Immunoglobulin A-specific Deficiency Induces Spontaneous Inflammation Specifically in the Ileum

Overview

Journal Gut

Specialty Gastroenterology

Date 2021 May 8

PMID 33963042

Citations 19

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

Affiliations

Soon will be listed here.

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; IgA) 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 Ca biosensor showed that IgA had elevated Ca signalling in Peyer's patch B cells. On the other hand, IgA 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.

Citing Articles

Gut IgA functionally interacts with systemic IgG to enhance antipneumococcal vaccine responses.

Gutzeit C, Grasset E, Matthews D, Maglione P, Britton G, Miller H Sci Adv. 2025; 11(7):eado9455.

PMID: 39937896 PMC: 11817949. DOI: 10.1126/sciadv.ado9455.

Microbial succinate promotes the response to metformin by upregulating secretory immunoglobulin a in intestinal immunity.

Zhang Y, Wang A, Zhao W, Qin J, Zhang Y, Liu B Gut Microbes. 2025; 17(1):2450871.

PMID: 39812329 PMC: 11740685. DOI: 10.1080/19490976.2025.2450871.

Metabolic rewiring controlled by HIF-1α tunes IgA-producing B-cell differentiation and intestinal inflammation.

Meng X, Asadi-Asadabad S, Cao S, Song R, Lin Z, Safhi M Cell Mol Immunol. 2024; 22(1):54-67.

PMID: 39543372 PMC: 11686098. DOI: 10.1038/s41423-024-01233-y.

Soil microbiome characterization and its future directions with biosensing.

DeFord L, Yoon J J Biol Eng. 2024; 18(1):50.

PMID: 39256848 PMC: 11389470. DOI: 10.1186/s13036-024-00444-1.

Gut microbiota contributes to high-altitude hypoxia acclimatization of human populations.

Su Q, Zhuang D, Li Y, Chen Y, Wang X, Ge M Genome Biol. 2024; 25(1):232.

PMID: 39198826 PMC: 11350960. DOI: 10.1186/s13059-024-03373-w.

References

Adachi T, Tsubata T . FRET-based Ca2+ measurement in B lymphocyte by flow cytometry and confocal microscopy. Biochem Biophys Res Commun. 2008; 367(2):377-82. DOI: 10.1016/j.bbrc.2007.12.142. View

Fagarasan S, Honjo T . Regulation of IgA synthesis at mucosal surfaces. Curr Opin Immunol. 2004; 16(3):277-83. DOI: 10.1016/j.coi.2004.03.005. View

Onizawa M, Nagaishi T, Kanai T, Nagano K, Oshima S, Nemoto Y . Signaling pathway via TNF-alpha/NF-kappaB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis. Am J Physiol Gastrointest Liver Physiol. 2009; 296(4):G850-9. DOI: 10.1152/ajpgi.00071.2008. View

Manfredi R, Coronado O, Marinacci G, Righi M, Calza L . Chron's disease, rare association with selective IgA immunodeficiency, and development of life-threatening bacterial infections. Scand J Infect Dis. 2004; 36(6-7):523-4. DOI: 10.1080/00365540410020190. View

Bunker J, Flynn T, Koval J, Shaw D, Meisel M, McDonald B . Innate and Adaptive Humoral Responses Coat Distinct Commensal Bacteria with Immunoglobulin A. Immunity. 2015; 43(3):541-53. PMC: 4575282. DOI: 10.1016/j.immuni.2015.08.007. View

Yamaji O, Nagaishi T, Totsuka T, Onizawa M, Suzuki M, Tsuge N . The development of colitogenic CD4(+) T cells is regulated by IL-7 in collaboration with NK cell function in a murine model of colitis. J Immunol. 2012; 188(6):2524-36. DOI: 10.4049/jimmunol.1100371. View

Kawamoto S, Tran T, Maruya M, Suzuki K, Doi Y, Tsutsui Y . The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Science. 2012; 336(6080):485-9. DOI: 10.1126/science.1217718. View

Palm N, de Zoete M, Cullen T, Barry N, Stefanowski J, Hao L . Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell. 2014; 158(5):1000-1010. PMC: 4174347. DOI: 10.1016/j.cell.2014.08.006. View

Ludvigsson J, Neovius M, Hammarstrom L . Association between IgA deficiency & other autoimmune conditions: a population-based matched cohort study. J Clin Immunol. 2014; 34(4):444-51. DOI: 10.1007/s10875-014-0009-4. View

10.

Suzuki M, Nagaishi T, Yamazaki M, Onizawa M, Watabe T, Sakamaki Y . Myosin light chain kinase expression induced via tumor necrosis factor receptor 2 signaling in the epithelial cells regulates the development of colitis-associated carcinogenesis. PLoS One. 2014; 9(2):e88369. PMC: 3919773. DOI: 10.1371/journal.pone.0088369. View

11.

Achatz G, Nitschke L, Lamers M . Effect of transmembrane and cytoplasmic domains of IgE on the IgE response. Science. 1997; 276(5311):409-11. DOI: 10.1126/science.276.5311.409. View

12.

Pizarro T, Pastorelli L, Bamias G, Garg R, Reuter B, Mercado J . SAMP1/YitFc mouse strain: a spontaneous model of Crohn's disease-like ileitis. Inflamm Bowel Dis. 2011; 17(12):2566-84. PMC: 3154989. DOI: 10.1002/ibd.21638. View

13.

Williams B, Hornig M, Parekh T, Lipkin W . Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. mBio. 2012; 3(1). PMC: 3252763. DOI: 10.1128/mBio.00261-11. View

14.

Harriman G, Bogue M, Rogers P, Finegold M, Pacheco S, Bradley A . Targeted deletion of the IgA constant region in mice leads to IgA deficiency with alterations in expression of other Ig isotypes. J Immunol. 1999; 162(5):2521-9. View

15.

Pabst O . New concepts in the generation and functions of IgA. Nat Rev Immunol. 2012; 12(12):821-32. DOI: 10.1038/nri3322. View

16.

Yel L . Selective IgA deficiency. J Clin Immunol. 2010; 30(1):10-6. PMC: 2821513. DOI: 10.1007/s10875-009-9357-x. View

17.

Kaisho T, Schwenk F, Rajewsky K . The roles of gamma 1 heavy chain membrane expression and cytoplasmic tail in IgG1 responses. Science. 1997; 276(5311):412-5. DOI: 10.1126/science.276.5311.412. View

18.

Wasilewska J, Kaczmarski M, Stasiak-Barmuta A, Tobolczyk J, Kowalewska E . Low serum IgA and increased expression of CD23 on B lymphocytes in peripheral blood in children with regressive autism aged 3-6 years old. Arch Med Sci. 2012; 8(2):324-31. PMC: 3361046. DOI: 10.5114/aoms.2012.28561. View

19.

Nagaishi T, Pao L, Lin S, Iijima H, Kaser A, Qiao S . SHP1 phosphatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms. Immunity. 2006; 25(5):769-81. DOI: 10.1016/j.immuni.2006.08.026. View

20.

Watabe T, Nagaishi T, Tsugawa N, Kojima Y, Jose N, Hosoya A . B cell activation in the cecal patches during the development of an experimental colitis model. Biochem Biophys Res Commun. 2018; 496(2):367-373. DOI: 10.1016/j.bbrc.2018.01.053. View