Suppression of epithelial proliferation and tumorigenesis by IgA

Fagarasan, S. Evolution, development, mechanism and function of IgA in the gut. Curr. Opin. Immunol. 20, 170–177 (2008).Article 
CAS 
PubMed 

Google Scholar 
Pabst, O. & Slack, E. IgA and the intestinal microbiota: the importance of being specific. Mucosal Immunol. 13, 12–21 (2020).Article 
CAS 
PubMed 

Google Scholar 
Huus, K. E., Petersen, C. & Finlay, B. B. Diversity and dynamism of IgA−microbiota interactions. Nat. Rev. Immunol. 21, 514–525 https://doi.org/10.1038/s41577-021-00506-1 (2021).Article 
CAS 
PubMed 

Google Scholar 
Catanzaro, J. R. et al. IgA-deficient humans exhibit gut microbiota dysbiosis despite secretion of compensatory IgM. Sci. Rep. 9, 13574 (2019).Article 
PubMed 
PubMed Central 

Google Scholar 
Yel, L. Selective IgA deficiency. J. Clin. Immunol. 30, 10–16 https://doi.org/10.1007/s10875-009-9357-x (2010).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Fadlallah, J. et al. Microbial ecology perturbation in human IgA deficiency. Sci. Transl. Med. 10, eaan1217 (2018).Article 
PubMed 

Google Scholar 
Conrey, P. E. et al. IgA deficiency destabilizes homeostasis toward intestinal microbes and increases systemic immune dysregulation. Sci. Immunol. 8, eade2335 (2023).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Moll, J. M. et al. Gut microbiota perturbation in IgA deficiency is influenced by IgA-autoantibody status. Gastroenterology 160, 2423–2434 https://doi.org/10.1053/j.gastro.2021.02.053 (2021).Article 
CAS 
PubMed 

Google Scholar 
Shroff, K. E., Meslin, K. & Cebra, J. J. Commensal enteric bacteria engender a self-limiting humoral mucosal immune response while permanently colonizing the gut. Infect. Immun. 63, 3904–3913 (1995).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Singh, K., Chang, C. & Gershwin, M. E. IgA deficiency and autoimmunity. Autoimmun. Rev. 13, 163–177 (2014).Article 
CAS 
PubMed 

Google Scholar 
Ludvigsson, J. F., Neovius, M., Ye, W. & Hammarström, L. IgA deficiency and risk of cancer: a population-based matched cohort study. J. Clin. Immunol. 35, 182–188 (2015).Article 
CAS 
PubMed 

Google Scholar 
Langford, T. D. et al. Central importance of immunoglobulin A in host defense against Giardia spp. Infect. Immun. 70, 11–18 (2002).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Blutt, S. E., Miller, A. D., Salmon, S. L., Metzger, D. W. & Conner, M. E. IgA is important for clearance and critical for protection from rotavirus infection. Mucosal Immunol. 5, 712–719 (2012).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Moor, K. et al. High-avidity IgA protects the intestine by enchaining growing bacteria. Nature 544, 498–502 (2017).Article 
CAS 
PubMed 

Google Scholar 
Jørgensen, S. F. et al. Selective IgA deficiency in humans is associated with reduced gut microbial diversity. J. Allergy Clin. Immunol. 143, 1969–1971(2019).Article 
PubMed 

Google Scholar 
Gatti, R. A. & Good, R. A. Occurrence of malignancy in immunodeficiency diseases: a literature review. Cancer 28, 89–98 (1971).Article 
CAS 
PubMed 

Google Scholar 
Filipovich, A. H., Mathur, A., Kamat, D., Kersey, J. H. & Shapiro, R. S. Lymphoproliferative disorders and other tumors complicating immunodeficiencies. Immunodeficiency 5, 91–112 (1994).CAS 
PubMed 

Google Scholar 
Ludvigsson, J. F., Neovius, M. & Hammarström, L. IgA deficiency & mortality: a population-based cohort study. J. Clin. Immunol. 33, 1317–1324 (2013).Article 
CAS 
PubMed 

Google Scholar 
Cunningham-Rundles, C., Pudifin, D. J., Armstrong, D. & Good, R. A. Selective IgA deficiency and neoplasia. Vox Sang. 38, 61–67 (1980).CAS 
PubMed 

Google Scholar 
Pulvirenti, F. et al. Gastric cancer is the leading cause of death in Italian adult patients with common variable immunodeficiency. Front. Immunol. 9, 2546 (2018).Article 
PubMed 
PubMed Central 

Google Scholar 
Shulzhenko, N. et al. Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut. Nat. Med. 17, 1585–1593 (2011).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Kawamoto, S. et al. The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Science 336, 485–489 (2012).Article 
CAS 
PubMed 

Google Scholar 
Kubinak, J. L. et al. MyD88 signaling in T cells directs IgA-mediated control of the microbiota to promote health. Cell Host Microbe 17, 153–163 (2015).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Suzuki, K. et al. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc. Natl Acad. Sci. USA 101, 1981–1986 (2004).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Fagarasan, S. et al. Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora. Science 298, 1424–1427 (2002).Article 
CAS 
PubMed 

Google Scholar 
Gopalakrishna, K. P. et al. Maternal IgA protects against the development of necrotizing enterocolitis in preterm infants. Nat. Med. 25, 1110–1115 (2019).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Kawamoto, S. et al. Foxp3+ T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity 41, 152–165 (2014).Article 
CAS 
PubMed 

Google Scholar 
Nagashima, K. et al. Identification of subepithelial mesenchymal cells that induce IgA and diversify gut microbiota. Nat. Immunol. 18, 675–682 (2017).Article 
CAS 
PubMed 

Google Scholar 
Peterson, D. A. et al. Characterizing the interactions between a naturally primed immunoglobulin A and its conserved Bacteroides thetaiotaomicron species-specific epitope in gnotobiotic mice. J. Biol. Chem. 290, 12630–12649 https://doi.org/10.1074/jbc.m114.633800 (2015).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Nakajima, A. et al. IgA regulates the composition and metabolic function of gut microbiota by promoting symbiosis between bacteria. J. Exp. Med. 215, 2019–2034 (2018).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Donaldson, G. P. et al. Gut microbiota utilize immunoglobulin A for mucosal colonization. Science 360, 795–800 (2018).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Rollenske, T. et al. Parallelism of intestinal secretory IgA shapes functional microbial fitness. Nature 598, 657–661 https://doi.org/10.1038/s41586-021-03973-7 (2021).Article 
CAS 
PubMed 

Google Scholar 
Harriman, G. R. et al. Targeted deletion of the IgA constant region in mice leads to IgA deficiency with alterations in expression of other Ig isotypes. J. Immunol. 162, 2521–2529 (1999).Article 
CAS 
PubMed 

Google Scholar 
Murthy, A. K., Dubose, C. N., Banas, J. A., Coalson, J. J. & Arulanandam, B. P. Contribution of polymeric immunoglobulin receptor to regulation of intestinal inflammation in dextran sulfate sodium-induced colitis. J. Gastroenterol. Hepatol. 21, 1372–1380 (2006).Article 
CAS 
PubMed 

Google Scholar 
Mathias, A. & Corthésy, B. N-Glycans on secretory component: mediators of the interaction between secretory IgA and gram-positive commensals sustaining intestinal homeostasis. Gut Microbes 2, 287–293 (2011).Article 
PubMed 

Google Scholar 
Kaetzel, C. S. The polymeric immunoglobulin receptor: bridging innate and adaptive immune responses at mucosal surfaces. Immunol. Rev. 206, 83–99 (2005).Article 
CAS 
PubMed 

Google Scholar 
Ramanan, D. et al. An immunologic mode of multigenerational transmission governs a gut Treg setpoint. Cell 181, 1276–1290 (2020).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
van der Post, S., Birchenough, G. M. H. & Held, J. M. NOX1-dependent redox signaling potentiates colonic stem cell proliferation to adapt to the intestinal microbiota by linking EGFR and TLR activation. Cell Rep. 35, 108949 (2021).Article 
PubMed 
PubMed Central 

Google Scholar 
Grivennikov, S. I. et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491, 254–258 (2012).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Ansari, Y. S. E. et al. T follicular helper cell expansion and hyperimmunoglobulinemia with spontaneous IgE production to dietary antigens in IgA-deficient mice. Mucosal Immunol. 18, 481–490 (2025).Article 
PubMed 
PubMed Central 

Google Scholar 
Clay, S. L., Fonseca-Pereira, D. & Garrett, W. S. Colorectal cancer: the facts in the case of the microbiota. J. Clin. Invest. 132, e155101 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Donaldson, G. P., Lee, S. M. & Mazmanian, S. K. Gut biogeography of the bacterial microbiota. Nat. Rev. Microbiol. 14, 20–32 (2015).Article 
PubMed 
PubMed Central 

Google Scholar 
Beumer, J. & Clevers, H. Cell fate specification and differentiation in the adult mammalian intestine. Nat. Rev. Mol. Cell Biol. 22, 39–53 (2021).Article 
CAS 
PubMed 

Google Scholar 
Tsang, D. K. L. et al. A single cell survey of the microbial impacts on the mouse small intestinal epithelium. Gut Microbes 14, 2108281 (2022).Article 
PubMed 
PubMed Central 

Google Scholar 
Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004).Article 
CAS 
PubMed 

Google Scholar 
Rundegren, J. & Arnold, R. R. Differentiation and interaction of secretory immunoglobulin A and a calcium-dependent parotid agglutinin for several bacterial strains. Infect. Immun. 55, 288–292 (1987).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Mollenhauer, J. et al. The genomic structure of the DMBT1gene: evidence for a region with susceptibility to genomic instability. Oncogene 18, 6233–6240 (1999).Article 
CAS 
PubMed 

Google Scholar 
Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015).Article 
PubMed 

Google Scholar 
Madsen, J. et al. CRP-ductin, the mouse homologue of gp-340/deleted in malignant brain tumors 1 (DMBT1), binds gram-positive and gram-negative bacteria and interacts with lung surfactant protein D. Eur. J. Immunol. 33, 2327–2336 (2003).Article 
CAS 
PubMed 

Google Scholar 
Reichhardt, M. P. et al. The salivary scavenger and agglutinin in early life: diverse roles in amniotic fluid and in the infant intestine. J. Immunol. 193, 5240–5248 (2014).Article 
CAS 
PubMed 

Google Scholar 
Hopkins, E. G. D., Roumeliotis, T. I., Mullineaux-Sanders, C., Choudhary, J. S. & Frankel, G. Intestinal epithelial cells and the microbiome undergo swift reprogramming at the inception of colonic Citrobacter rodentium infection. mBio 10, e00062-19 (2019).Article 
PubMed 
PubMed Central 

Google Scholar 
Müller, H., Nagel, C., Weiss, C., Mollenhauer, J. & Poeschl, J. Deleted in malignant brain tumors 1 (DMBT1) elicits increased VEGF and decreased IL-6 production in type II lung epithelial cells. BMC Pulm. Med. 15, 32 (2015).Article 
PubMed 
PubMed Central 

Google Scholar 
Fre, S. et al. Notch signals control the fate of immature progenitor cells in the intestine. Nature 435, 964–968 (2005).Article 
CAS 
PubMed 

Google Scholar 
van Es, J. H. et al. Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959–963 (2005).Article 
PubMed 

Google Scholar 
The Tabula Muris Consortium. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 562, 367–372 (2018).Article 
CAS 

Google Scholar 
The Tabula Sapiens Consortium. The Tabula Sapiens: a multiple-organ, single-cell transcriptomic atlas of humans. Science 376, eabl4896 (2022).Article 

Google Scholar 
Kabatnik, S. et al. Spatial characterization and stratification of colorectal adenomas by deep visual proteomics. iScience 27, 110620 (2024).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Tang, Y. et al. MZB1-mediated IgA secretion suppresses the development and progression of colorectal cancer triggered by gut inflammation. Mucosal Immunol. 17, 450–460 https://doi.org/10.1016/j.mucimm.2023.12.002 (2024).Article 
CAS 
PubMed 

Google Scholar 
Biswas, S. et al. IgA transcytosis and antigen recognition govern ovarian cancer immunity. Nature 591, 464–470 (2021).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Pelka, K. et al. Spatially organized multicellular immune hubs in human colorectal cancer. Cell 184, 4734–4752 (2021).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Dogan, I. et al. Multiple layers of B cell memory with different effector functions. Nat. Immunol. 10, 1292–1299 (2009).Article 
CAS 
PubMed 

Google Scholar 
Robertson, S. J. et al. Comparison of co-housing and littermate methods for microbiota standardization in mouse models. Cell Rep. 27, 1910–1919 (2019).Article 
CAS 
PubMed 

Google Scholar 
Quadros, R. M. et al. Easi-CRISPR: a robust method for one-step generation of mice carrying conditional and insertion alleles using long ssDNA donors and CRISPR ribonucleoproteins. Genome Biol. 18, 92 (2017).Article 
PubMed 
PubMed Central 

Google Scholar 
Dmitrieva-Posocco, O. et al. β-Hydroxybutyrate suppresses colorectal cancer. Nature 605, 160–165 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Brugiroux, S. et al. Genome-guided design of a defined mouse microbiota that confers colonization resistance against Salmonella enterica serovar Typhimurium. Nat. Microbiol. 2, 16215 (2016).Article 
CAS 
PubMed 

Google Scholar 
Mandal, S. et al. Analysis of composition of microbiomes: a novel method for studying microbial composition. Microb. Ecol. Health Dis. 26, 27663 (2015).PubMed 
PubMed Central 

Google Scholar 
Earley, Z. M. et al. GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology. Immunity 56, 43–57 (2023).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Bharathkar, S. K. et al. The structures of secretory and dimeric immunoglobulin A. eLife 9, e56098 (2020).Article 
CAS 

Google Scholar 
Dreyfus, C. et al. Highly Conserved Protective Epitopes on Influenza B Viruses. Science 337, 1343–1348 (2012).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Miyoshi, H. & Stappenbeck, T. S. In vitro expansion and genetic modification of gastrointestinal stem cells in spheroid culture. Nat. Protoc. 8, 2471–2482 (2013).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Sanjana, N. E., Shalem, O. & Zhang, F. Improved vectors and genome-wide libraries for CRISPR screening. Nat. Methods 11, 783–784 (2014).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Roper, J. et al. In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis. Nat. Biotechnol. 35, 569–576 (2017).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar