Immunoglobulin A-specific deficiency induces spontaneous inflammation specifically in the ileum.

Abstract

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.

• Authors: Takashi Nagaishi, Taro Watabe, Kunihiko Kotake, Toshihiko Kumazawa, Tomomi Aida, Kohichi Tanaka, Ryuichi Ono, Fumitoshi Ishino, Takako Usami, Takamasa Miura, Satomi Hirakata, Hiroko Kawasaki, Naoya Tsugawa, Daiki Yamada, Kazuhiro Hirayama, Soichiro Yoshikawa, Hajime Karasuyama, Ryuichi Okamoto, Mamoru Watanabe, Richard S Blumberg, Takahiro Adachi
• Journal: Gut (Gut) Vol. 71 Issue 3 Pg. 487-496 (03 2022) ISSN: 1468-3288 [Electronic] England
• PMID: 33963042 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Cytokines
• Immunoglobulin A

Topics

• Animals
• B-Lymphocytes (physiology)
• Cytokines (metabolism)
• Disease Models, Animal
• Female
• Gastrointestinal Microbiome
• Homeostasis
• Ileitis (etiology, metabolism, pathology)
• Ileum (metabolism, pathology, ultrastructure)
• Immunoglobulin A (physiology)
• Inflammation (etiology, metabolism, pathology)
• Intravital Microscopy
• Male
• Mice
• Mice, Mutant Strains
• T-Lymphocytes (physiology)