Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Rethinking mucosal antibody responses: IgM, IgG and IgD join IgA


Humoral immune responses at mucosal surfaces have historically focused on IgA. Growing evidence highlights the complexity of IgA-inducing pathways and the functional impact of IgA on mucosal commensal bacteria. In the gut, IgA contributes to the establishment of a mutualistic host–microbiota relationship that is required to maintain homeostasis and prevent disease. This Review discusses how mucosal IgA responses occur in an increasingly complex humoral defence network that also encompasses IgM, IgG and IgD. Aside from integrating the protective functions of IgA, these hitherto neglected mucosal antibodies may strengthen the communication between mucosal and systemic immune compartments.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Inductive pathways and protective strategies of intestinal IgA and IgM.
Fig. 2: Impact of gut metabolites on gut IgA and systemic IgG responses.
Fig. 3: IgG in the neonatal gut mucosa and IgD in the aerodigestive mucosa.


  1. 1.

    Sansonetti, P. J. War and peace at mucosal surfaces. Nat. Rev. Immunol. 4, 953–964 (2004).

    CAS  PubMed  Google Scholar 

  2. 2.

    Slack, E. et al. Innate and adaptive immunity cooperate flexibly to maintain host–microbiota mutualism. Science 325, 617–620 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Kato, L. M., Kawamoto, S., Maruya, M. & Fagarasan, S. The role of the adaptive immune system in regulation of gut microbiota. Immunol. Rev. 260, 67–75 (2014).

    CAS  PubMed  Google Scholar 

  4. 4.

    Macpherson, A. J., Yilmaz, B., Limenitakis, J. P. & Ganal-Vonarburg, S. C. IgA function in relation to the intestinal microbiota. Annu. Rev. Immunol. 36, 359–381 (2018).

    CAS  PubMed  Google Scholar 

  5. 5.

    Peterson, D. A., McNulty, N. P., Guruge, J. L. & Gordon, J. I. IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe 2, 328–339 (2007).

    CAS  PubMed  Google Scholar 

  6. 6.

    Okai, S. et al. Intestinal IgA as a modulator of the gut microbiota. Gut Microbes 8, 486–492 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Donaldson, G. P. et al. Gut microbiota utilize immunoglobulin A for mucosal colonization. Science 360, 795–800 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    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). Together with reference 7, this work provides an elegant demonstration of the mechanisms whereby commensal-specific and non-specific IgA responses promote host–microbiota symbiosis and homeostasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Gabanyi, I. et al. Neuro-immune interactions drive tissue programming in intestinal macrophages. Cell 164, 378–391 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

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

    CAS  PubMed  Google Scholar 

  11. 11.

    Fritz, J. H. et al. Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut. Nature 481, 199–203 (2012).

    CAS  Google Scholar 

  12. 12.

    Bermejo, D. A. et al. Trypanosoma cruzi trans-sialidase initiates a program independent of the transcription factors RORγ and Ahr that leads to IL-17 production by activated B cells. Nat. Immunol. 14, 514–522 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Palm, N. W. et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 158, 1000–1010 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Shalapour, S. et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 521, 94–98 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Rojas, O. L. et al. Recirculating intestinal IgA-producing cells regulate neuroinflammation via IL-10. Cell 176, 610–624.e18 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Macpherson, A. J., McCoy, K. D., Johansen, F. E. & Brandtzaeg, P. The immune geography of IgA induction and function. Mucosal Immunol. 1, 11–22 (2008).

    CAS  PubMed  Google Scholar 

  17. 17.

    Gutzeit, C., Magri, G. & Cerutti, A. Intestinal IgA production and its role in host–microbe interaction. Immunol. Rev. 260, 76–85 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Fagarasan, S., Kawamoto, S., Kanagawa, O. & Suzuki, K. Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu. Rev. Immunol. 28, 243–273 (2010).

    CAS  PubMed  Google Scholar 

  19. 19.

    Bunker, J. J. & Bendelac, A. IgA responses to microbiota. Immunity 49, 211–224 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Bunker, J. J. et al. Innate and adaptive humoral responses coat distinct commensal bacteria with immunoglobulin A. Immunity 43, 541–553 (2015). This study shows that TI and TD IgA responses target non-overlapping components of the gut microbiota.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Bunker, J. J. et al. Natural polyreactive IgA antibodies coat the intestinal microbiota. Science 358 (2017).

  22. 22.

    Wilmore, J. R. et al. Commensal microbes induce serum IgA responses that protect against polymicrobial sepsis. Cell Host Microbe 23, 302–311.e3 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Hapfelmeier, S. et al. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science 328, 1705–1709 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Jahnsen, F. L., Baekkevold, E. S., Hov, J. R. & Landsverk, O. J. Do long-lived plasma cells maintain a healthy microbiota in the gut? Trends Immunol. 39, 196–208 (2018).

    CAS  PubMed  Google Scholar 

  25. 25.

    Brandtzaeg, P. & Johansen, F. E. Mucosal B cells: phenotypic characteristics, transcriptional regulation, and homing properties. Immunol. Rev. 206, 32–63 (2005).

    CAS  PubMed  Google Scholar 

  26. 26.

    Phalipon, A. et al. Secretory component: a new role in secretory IgA-mediated immune exclusion in vivo. Immunity 17, 107–115 (2002).

    CAS  PubMed  Google Scholar 

  27. 27.

    Planer, J. D. et al. Development of the gut microbiota and mucosal IgA responses in twins and gnotobiotic mice. Nature 534, 263–266 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Faith, J. J. et al. The long-term stability of the human gut microbiota. Science 341, 1237439 (2013).

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Lindner, C. et al. Age, microbiota, and T cells shape diverse individual IgA repertoires in the intestine. J. Exp. Med. 209, 365–377 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Magri, G. et al. Human secretory IgM emerges from plasma cells clonally related to gut memory B cells and targets highly diverse commensals. Immunity 47, 118–134.e8 (2017). This work demonstrates that the human intestine sustains abundant IgM responses that target a fraction of putatively beneficial commensals together with IgA.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Corthesy, B. Multi-faceted functions of secretory IgA at mucosal surfaces. Front. Immunol. 4, 185 (2013).

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Pasquier, B. et al. Identification of FcαRI as an inhibitory receptor that controls inflammation: dual role of FcRγ ITAM. Immunity 22, 31–42 (2005).

    CAS  PubMed  Google Scholar 

  33. 33.

    Monteiro, R. C. & Van De Winkel, J. G. IgA Fc receptors. Annu. Rev. Immunol. 21, 177–204 (2003).

    CAS  PubMed  Google Scholar 

  34. 34.

    Breedveld, A. & van Egmond, M. IgA and FcαRI: pathological roles and therapeutic opportunities. Front. Immunol. 10, 553 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Shibuya, A. & Honda, S. Immune regulation by Fcα/μ receptor (CD351) on marginal zone B cells and follicular dendritic cells. Immunol. Rev. 268, 288–295 (2015).

    CAS  PubMed  Google Scholar 

  36. 36.

    Mathias, A., Longet, S. & Corthesy, B. Agglutinating secretory IgA preserves intestinal epithelial cell integrity during apical infection by Shigella flexneri. Infect. Immun. 81, 3027–3034 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Lycke, N. Y. & Bemark, M. The regulation of gut mucosal IgA B-cell responses: recent developments. Mucosal Immunol. 10, 1361–1374 (2017).

    CAS  PubMed  Google Scholar 

  38. 38.

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

    CAS  PubMed  Google Scholar 

  39. 39.

    Lindner, C. et al. Diversification of memory B cells drives the continuous adaptation of secretory antibodies to gut microbiota. Nat. Immunol. 16, 880–888 (2015). This seminal study shows how adult intestinal IgA responses largely involve re-entry of pre-existing IgA class-switched memory B cells into mucosal germinal centres.

    CAS  PubMed  Google Scholar 

  40. 40.

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

    CAS  PubMed  Google Scholar 

  41. 41.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Wang, S. et al. MyD88 adaptor-dependent microbial sensing by regulatory T cells promotes mucosal tolerance and enforces commensalism. Immunity 43, 289–303 (2015).

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Hirota, K. et al. Plasticity of Th17 cells in Peyer’s patches is responsible for the induction of T cell-dependent IgA responses. Nat. Immunol. 14, 372–379 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Lecuyer, E. et al. Segmented filamentous bacterium uses secondary and tertiary lymphoid tissues to induce gut IgA and specific T helper 17 cell responses. Immunity 40, 608–620 (2014).

    CAS  PubMed  Google Scholar 

  45. 45.

    Okai, S. et al. High-affinity monoclonal IgA regulates gut microbiota and prevents colitis in mice. Nat. Microbiol. 1, 16103 (2016).

    CAS  PubMed  Google Scholar 

  46. 46.

    Ansaldo, E. et al. Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis. Science 364, 1179–1184 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    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).

    CAS  PubMed  Google Scholar 

  49. 49.

    Cullender, T. C. et al. Innate and adaptive immunity interact to quench microbiome flagellar motility in the gut. Cell Host Microbe 14, 571–581 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Oh, J. Z. et al. TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination. Immunity 41, 478–492 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Fulde, M. et al. Neonatal selection by Toll-like receptor 5 influences long-term gut microbiota composition. Nature 560, 489–493 (2018).

    CAS  PubMed  Google Scholar 

  52. 52.

    Neutra, M. R., Mantis, N. J. & Kraehenbuhl, J. P. Collaboration of epithelial cells with organized mucosal lymphoid tissues. Nat. Immunol. 2, 1004–1009 (2001).

    CAS  PubMed  Google Scholar 

  53. 53.

    Hamada, H. et al. Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine. J. Immunol. 168, 57–64 (2002).

    CAS  PubMed  Google Scholar 

  54. 54.

    Kadaoui, K. A. & Corthesy, B. Secretory IgA mediates bacterial translocation to dendritic cells in mouse Peyer’s patches with restriction to mucosal compartment. J. Immunol. 179, 7751–7757 (2007).

    CAS  PubMed  Google Scholar 

  55. 55.

    Hase, K. et al. Uptake through glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune response. Nature 462, 226–230 (2009).

    CAS  PubMed  Google Scholar 

  56. 56.

    Rochereau, N. et al. Dectin-1 is essential for reverse transcytosis of glycosylated SIgA–antigen complexes by intestinal M cells. PLOS Biol. 11, e1001658 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Neutra, M. R. & Kozlowski, P. A. Mucosal vaccines: the promise and the challenge. Nat. Rev. Immunol. 6, 148–158 (2006).

    CAS  PubMed  Google Scholar 

  58. 58.

    Reboldi, A. et al. IgA production requires B cell interaction with subepithelial dendritic cells in Peyer’s patches. Science 352, aaf4822 (2016). This elegant study reveals how dendritic cells and ILC3s from the sub-epithelial dome of Peyer’s patches orchestrate IgM-to-IgA class switching in B cells.

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Mazzini, E., Massimiliano, L., Penna, G. & Rescigno, M. Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1+ macrophages to CD103+ dendritic cells. Immunity 40, 248–261 (2014).

    CAS  PubMed  Google Scholar 

  60. 60.

    Fransen, F. et al. BALB/c and C57BL/6 mice differ in polyreactive IgA abundance, which impacts the generation of antigen-specific IgA and microbiota diversity. Immunity 43, 527–540 (2015).

    CAS  PubMed  Google Scholar 

  61. 61.

    McDole, J. R. et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 483, 345–349 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Komban, R. J. et al. Activated Peyer’s patch B cells sample antigen directly from M cells in the subepithelial dome. Nat. Commun. 10, 2423 (2019).

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Cerutti, A. The regulation of IgA class switching. Nat. Rev. Immunol. 8, 421–434 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Crotty, S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011).

    CAS  PubMed  Google Scholar 

  65. 65.

    Cong, Y., Feng, T., Fujihashi, K., Schoeb, T. R. & Elson, C. O. A dominant, coordinated T regulatory cell–IgA response to the intestinal microbiota. Proc. Natl Acad. Sci. USA 106, 19256–19261 (2009).

    CAS  PubMed  Google Scholar 

  66. 66.

    Magri, G. et al. Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells. Nat. Immunol. 15, 354–364 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Roco, J. A. et al. Class-switch recombination occurs infrequently in germinal centers. Immunity 51, 337–350.e7 (2019).

    CAS  PubMed  Google Scholar 

  68. 68.

    Biram, A. et al. BCR affinity differentially regulates colonization of the subepithelial dome and infiltration into germinal centers within Peyer’s patches. Nat. Immunol. 20, 482–492 (2019).

    CAS  PubMed  Google Scholar 

  69. 69.

    Melo-Gonzalez, F. et al. Antigen-presenting ILC3 regulate T cell-dependent IgA responses to colonic mucosal bacteria. J. Exp. Med. 216, 728–742 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Grootjans, J. et al. Epithelial endoplasmic reticulum stress orchestrates a protective IgA response. Science 363, 993–998 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    He, B. et al. Intestinal bacteria trigger T cell-independent immunoglobulin A2 class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 26, 812–826 (2007).

    CAS  PubMed  Google Scholar 

  72. 72.

    Wang, Y. et al. An LGG-derived protein promotes IgA production through upregulation of APRIL expression in intestinal epithelial cells. Mucosal Immunol. 10, 373–384 (2017).

    CAS  PubMed  Google Scholar 

  73. 73.

    Kim, M. & Kim, C. H. Regulation of humoral immunity by gut microbial products. Gut Microbes 8, 392–399 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Tan, J. et al. Dietary fiber and bacterial SCFA enhance oral tolerance and protect against food allergy through diverse cellular pathways. Cell Rep. 15, 2809–2824 (2016).

    CAS  PubMed  Google Scholar 

  75. 75.

    Wu, W. et al. Microbiota metabolite short-chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43. Mucosal Immunol. 10, 946–956 (2017).

    CAS  PubMed  Google Scholar 

  76. 76.

    Kunisawa, J. et al. Regulation of intestinal IgA responses by dietary palmitic acid and its metabolism. J. Immunol. 193, 1666–1671 (2014).

    CAS  PubMed  Google Scholar 

  77. 77.

    Kim, M., Qie, Y., Park, J. & Kim, C. H. Gut microbial metabolites fuel host antibody responses. Cell Host Microbe 20, 202–214 (2016). This paper dissects the mechanisms whereby gut microbiota-derived SCFAs enhance intestinal IgA and systemic IgG responses.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Elson, C. O. & Cong, Y. Host–microbiota interactions in inflammatory bowel disease. Gut Microbes 3 (2012).

  81. 81.

    Park, J. et al. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR–S6K pathway. Mucosal Immunol. 8, 80–93 (2015).

    CAS  PubMed  Google Scholar 

  82. 82.

    McCoy, K. D., Ronchi, F. & Geuking, M. B. Host–microbiota interactions and adaptive immunity. Immunol. Rev. 279, 63–69 (2017).

    CAS  PubMed  Google Scholar 

  83. 83.

    Schena, F. et al. Dependence of immunoglobulin class switch recombination in B cells on vesicular release of ATP and CD73 ectonucleotidase activity. Cell Rep. 3, 1824–1831 (2013).

    CAS  PubMed  Google Scholar 

  84. 84.

    Proietti, M. et al. ATP released by intestinal bacteria limits the generation of protective IgA against enteropathogens. Nat. Commun. 10, 250 (2019).

    PubMed  PubMed Central  Google Scholar 

  85. 85.

    Uchimura, Y. et al. Antibodies set boundaries limiting microbial metabolite penetration and the resultant mammalian host response. Immunity 49, 545–559.e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Brandtzaeg, P., Baekkevold, E. S. & Morton, H. C. From B to A the mucosal way. Nat. Immunol. 2, 1093–1094 (2001).

    CAS  PubMed  Google Scholar 

  87. 87.

    Wesemann, D. R. et al. Microbial colonization influences early B-lineage development in the gut lamina propria. Nature 501, 112–115 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Rosshart, S. P. et al. Wild mouse gut microbiota promotes host fitness and improves disease resistance. Cell 171, 1015–1028.e13 (2017). This study shows that standard laboratory mice transplanted with the natural microbiota from a closely related population of wild mice exhibit increased survival and enhanced resistance to disease.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Rollenske, T. et al. Cross-specificity of protective human antibodies against Klebsiella pneumoniae LPS O-antigen. Nat. Immunol. 19, 617–624 (2018).

    CAS  PubMed  Google Scholar 

  90. 90.

    Zeng, M. Y. et al. Gut microbiota-induced immunoglobulin G controls systemic infection by symbiotic bacteria and pathogens. Immunity 44, 647–658 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Fadlallah, J. et al. Synergistic convergence of microbiota-specific systemic IgG and secretory IgA. J. Allergy Clin. Immunol. 143, 1575–1585.e4 (2019).

    CAS  PubMed  Google Scholar 

  92. 92.

    Koch, M. A. et al. Maternal IgG and IgA antibodies dampen mucosal T helper cell responses in early life. Cell 165, 827–841 (2016). This seminal study demonstrates how milk-derived IgA and IgG exert an unexpected anti-inflammatory function in the intestinal mucosa of breast-feeding neonates.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Brandtzaeg, P. Mucosal immunity: integration between mother and the breast-fed infant. Vaccine 21, 3382–3388 (2003).

    CAS  PubMed  Google Scholar 

  94. 94.

    Gomez de Aguero, M. et al. The maternal microbiota drives early postnatal innate immune development. Science 351, 1296–1302 (2016). This elegant article shows that the maternal microbiota shapes the neonatal immune system to avoid pro-inflammatory responses against commensal microorganisms.

    PubMed  Google Scholar 

  95. 95.

    Gopalakrishna, K. P. et al. Maternal IgA protects against the development of necrotizing enterocolitis in preterm infants. Nat. Med. (2019).

  96. 96.

    Flajnik, M. F. Comparative analyses of immunoglobulin genes: surprises and portents. Nat. Rev. Immunol. 2, 688–698 (2002).

    CAS  PubMed  Google Scholar 

  97. 97.

    Gutzeit, C., Chen, K. & Cerutti, A. The enigmatic function of IgD: some answers at last. Eur. J. Immunol. 48, 1101–1113 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Baumgarth, N. The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat. Rev. Immunol. 11, 34–46 (2011).

    CAS  PubMed  Google Scholar 

  99. 99.

    Chou, M. Y. et al. Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans. J. Clin. Invest. 119, 1335–1349 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Ehrenstein, M. R. & Notley, C. A. The importance of natural IgM: scavenger, protector and regulator. Nat. Rev. Immunol. 10, 778–786 (2010).

    CAS  PubMed  Google Scholar 

  101. 101.

    Kubagawa, H. et al. Functional roles of the IgM Fc receptor in the immune system. Front. Immunol. 10, 945 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Czajkowsky, D. M. et al. IgM, FcμRs, and malarial immune evasion. J. Immunol. 184, 4597–4603 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Gupta, S. & Gupta, A. Selective IgM deficiency — an underestimated primary immunodeficiency. Front. Immunol. 8, 1056 (2017).

    PubMed  PubMed Central  Google Scholar 

  104. 104.

    Bohannon, C. et al. Long-lived antigen-induced IgM plasma cells demonstrate somatic mutations and contribute to long-term protection. Nat. Commun. 7, 11826 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Fadlallah, J. et al. Microbial ecology perturbation in human IgA deficiency. Sci. Transl Med. 10 (2018). This study shows that the lack of intestinal IgA in patients with selective IgA deficiency causes perturbations of the gut microbiota that are not compensated by IgM.

  106. 106.

    Brandtzaeg, P. et al. in The human mucosal B-cell system 617–654 (Elsevier, 2005).

  107. 107.

    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).

    CAS  PubMed  Google Scholar 

  108. 108.

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

    PubMed  PubMed Central  Google Scholar 

  109. 109.

    Jorgensen, S. F. et al. Selective IgA deficiency in humans is associated with reduced gut microbial diversity. J. Allergy Clin. Immunol. 143, 1969–1971.e11 (2019).

    PubMed  Google Scholar 

  110. 110.

    Kirkland, D. et al. B cell-intrinsic MyD88 signaling prevents the lethal dissemination of commensal bacteria during colonic damage. Immunity 36, 228–238 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Bioley, G. et al. Plasma-derived polyreactive secretory-like IgA and IgM opsonizing Salmonella enterica Typhimurium reduces invasion and gut tissue inflammation through agglutination. Front. Immunol. 8, 1043 (2017).

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Brandtzaeg, P. et al. The B-cell system of human mucosae and exocrine glands. Immunol. Rev. 171, 45–87 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Pinto, D. et al. A functional BCR in human IgA and IgM plasma cells. Blood 121, 4110–4114 (2013).

    CAS  PubMed  Google Scholar 

  114. 114.

    Le Gallou, S. et al. A splenic IgM memory subset with antibacterial specificities is sustained from persistent mucosal responses. J. Exp. Med. 215, 2035–2053 (2018).

    PubMed  PubMed Central  Google Scholar 

  115. 115.

    Zhao, Y. et al. Spatiotemporal segregation of human marginal zone and memory B cell populations in lymphoid tissue. Nat. Commun. 9, 3857 (2018).

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Bjerke, K. & Brandtzaeg, P. Terminally differentiated human intestinal B cells. IgA and IgG subclass-producing immunocytes in the distal ileum, including Peyer’s patches, compared with lymph nodes and palatine tonsils. Scand. J. Immunol. 32, 61–67 (1990).

    CAS  PubMed  Google Scholar 

  117. 117.

    Bjerke, K., Brandtzaeg, P. & Rognum, T. O. Distribution of immunoglobulin producing cells is different in normal human appendix and colon mucosa. Gut 27, 667–674 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Rath, T., Baker, K., Pyzik, M. & Blumberg, R. S. Regulation of immune responses by the neonatal Fc receptor and its therapeutic implications. Front. Immunol. 5, 664 (2014).

    PubMed  Google Scholar 

  119. 119.

    Lu, L. L., Suscovich, T. J., Fortune, S. M. & Alter, G. Beyond binding: antibody effector functions in infectious diseases. Nat. Rev. Immunol. 18, 46–61 (2018).

    CAS  PubMed  Google Scholar 

  120. 120.

    Rengarajan, S. et al. Dynamic immunoglobulin responses to gut bacteria during inflammatory bowel disease. Gut Microbes (2019).

    Article  PubMed  Google Scholar 

  121. 121.

    Benckert, J. et al. The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific. J. Clin. Invest. 121, 1946–1955 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009).

    CAS  PubMed  Google Scholar 

  123. 123.

    Katchar, K. et al. Association between IgG2 and IgG3 subclass responses to toxin A and recurrent Clostridium difficile-associated disease. Clin. Gastroenterol. Hepatol. 5, 707–713 (2007).

    CAS  PubMed  Google Scholar 

  124. 124.

    Bry, L. & Brenner, M. B. Critical role of T cell-dependent serum antibody, but not the gut-associated lymphoid tissue, for surviving acute mucosal infection with Citrobacter rodentium, an attaching and effacing pathogen. J. Immunol. 172, 433–441 (2004).

    CAS  PubMed  Google Scholar 

  125. 125.

    Kamada, N. et al. Humoral immunity in the gut selectively targets phenotypically virulent attaching-and-effacing bacteria for intraluminal elimination. Cell Host Microbe 17, 617–627 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Caballero-Flores, G. et al. Maternal immunization confers protection to the offspring against an attaching and effacing pathogen through delivery of IgG in breast milk. Cell Host Microbe 25, 313–323.e4 (2019). This work shows that pathogen-specific IgG in breast milk induced during maternal infection or immunization can protect neonates against intestinal infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Castro-Dopico, T. et al. Anti-commensal IgG drives intestinal inflammation and type 17 immunity in ulcerative colitis. Immunity 50, 1099–1114.e10 (2019). This work dissects the mechanisms whereby commensal-specific IgG causes gut inflammation in ulcerative colitis.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Harris, N. L. et al. Mechanisms of neonatal mucosal antibody protection. J. Immunol. 177, 6256–6262 (2006).

    CAS  PubMed  Google Scholar 

  129. 129.

    Verhasselt, V. et al. Breast milk-mediated transfer of an antigen induces tolerance and protection from allergic asthma. Nat. Med. 14, 170–175 (2008).

    CAS  PubMed  Google Scholar 

  130. 130.

    Ohsaki, A. et al. Maternal IgG immune complexes induce food allergen-specific tolerance in offspring. J. Exp. Med. 215, 91–113 (2018).

    PubMed  PubMed Central  Google Scholar 

  131. 131.

    Yoshida, M. et al. Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria. J. Clin. Invest. 116, 2142–2151 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Agarwal, S., Smereka, P., Harpaz, N., Cunningham-Rundles, C. & Mayer, L. Characterization of immunologic defects in patients with common variable immunodeficiency (CVID) with intestinal disease. Inflamm. Bowel Dis. 17, 251–259 (2011).

    PubMed  PubMed Central  Google Scholar 

  133. 133.

    Berkowska, M. A. et al. Persistent polyclonal B-cell lymphocytosis: extensively proliferated CD27+IgM+IgD+ memory B cells with a distinctive immunophenotype. Leukemia 28, 1560–1564 (2014).

    CAS  PubMed  Google Scholar 

  134. 134.

    Yoshida, M. et al. Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells. Immunity 20, 769–783 (2004).

    CAS  PubMed  Google Scholar 

  135. 135.

    Okada, S. et al. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science 349, 606–613 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Watkins, J. D. et al. Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission. AIDS 27, F13–F20 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Chen, K. & Cerutti, A. New insights into the enigma of immunoglobulin D. Immunol. Rev. 237, 1–20 (2010).

    Google Scholar 

  138. 138.

    Arpin, C. et al. The normal counterpart of IgD myeloma cells in germinal center displays extensively mutated IgVH gene, Cμ–Cδ switch, and λ light chain expression. J. Exp. Med. 187, 1169–1178 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Chen, K. et al. Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell-stimulating programs in basophils. Nat. Immunol. 10, 889–898 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Rouaud, P. et al. Elucidation of the enigmatic IgD class-switch recombination via germline deletion of the IgH 3′ regulatory region. J. Exp. Med. 211, 975–985 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Choi, J. H. et al. IgD class switching is initiated by microbiota and limited to mucosa-associated lymphoid tissue in mice. Proc. Natl Acad. Sci. USA 114, E1196–E1204 (2017). This study shows that mucosal IgD responses, including IgM-to-IgD class switching, are largely driven by the microbiota and target a fraction of commensal bacteria.

    CAS  PubMed  Google Scholar 

  142. 142.

    Shan, M. et al. Secreted IgD amplifies humoral T helper 2 cell responses by binding basophils via galectin-9 and CD44. Immunity 49, 709–724.e8 (2018). This work indicates that secreted IgD amplifies humoral T H2 cell immunity by activating basophils and mast cells through a receptor complex that involves galectin 9 and CD44.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Cerutti, A., Chen, K. & Chorny, A. Immunoglobulin responses at the mucosal interface. Annu. Rev. Immunol. 29, 273–293 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Zhai, G. T. et al. IgD-activated mast cells induce IgE synthesis in B cells in nasal polyps. J. Allergy Clin. Immunol. 142, 1489–1499.e23 (2018).

    CAS  PubMed  Google Scholar 

  145. 145.

    Johansen, F. E. et al. Regional induction of adhesion molecules and chemokine receptors explains disparate homing of human B cells to systemic and mucosal effector sites: dispersion from tonsils. Blood 106, 593–600 (2005).

    CAS  PubMed  Google Scholar 

  146. 146.

    Koelsch, K. et al. Mature B cells class switched to IgD are autoreactive in healthy individuals. J. Clin. Invest. 117, 1558–1565 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Moura, I. C. et al. Identification of the transferrin receptor as a novel immunoglobulin (Ig)A1 receptor and its enhanced expression on mesangial cells in IgA nephropathy. J. Exp. Med. 194, 417–425 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Delacour, D. et al. Galectin-4 and sulfatides in apical membrane trafficking in enterocyte-like cells. J. Cell Biol. 169, 491–501 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Matysiak-Budnik, T. et al. Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease. J. Exp. Med. 205, 143–154 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Zheng, N. Y. et al. Human immunoglobulin selection associated with class switch and possible tolerogenic origins for Cδ class-switched B cells. J. Clin. Invest. 113, 1188–1201 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Burton, D. R., Stanfield, R. L. & Wilson, I. A. Antibody vs. HIV in a clash of evolutionary titans. Proc. Natl Acad. Sci. USA 102, 14943–14948 (2005).

    CAS  PubMed  Google Scholar 

  152. 152.

    Perdiguero, P. et al. Teleost IgD+IgM B cells mount clonally expanded and mildly mutated intestinal IgD responses in the absence of lymphoid follicles. Cell Rep. 29, 4223–4235.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Nguyen, T. G. Immune-modulation via IgD B-cell receptor suppresses allergic skin inflammation in experimental contact hypersensitivity models despite of a Th2-favoured humoral response. Immunol. Lett. 203, 29–39 (2018).

    CAS  PubMed  Google Scholar 

  154. 154.

    Marichal, T. et al. A beneficial role for immunoglobulin E in host defense against honeybee venom. Immunity 39, 963–975 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Kim, Y. et al. Hyaluronic acid targets CD44 and inhibits FcεRI signaling involving PKCδ, Rac1, ROS, and MAPK to exert anti-allergic effect. Mol. Immunol. 45, 2537–2547 (2008).

    CAS  PubMed  Google Scholar 

  156. 156.

    Niki, T. et al. Galectin-9 is a high affinity IgE-binding lectin with anti-allergic effect by blocking IgE–antigen complex formation. J. Biol. Chem. 284, 32344–32352 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Liu, Y. J. et al. Normal human IgD+IgM germinal center B cells can express up to 80 mutations in the variable region of their IgD transcripts. Immunity 4, 603–613 (1996).

    CAS  PubMed  Google Scholar 

  158. 158.

    Swenson, C. D. et al. Human T cell IgD receptors react with O-glycans on both human IgD and IgA1. Eur. J. Immunol. 28, 2366–2372 (1998).

    CAS  PubMed  Google Scholar 

  159. 159.

    Maurer, M. A. et al. Glycosylation of human IgA directly inhibits influenza A and other sialic-acid-binding viruses. Cell Rep. 23, 90–99 (2018). This study shows that N-linked glycans from human IgA interfere with the cell surface attachment of influenza A and other enveloped viruses via sialic acid-containing receptors.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160.

    Horns, F. et al. Lineage tracing of human B cells reveals the in vivo landscape of human antibody class switching. eLife 5, e16578 (2016).

    PubMed  PubMed Central  Google Scholar 

  161. 161.

    Ellebrecht, C. T. et al. Autoreactive IgG and IgA B cells evolve through distinct subclass switch pathways in the autoimmune disease pemphigus vulgaris. Cell Rep. 24, 2370–2380 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Ubelhart, R. et al. Responsiveness of B cells is regulated by the hinge region of IgD. Nat. Immunol. 16, 534–543 (2015).

    PubMed  Google Scholar 

  163. 163.

    Amin, A. R. et al. The immunoaugmenting properties of murine IgD reside in its Cδ1 and Cδ3 regions: potential role for IgD-associated glycans. Int. Immunol. 5, 607–614 (1993).

    CAS  PubMed  Google Scholar 

Download references


The authors thank the US National Institutes of Health (NIH) (grant P01 AI61093 to A.C. and grants R21 AI122256, R21 AI138089 and P30 AC22453 to K.C.), the Ministry of Economy and Competitiveness (MINECO) (grants SAF2014-52483-R and RTI2018-093894-B-I00 to A.C.), the Burroughs Wellcome fund preterm birth initiative (1013738 to K.C.), the strategic plan of research and innovation in health (PERIS) 2016–2020 from Generalitat de Catalunya (to G.M.) and the Swedish Research Council 2015-06486 and Swedish Society of Medicine (postdoctoral fellowship to E.K.G.).

Author information




All authors contributed to the review and editing of the manuscript before submission. A.C., G.M. and E.K.G. researched data for the article and discussed the content. A.C., K.C. and G.M. wrote the article.

Corresponding author

Correspondence to Andrea Cerutti.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Immunology thanks G. Gorochov and the other, anonymous reviewers for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Immune exclusion

Active impairment of microbial penetration through the gut epithelium that includes anchoring of intraluminal bacteria to mucus as well as attenuation of bacterial motility, growth and adhesion to gut epithelium by secretory IgA.

Immune inclusion

Pro-microbial activity mediated by secretory IgA and mucus that promotes the growth of beneficial bacteria while preventing potentially harmful microorganisms from colonizing the same mucosal niche.

Isolated lymphoid follicles

Single intestinal lymphoid aggregates with or without germinal centres, disseminated along the small intestine in mice and both the small and large intestines in humans, which develop in association with the follicle-associated epithelium and function as dynamic immune reservoirs for T cell-independent or T cell-dependent induction of IgA.

M cells

Specialized antigen-capturing epithelial-like cells from the follicle-associated epithelium that initiate intestinal immune responses by transporting intraluminal antigens into Peyer’s patches and isolated lymphoid follicles with the help of dendritic cells, macrophages and B cells.

Somatic hypermutation

A germinal centre-associated process that promotes antibody affinity maturation by introducing V(D)J gene point mutations through a molecular machinery that includes the DNA-editing enzyme activation-induced cytidine deaminase.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chen, K., Magri, G., Grasset, E.K. et al. Rethinking mucosal antibody responses: IgM, IgG and IgD join IgA. Nat Rev Immunol 20, 427–441 (2020).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing