Immunoglobulin A–specific deficiency induces spontaneous inflammation specifically in the ileum

Abstract

ObjectiveAlthough immunoglobulin A (IgA) is abundantly expressed in the gut and known to be an important component of mucosal barriers against luminal pathogens, its precise function remains unclear. Therefore, we tried to elucidate the effect of IgA on gut homeostasis maintenance and its mechanism.DesignWe generated various IgA mutant mouse lines using the CRISPR/Cas9 genome editing system. Then, we evaluated the effect on the small intestinal homeostasis, pathology, intestinal microbiota, cytokine production, and immune cell activation using intravital imaging.ResultsWe obtained two lines, with one that contained a <50 base pair deletion in the cytoplasmic region of the IgA allele (IgA tail-mutant; IgAtm/tm) and the other that lacked the most constant region of the IgH α chain, which resulted in the deficiency of IgA production (IgA−/−). IgA−/− exhibited spontaneous inflammation in the ileum but not the other parts of the gastrointestinal tract. Associated with this, there were significantly increased lamina propria CD4+ T cells, elevated productions of IFN-γ and IL-17, increased ileal segmented filamentous bacteria and skewed intestinal microflora composition. Intravital imaging using Ca2+ biosensor showed that IgA−/− had elevated Ca2+ signalling in Peyer’s patch B cells. On the other hand, IgAtm/tm seemed to be normal, suggesting that the IgA cytoplasmic tail is dispensable for the prevention of the intestinal disorder.ConclusionIgA plays an important role in the mucosal homeostasis associated with the regulation of intestinal microbiota and protection against mucosal inflammation especially in the ileum.

Metabolites and secretory immunoglobulins: messengers and effectors of the host–microbiota intestinal equilibrium

“…Pigr -/mice, deficient in SIgA and SIgM, display significant degradation of the gut epithelial barrier, as reflected by the leakage of serum proteins and elevated concentrations of fecal albumin [12], lower cecal microbial diversity, and higher susceptibility to dextran sulfate sodium (DSS)-induced colitis compared with wild-type (WT) mice [13]. Mice with selective IgA deficiency (IghA -/-) also host a less diverse microbiota compared with WT littermates, suggesting an important role for IgA in regulating intestinal microbiota and homeostasis [14].…”

“…Indeed, IgG-, IgM-, and IgA-bound bacteria are significantly increased in the feces of patients with IBD compared with healthy controls, and high IgG and IgA bacterial coatings have correlated with CD activity [70,71]. Furthermore, SIgAD is a risk factor for IBD in humans [72] and Igha -/mice display exacerbated colitis [14], reinforcing the importance of IgA in shaping a diverse microbiota and, thus, limiting IBD onset. However, several observations also suggest a detrimental role of increased Ig production in maintaining a state of inflammation.…”

Ingestion of miso regulates immunological robustness in mice

“…These feeds were standardized at a salt content of 1.4 w/w%. IL-22 deficient mice were generated by a genome editing system of the CRISPR/Cas9 as described previously [17]. A transgenic mouse line expressing YC3.60 for intravital imaging was described previously [18].…”

Immunoglobulin A, an Active Liaison for Host-Microbiota Homeostasis

“…Another metagenomic study demonstrated that SIgAD patients had reduced microbial diversity but were enriched with opportunistic bacteria like Escherichia coli [130]. As with humans, the mouse model of IgA deficiency (IgA −/− ) resulted in spontaneous inflammation specifically in the ileum, and segmented filamentous bacteria (SFB) were noted to bloom in IgA −/− mice within the inherited dysbiotic microbiota [131]. As studies linking SIgAD and the gut microbiota are only a few years old, more research is needed to uncover what effects these have on the autoimmune disease progression.…”