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Commensal bacteria–derived signals regulate basophil hematopoiesis and allergic inflammation

Abstract

Commensal bacteria that colonize mammalian barrier surfaces are reported to influence T helper type 2 (TH2) cytokine-dependent inflammation and susceptibility to allergic disease, although the mechanisms that underlie these observations are poorly understood. In this report, we find that deliberate alteration of commensal bacterial populations via oral antibiotic treatment resulted in elevated serum IgE concentrations, increased steady-state circulating basophil populations and exaggerated basophil-mediated TH2 cell responses and allergic inflammation. Elevated serum IgE levels correlated with increased circulating basophil populations in mice and subjects with hyperimmunoglobulinemia E syndrome. Furthermore, B cell–intrinsic expression of myeloid differentiation factor 88 (MyD88) was required to limit serum IgE concentrations and circulating basophil populations in mice. Commensal-derived signals were found to influence basophil development by limiting proliferation of bone marrow–resident precursor populations. Collectively, these results identify a previously unrecognized pathway through which commensal-derived signals influence basophil hematopoiesis and susceptibility to TH2 cytokine–dependent inflammation and allergic disease.

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Figure 1: Elevated steady-state serum IgE levels and circulating basophils in antibiotic-treated or germ-free mice.
Figure 2: Exaggerated basophil-mediated allergic airway inflammation and TH2 cell responses in antibiotic-treated mice.
Figure 3: IgE correlates with circulating basophil populations in mice.
Figure 4: Serum IgE concentrations correlate with circulating basophil populations in human subjects with hyperimmunoglobulinemia E syndrome, and IgE-specific antibody treatment reduces serum IgE levels and circulating basophil populations in germ-free mice.
Figure 5: Elevated serum IgE concentrations and circulating basophil populations in mice lacking B cell–intrinsic MyD88 signaling.
Figure 6: Dysregulated basophil development in germ-free or antibiotic-treated mice.

References

  1. Eder, W., Ege, M.J. & von Mutius, E. The asthma epidemic. N. Engl. J. Med. 355, 2226–2235 (2006).

    CAS  Article  Google Scholar 

  2. Bahadori, K. et al. Economic burden of asthma: a systematic review. BMC Pulm. Med. 9, 24 (2009).

    Article  Google Scholar 

  3. Mowen, K.A. & Glimcher, L.H. Signaling pathways in TH2 development. Immunol. Rev. 202, 203–222 (2004).

    CAS  Article  Google Scholar 

  4. Holgate, S.T. Pathogenesis of asthma. Clin. Exp. Allergy 38, 872–897 (2008).

    CAS  Article  Google Scholar 

  5. Vercelli, D. Discovering susceptibility genes for asthma and allergy. Nat. Rev. Immunol. 8, 169–182 (2008).

    CAS  Article  Google Scholar 

  6. Zeiger, R.S. Food allergen avoidance in the prevention of food allergy in infants and children. Pediatrics 111, 1662–1671 (2003).

    Google Scholar 

  7. Gilliland, F.D. Outdoor air pollution, genetic susceptibility, and asthma management: opportunities for intervention to reduce the burden of asthma. Pediatrics 123 (suppl. 3), S168–S173 (2009).

    Article  Google Scholar 

  8. Ege, M.J. et al. Exposure to environmental microorganisms and childhood asthma. N. Engl. J. Med. 364, 701–709 (2011).

    CAS  Article  Google Scholar 

  9. Eckburg, P.B., Lepp, P.W. & Relman, D.A. Archaea and their potential role in human disease. Infect. Immun. 71, 591–596 (2003).

    CAS  Article  Google Scholar 

  10. Whitman, W.B., Coleman, D.C. & Wiebe, W.J. Prokaryotes: the unseen majority. Proc. Natl. Acad. Sci. USA 95, 6578–6583 (1998).

    CAS  Article  Google Scholar 

  11. Ley, R.E., Peterson, D.A. & Gordon, J.I. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124, 837–848 (2006).

    CAS  Article  Google Scholar 

  12. Kalliomäki, M. et al. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J. Allergy Clin. Immunol. 107, 129–134 (2001).

    Article  Google Scholar 

  13. Kummeling, I. et al. Early life exposure to antibiotics and the subsequent development of eczema, wheeze, and allergic sensitization in the first 2 years of life: the KOALA Birth Cohort Study. Pediatrics 119, e225–e231 (2007).

    Article  Google Scholar 

  14. Marra, F. et al. Antibiotic use in children is associated with increased risk of asthma. Pediatrics 123, 1003–1010 (2009).

    Article  Google Scholar 

  15. Bashir, M.E., Louie, S., Shi, H.N. & Nagler-Anderson, C. Toll-like receptor 4 signaling by intestinal microbes influences susceptibility to food allergy. J. Immunol. 172, 6978–6987 (2004).

    CAS  Article  Google Scholar 

  16. Noverr, M.C., Noggle, R.M., Toews, G.B. & Huffnagle, G.B. Role of antibiotics and fungal microbiota in driving pulmonary allergic responses. Infect. Immun. 72, 4996–5003 (2004).

    CAS  Article  Google Scholar 

  17. Noverr, M.C., Falkowski, N.R., McDonald, R.A., McKenzie, A.N. & Huffnagle, G.B. Development of allergic airway disease in mice following antibiotic therapy and fungal microbiota increase: role of host genetics, antigen, and interleukin-13. Infect. Immun. 73, 30–38 (2005).

    CAS  Article  Google Scholar 

  18. Herbst, T. et al. Dysregulation of allergic airway inflammation in the absence of microbial colonization. Am. J. Respir. Crit. Care Med. 184, 198–205 (2011).

    CAS  Article  Google Scholar 

  19. Paul, W.E. & Zhu, J. How are TH2-type immune responses initiated and amplified? Nat. Rev. Immunol. 10, 225–235 (2010).

    CAS  Article  Google Scholar 

  20. McCoy, K.D. et al. Natural IgE production in the absence of MHC class II cognate help. Immunity 24, 329–339 (2006).

    CAS  Article  Google Scholar 

  21. Sudo, N. et al. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J. Immunol. 159, 1739–1745 (1997).

    CAS  Google Scholar 

  22. Kitaura, J. et al. Evidence that IgE molecules mediate a spectrum of effects on mast cell survival and activation via aggregation of the FcɛRI. Proc. Natl. Acad. Sci. USA 100, 12911–12916 (2003).

    CAS  Article  Google Scholar 

  23. Hill, D.A. et al. Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol. 3, 148–158 (2010).

    CAS  Article  Google Scholar 

  24. Smith, K., McCoy, K.D. & Macpherson, A.J. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin. Immunol. 19, 59–69 (2007).

    CAS  Article  Google Scholar 

  25. Hammad, H. et al. Inflammatory dendritic cells—not basophils—are necessary and sufficient for induction of TH2 immunity to inhaled house dust mite allergen. J. Exp. Med. 207, 2097–2111 (2010).

    CAS  Article  Google Scholar 

  26. Mohrs, K., Wakil, A.E., Killeen, N., Locksley, R.M. & Mohrs, M. A two-step process for cytokine production revealed by IL-4 dual-reporter mice. Immunity 23, 419–429 (2005).

    CAS  Article  Google Scholar 

  27. Perrigoue, J.G. et al. MHC class II–dependent basophil-CD4+ T cell interactions promote TH2 cytokine-dependent immunity. Nat. Immunol. 10, 697–705 (2009).

    CAS  Article  Google Scholar 

  28. Sokol, C.L., Barton, G.M., Farr, A.G. & Medzhitov, R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat. Immunol. 9, 310–318 (2008).

    CAS  Article  Google Scholar 

  29. Yoshimoto, T. et al. Basophils contribute to TH2-IgE responses in vivo via IL-4 production and presentation of peptide–MHC class II complexes to CD4+ T cells. Nat. Immunol. 10, 706–712 (2009).

    CAS  Article  Google Scholar 

  30. Sokol, C.L. et al. Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat. Immunol. 10, 713–720 (2009).

    CAS  Article  Google Scholar 

  31. Sullivan, B.M. et al. Genetic analysis of basophil function in vivo. Nat. Immunol. 12, 527–535 (2011).

    CAS  Article  Google Scholar 

  32. Novey, H.S., Marchioli, L.E., Sokol, W.N. & Wells, I.D. Papain-induced asthma–physiological and immunological features. J. Allergy Clin. Immunol. 63, 98–103 (1979).

    CAS  Article  Google Scholar 

  33. Phythian-Adams, A.T. et al. CD11c depletion severely disrupts Th2 induction and development in vivo. J. Exp. Med. 207, 2089–2096 (2010).

    CAS  Article  Google Scholar 

  34. Siracusa, M.C. et al. TSLP promotes interleukin-3–independent basophil haematopoiesis and type 2 inflammation. Nature 477, 229–233 (2011).

    CAS  Article  Google Scholar 

  35. Xiang, Z., Moller, C. & Nilsson, G. IgE-receptor activation induces survival and Bfl-1 expression in human mast cells but not basophils. Allergy 61, 1040–1046 (2006).

    CAS  Article  Google Scholar 

  36. Mombaerts, P. et al. RAG-1–deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992).

    CAS  Article  Google Scholar 

  37. Delphin, S. & Stavnezer, J. Characterization of an interleukin 4 (IL-4) responsive region in the immunoglobulin heavy chain germline epsilon promoter: regulation by NF-IL-4, a C/EBP family member and NF-κB/p50. J. Exp. Med. 181, 181–192 (1995).

    CAS  Article  Google Scholar 

  38. Engelhardt, K.R. et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J. Allergy Clin. Immunol. 124, 1289-302.e4 (2009).

    CAS  Article  Google Scholar 

  39. Zhang, Q. et al. Combined immunodeficiency associated with DOCK8 mutations. N. Engl. J. Med. 361, 2046–2055 (2009).

    CAS  Article  Google Scholar 

  40. Holgate, S. et al. The use of omalizumab in the treatment of severe allergic asthma: A clinical experience update. Respir. Med. 103, 1098–1113 (2009).

    Article  Google Scholar 

  41. Pace, E. et al. Clinical benefits of 7 years of treatment with omalizumab in severe uncontrolled asthmatics. J. Asthma 48, 387–392 (2011).

    CAS  Article  Google Scholar 

  42. Lin, H. et al. Omalizumab rapidly decreases nasal allergic response and FcepsilonRI on basophils. J. Allergy Clin. Immunol. 113, 297–302 (2004).

    CAS  Article  Google Scholar 

  43. Shiratori, I. et al. Down-regulation of basophil function by human CD200 and human herpesvirus-8 CD200. J. Immunol. 175, 4441–4449 (2005).

    CAS  Article  Google Scholar 

  44. Schnare, M. et al. Toll-like receptors control activation of adaptive immune responses. Nat. Immunol. 2, 947–950 (2001).

    CAS  Article  Google Scholar 

  45. Clarke, T.B. et al. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat. Med. 16, 228–231 (2010).

    CAS  Article  Google Scholar 

  46. Hall, J.A. et al. Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity 29, 637–649 (2008).

    CAS  Article  Google Scholar 

  47. Liu, N., Ohnishi, N., Ni, L., Akira, S. & Bacon, K.B. CpG directly induces T-bet expression and inhibits IgG1 and IgE switching in B cells. Nat. Immunol. 4, 687–693 (2003).

    CAS  Article  Google Scholar 

  48. Gessner, A., Mohrs, K. & Mohrs, M. Mast cells, basophils, and eosinophils acquire constitutive IL-4 and IL-13 transcripts during lineage differentiation that are sufficient for rapid cytokine production. J. Immunol. 174, 1063–1072 (2005).

    CAS  Article  Google Scholar 

  49. Siracusa, M.C., Perrigoue, J.G., Comeau, M.R. & Artis, D. New paradigms in basophil development, regulation and function. Immunol. Cell Biol. 88, 275–284 (2010).

    Article  Google Scholar 

  50. Ohmori, K. et al. IL-3 induces basophil expansion in vivo by directing granulocyte-monocyte progenitors to differentiate into basophil lineage-restricted progenitors in the bone marrow and by increasing the number of basophil/mast cell progenitors in the spleen. J. Immunol. 182, 2835–2841 (2009).

    CAS  Article  Google Scholar 

  51. Layland, L.E., Wagner, H. & da Costa, C.U. Lack of antigen-specific TH1 response alters granuloma formation and composition in Schistosoma mansoni-infected MyD88−/− mice. Eur. J. Immunol. 35, 3248–3257 (2005).

    CAS  Article  Google Scholar 

  52. Ku, C.L. et al. Selective predisposition to bacterial infections in IRAK-4–deficient children: IRAK-4–dependent TLRs are otherwise redundant in protective immunity. J. Exp. Med. 204, 2407–2422 (2007).

    CAS  Article  Google Scholar 

  53. Kim, B.S. et al. Conversion of TH2 memory cells into Foxp3+ regulatory T cells suppressing TH2-mediated allergic asthma. Proc. Natl. Acad. Sci. USA 107, 8742–8747 (2010).

    CAS  Article  Google Scholar 

  54. Fink, L.N. et al. Establishment of tolerance to commensal bacteria requires a complex microbiota and is accompanied by decreased intestinal chemokine expression. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G55–G65 (2011).

    Article  Google Scholar 

  55. Redhu, N.S. et al. IgE induces transcriptional regulation of thymic stromal lymphopoietin in human airway smooth muscle cells. J. Allergy Clin. Immunol. 128, 892-896.e2 (2011).

    CAS  Article  Google Scholar 

  56. Chen, M.L., Yan, B.S., Bando, Y., Kuchroo, V.K. & Weiner, H.L. Latency-associated peptide identifies a novel CD4+CD25+ regulatory T cell subset with TGFβ-mediated function and enhanced suppression of experimental autoimmune encephalomyelitis. J. Immunol. 180, 7327–7337 (2008).

    CAS  Article  Google Scholar 

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Acknowledgements

We thank members of the Artis lab for helpful discussions; M.R. Comeau (Tslp−/− mice, Amgen), H. Oettgen (Igh-7−/− mice, Harvard University) and J. Weiser (Nod1−/− mice, University of Pennsylvania) for providing access to mice; L. Shawver, R. Sinha and R. Custers-Allen for assistance with data; J. Sawalle-Belohradsky and B. Hagl for performing DOCK8 sequencing; A. Jansson, G. Notheis, B.H. Belohradsky, M. Albert and the referring physicians for patient care; the Matthew J. Ryan Veterinary Hospital Pathology Lab; the National Institute of Diabetes and Digestive and Kidney Disease Center for the Molecular Studies in Digestive and Liver Disease Molecular Pathology and Imaging Core (DK50306); the Abramson Cancer Center Flow Cytometry and Cell Sorting Resource Laboratory (supported by US National Cancer Institute Comprehensive Cancer Center Support grant (2-P30 CA016520) for technical advice and support; and the University of Pennsylvania Gnotobiotic Mouse Facility for germ-free mice. Research in the Artis lab is supported by the US National Institutes of Health (AI061570, AI087990, AI074878, AI095608, AI083480 and AI095466 to D.A.; T32-AI060516 to D.A.H.; F32-AI085828 to M.C.S.; T32-AI05528 to M.C.A.) the Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Disease Award (D.A.), the Penn Genome Frontiers Institute (D.A. and F.D.B.), and pilot grants from the University of Pennsylvania Veterinary Center of Infectious Diseases (D.A.). Additional National Institutes of Health support provided by HL107589 and HL111501 to T.K., AI067946 to J.S.O. and UH2DK083981 to F.D.B.

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D.A.H., M.C.S., M.C.A., B.S.K., D.K. and D.A. designed and performed the research; D.F.L., E.D.R., J.S.O., M.K., T.K. and F.D.B. provided reagents; D.A.H., M.C.S., M.C.A., B.S.K. and D.A. analyzed the data; D.A.H., M.C.S. and D.A. wrote the manuscript.

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Correspondence to David Artis.

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Hill, D., Siracusa, M., Abt, M. et al. Commensal bacteria–derived signals regulate basophil hematopoiesis and allergic inflammation. Nat Med 18, 538–546 (2012). https://doi.org/10.1038/nm.2657

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