RT Journal Article
SR Electronic
T1 Immunoglobulin A–specific deficiency induces spontaneous inflammation specifically in the ileum
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP gutjnl-2020-322873
DO 10.1136/gutjnl-2020-322873
A1 Takashi Nagaishi
A1 Taro Watabe
A1 Kunihiko Kotake
A1 Toshihiko Kumazawa
A1 Tomomi Aida
A1 Kohichi Tanaka
A1 Ryuichi Ono
A1 Fumitoshi Ishino
A1 Takako Usami
A1 Takamasa Miura
A1 Satomi Hirakata
A1 Hiroko Kawasaki
A1 Naoya Tsugawa
A1 Daiki Yamada
A1 Kazuhiro Hirayama
A1 Soichiro Yoshikawa
A1 Hajime Karasuyama
A1 Ryuichi Okamoto
A1 Mamoru Watanabe
A1 Richard S Blumberg
A1 Takahiro Adachi
YR 2021
UL http://gut.bmj.com/content/early/2021/05/07/gutjnl-2020-322873.abstract
AB Objective Although 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.Design We 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.Results We 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.Conclusion IgA plays an important role in the mucosal homeostasis associated with the regulation of intestinal microbiota and protection against mucosal inflammation especially in the ileum.Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as online supplemental information. DNA sequences were deposited in the DDBJ Sequence Read Archive under accession number DRA005447.