Journal Article

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

Ishino, Fumitoshi, Kotake, Kunihiko, Tsugawa, Naoya, Watanabe, Mamoru, Blumberg, Richard S, Kumazawa, Toshihiko, Miura, Takamasa, Kawasaki, Hiroko, Yamada, Daiki, Hirayama, Kazuhiro, Adachi, Takahiro, Karasuyama, Hajime, Usami, Takako, Yoshikawa, Soichiro, Nagaishi, Takashi, Tanaka, Kohichi, Ono, Ryuichi, Aida, Tomomi, Hirakata, Satomi, Watabe, Taro, Okamoto, Ryuichi

2022

Overview

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.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD
• Subject: Animals / Autoimmune diseases / B-Lymphocytes - physiology / Biosensors / Bowel disease / Calcium imaging / Calcium signalling / CD4 antigen / Cell activation / College professors / Colon / Constant region / CRISPR / Cytokines / Cytokines - metabolism / Digestive system / Disease Models, Animal / Female / Filamentous bacteria / Gastrointestinal Microbiome / Gastrointestinal tract / Gene deletion / Genome editing / Genomes / Heavy chains / Homeostasis / IgA / ileitis / Ileitis - etiology / Ileitis - metabolism / Ileitis - pathology / Ileum - metabolism / Ileum - pathology / Ileum - ultrastructure / Immunoglobulin A / Immunoglobulin A - physiology / Immunoglobulins / Inflammation / Inflammation - etiology / Inflammation - metabolism / Inflammation - pathology / Interleukin 17 / intestinal bacteria / Intestinal inflammation / Intestinal microflora / Intestine / Intravital Microscopy / Lymphocytes B / Lymphocytes T / Male / Mice / Mice, Mutant Strains / Microbiota / Mucosa / mucosal barrier / Mutants / Mutation / Proteins / Rodents / Scanning electron microscopy / Signal transduction / Small intestine / T-Lymphocytes - physiology / γ-Interferon