the gut and to locally switch to IgA (21,46).…”

The Effects of Secretory IgA in the Mucosal Immune System

“…As is well-known, some patients with selective IgA deficiency show clinically asymptomatic or mild infections but have a higher risk of allergy and autoimmunity [61]. Researches show that both secretory IgM and systemic IgG can replace part of sIgA and establish the second defense line [62,63]. Is sIgA a redundant component in the immune system?…”

Current Understanding and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity

“…The disruption of this feedback loop by low IgA levels and an unhealthy microbiome leads to reduction in T R cells and subsequent immune dysregulation. Importantly, systemic IgG responses may be significant in preventing inflammation in those with IgA deficiency as a consequence of microbial dysbiosis (107). Such protective IgG responses may be significantly impaired in some CVID patients, thus predisposing to inflammation and, potentially, autoimmune disease.…”