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.
Funder
Tojuro Iijima Foundation for Food Science and Technology
Challenging Exploratory Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology
Joint Usage/Research Program of TMDU Medical Research Institute
Naoki Tsuchida Memorial Research Grant
Practical Research Project for Rare/Intractable Disease from Japan Agency for Medical Research and Development
Mishima Kaiun Memorial Foundation
Scientific Research on Innovative Area from the Japanese Ministry of Education, Culture, Sports, Science and Technology
Scientific Research-B from the Japanese Ministry of Education, Culture, Sports, Science and Technology
Nipponham Foundation
Yamada Foundation
Memorial Fund of Nihon University Medical Alumni Association
Japan Foundation for Applied Enzymology
Scientific Research-S from the Japanese Ministry of Education, Culture, Sports, Science and Technology
RO1 Grants from the National Institutes of Health
Scientific Research-C from the Japanese Ministry of Education, Culture, Sports, Science and Technology
Takeda Science Foundation
Foundation for Advancement of International Science
Abbott Japan Allergy Research Award