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Some gut bacterial pathogens can escape antibody-mediated immunity by changing surface-exposed antigens, such as O-antigens. But by using vaccines targeting specific O-antigens to induce immunoglobulin A responses in the gut, such pathogens can also be directed to evolve towards expressing O-antigen variants that impair gut colonization.

Secretory IgA protects mucosal surfaces. Honjo and colleagues show that somatic hypermutation of IgA dependent on the cytidine deaminase AID is necessary to maintain gut immune homeostasis and shapes the intestinal microflora population. To elucidate the specific role of somatic hypermutation (SHM) in mucosal immunity, we generated mice carrying a knock-in point mutation in Aicda , which encodes activation-induced cytidine deaminase (AID), an enzyme essential to SHM and class-switch recombination (CSR). These mutant AID G23S mice had much less SHM but had normal amounts of immunoglobulin in both serum and intestinal secretions. AID G23S mice developed hyperplasia of germinal center B cells in gut-associated lymphoid tissues, accompanied by expansion of microflora in the small intestine. Moreover, AID G23S mice had more translocation of Yersinia enterocolitica into mesenteric lymph nodes and were more susceptible than wild-type mice to oral challenge with cholera toxin. Together our results indicate that SHM is critical in maintaining intestinal homeostasis and efficient mucosal defense.

IgA is the most abundantly produced antibody in the body and plays a crucial role in gut homeostasis and mucosal immunity. IgA forms a dimer that covalently associates with the joining (J) chain, which is essential for IgA transport into the mucosa. Here, we demonstrate that the marginal zone B and B-1 cell-specific protein (MZB1) interacts with IgA through the α-heavy-chain tailpiece dependent on the penultimate cysteine residue and prevents the intracellular degradation of α-light-chain complexes. Moreover, MZB1 promotes J-chain binding to IgA and the secretion of dimeric IgA. MZB1-deficient mice are impaired in secreting large amounts of IgA into the gut in response to acute inflammation and develop severe colitis. Oral administration of a monoclonal IgA significantly ameliorated the colitis, accompanied by normalization of the gut microbiota composition. The present study identifies a molecular chaperone that promotes J-chain binding to IgA and reveals an important mechanism that controls the quantity, quality, and function of IgA.

BackgroundThe imbalance of commensal bacteria is called dysbiosis in intestinal microflora. Secreted IgA in the intestinal lumen plays an important role in the regulation of microbiota. Although dysbiosis of gut bacteria is reported in IBD patients, it remains unclear what makes dysbiosis of their microflora. The intervention method for remedy of dysbiosis in IBD patients is not well established. In this study, we focused on the quality of human endogenous IgA and investigated whether mouse monoclonal IgA which binds to selectively colitogenic bacteria can modulate human gut microbiota with IBD patients.MethodsIgA-bound and -unbound bacteria were sorted by MACS and cell sorter. Sorted bacteria were analyzed by 16S rRNA sequencing to investigate what kinds of bacteria endogenous IgA or mouse IgA recognized in human gut microbiota. To evaluate the effect of mouse IgA, gnotobiotic mice with IBD patient microbiota were orally administrated with mouse IgA and analyzed gut microbiota.ResultsWe show that human endogenous IgA has abnormal binding activity to gut bacteria in IBD patients. Mouse IgA can bind to human microbiota and bind to selectively colitogenic bacteria. The rW27, especially, has a growth inhibitory activity to human colitogenic bacteria. Furthermore, oral administration of mouse IgA reduced an inflammation biomarker, fecal lipocalin 2, in mice colonized with IBD patient-derived microbiota, and improved dysbiosis of IBD patient sample.ConclusionOral treatment of mouse IgA can treat gut dysbiosis in IBD patients by modulating gut microbiota.

W27 monoclonal immunoglobulin A (IgA) suppresses pathogenic Escherichia coli cell growth; however, its effect on the human intestine remains unclear. We aimed to determine how W27 IgA affects the human colonic microbiota using the in vitro microbiota model. This model was established using fecal samples collected from 12 healthy volunteers; after anaerobic cultivation, each model was found to retain the genera found in the original human fecal samples. After pre-incubating W27 IgA with the respective fecal sample under aerobic conditions, the mixture of W27 IgA (final concentration, 0.5 μg/mL) and each fecal sample was added to the in vitro microbiota model and cultured under anaerobic conditions. Next-generation sequencing of the bacterial 16S rRNA gene revealed that W27 IgA significantly decreased the relative abundance of bacteria related to the genus Escherichia in the model. Additionally, at a final concentration of 5 μg/mL, W27 IgA delayed growth in the pure culture of Escherichia coli isolated from human fecal samples. Our study thus revealed the suppressive effect of W27 IgA on the genus Escherichia at relatively low-concentrations and the usefulness of an in vitro microbiota model to evaluate the effect of IgA as a gut microbiota regulator.

Introduction: Gut microbiota alterations cause inflammation in patients with ulcerative colitis (UC). Fecal microbiota transplantation (FMT) enables manipulating the microbiota’s composition, but the mechanisms underlying colonization of the posttransplantation microbiota are poorly understood. Methods: In this open-label, nonrandomized study, the FMT efficacy and changes in the gut microbiota were evaluated in 8 UC patients with mild-to-moderately active endoscopic colonic lesions. Compositional changes in the fecal and mucosal microbiotas between donors and recipients were examined via 16S rRNA-based sequencing. To investigate the effects of oral corticosteroids on microbiota colonization, FMT was performed in germ-free prednisolone (PSL)-administered mice to examine the factors determining colonization. Results: Four UC patients achieved clinical remission (CR) after FMT, and 3 also achieved endoscopic remission. The fecal microbiotas of the CR patients changed similar to those of the donors after FMT. The mucin-coding gene, MUC2, was less expressed in the colons of the PSL-dependent patients than in the PSL-free patients. In the mice, PSL treatment decreased the fecal mucin production and altered the posttransplantation fecal microbiota composition. Adding either exogenous mucin or the mucin secretagogue, rebamipide, partially alleviated the PSL-induced dysbiosis of the gut microbiota. Administering rebamipide with FMT from healthy donors relieved inflammation in mice with Enterococcus faecium-induced colitis. Conclusion: Colonic mucin controlled the gut microbiota composition, and oral corticosteroid treatment modified the gut microbiota partly by reducing the colonic mucin.

Activation-induced cytidine deaminase (AID) is a molecule central to initiating class switch recombination, somatic hypermutation, and gene conversion of Ig genes. However, its mechanism to initiate these genetic alterations is still unclear. AID can convert cytosine to uracil on either mRNA or DNA and is involved in DNA cleavage. Although these events are expected to take place in the nucleus, overexpressed AID was found predominantly in the cytoplasm. Here, we demonstrated that AID is a nucleocytoplasmic shuttling protein with a bipartite nuclear localization signal and a nuclear export signal in its N and C termini, respectively. In addition to previously identified genetic, structural, and biochemical similarities of AID with apolipoprotein B mRNA editing catalytic polypeptide 1, an RNA editing enzyme of ApoB100 mRNA, the present finding provides another aspect to their resemblance, suggesting that both may have homologous reaction mechanisms.

Activation-induced cytidine deaminase (AID) is essential for class-switch recombination (CSR) and somatic hypermutation (SHM). Mutants with changes in the C-terminal region of AID retain SHM but lose CSR activity. Here we describe five mutants with alterations in the N-terminal region of AID that caused selective deficiency in SHM but retained CSR, suggesting that the CSR and SHM activities of AID may dissociate via interaction of CSR- or SHM-specific cofactors with different domains of AID. Unlike cells expressing C-terminal AID mutants, B cells expressing N-terminal AID mutants had mutations in the switch μ region, indicating that such mutations are generated by reactions involved in CSR but not SHM. Thus, we propose that separate domains of AID interact with specific cofactors to regulate these two distinct genetic events in a target-specific way.