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Asthma: an epidemic of dysregulated immunity

Abstract

The remarkable increase in asthma prevalence that has occurred over the last two decades is thought to be caused by changes in the environment due to improved hygiene and fewer childhood infections. However, the specific infections that limit T helper type 2 (TH2)-biased inflammation and asthma are not fully known. Infectious organisms, including commensal bacteria in the gastrointestinal tract and hepatitis A virus, may normally induce the development of regulatory T (TR) cells and protective immunity that limit airway inflammation and promote tolerance to respiratory allergens. In the absence of such infections, TH2 cells—which are developmentally related to TR cells—develop instead and coordinate the development of asthmatic inflammation.

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Figure 1: Asthma is a complex genetic trait caused by environmental factors in genetically predisposed individuals.

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Figure 2: DCs direct the development of TH1, TH2 and TR cells.

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References

  1. 1

    Cookson, W. The alliance of genes and environment in asthma and allergy. Nature 402, (Suppl. B) B5–10 (1999).

    CAS  PubMed  Google Scholar 

  2. 2

    Van Eerdewegh, P. et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature (doi:10.1038/nature00878, 10 July 2002).

  3. 3

    Fahy, J.V., Corry, D.B. & Boushey, H.A. Airway inflammation and remodeling in asthma. Curr. Opin. Pulm. Med. 6, 15–20 (2000).

    CAS  PubMed  Google Scholar 

  4. 4

    von Mutius, E. The environmental predictors of allergic disease. J. Allergy Clin. Immunol. 105, 9–19 (2000).

    CAS  PubMed  Google Scholar 

  5. 5

    Strachan, D.P. Hay fever, hygiene, and household size. Brit. Med. J. 299, 1259–1260 (1989).

    CAS  PubMed  Google Scholar 

  6. 6

    von Mutius, E. et al. Skin test reactivity and number of siblings. Brit. Med. J. 308, 692–695 (1994).

    CAS  PubMed  Google Scholar 

  7. 7

    Ball, T.M. et al. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N. Engl. J. Med. 343, 538–543 (2000).

    CAS  PubMed  Google Scholar 

  8. 8

    Riedler, J. et al. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 358, 1129–1133 (2001).

    CAS  PubMed  Google Scholar 

  9. 9

    Platts-Mills, T., Vaughan, J., Squillace, S., Woodfolk, J. & Sporik, R. Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet 357, 752–756 (2001).

    CAS  PubMed  Google Scholar 

  10. 10

    McKeever, T.M. et al. Early exposure to infections and antibiotics and the incidence of allergic disease: a birth cohort study with the West Midlands General Practice Research Database. J. Allergy Clin. Immunol. 109, 43–50 (2002).

    PubMed  Google Scholar 

  11. 11

    Shirakawa, T., Enomoto, T., Shimazu, S. & Hopkin, J.M. The inverse association between tuberculin responses and atopic disorder. Science 275, 77–79 (1997).

    CAS  PubMed  Google Scholar 

  12. 12

    von Hertzen L. et al. Mycobacterium tuberculosis infection and the subsequent development of asthma and allergic conditions. J. Allergy Clin. Immunol. 104, 1211–1214 (1999).

    CAS  PubMed  Google Scholar 

  13. 13

    Strannegard, I.L., Larsson, L.O., Wennergren, G. & Strannegard, O. Prevalence of allergy in children in relation to prior BCG vaccination and infection with atypical mycobacteria. Allergy 53, 249–254 (1998).

    CAS  PubMed  Google Scholar 

  14. 14

    Lynch, N.R. et al. Relationship between helminthic infection and IgE response in atopic and nonatopic children in a tropical environment. J. Allergy Clin. Immunol. 101, 217–221 (1998).

    CAS  PubMed  Google Scholar 

  15. 15

    Gern, J.E. & Busse, W.W. Relationship of viral infections to wheezing illnesses and asthma. Nature Rev. Immunol. 2, 132–138 (2002).

    CAS  Google Scholar 

  16. 16

    Stein, R.T. et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 354, 541–545 (1999).

    CAS  PubMed  Google Scholar 

  17. 17

    Bjorksten, B., Naaber, P., Sepp, E. & Mikelsaar, M. The intestinal microflora in allergic Estonian and Swedish 2-year-old children. Clin. Exp. Allergy 29, 342–346 (1999).

    CAS  PubMed  Google Scholar 

  18. 18

    Kalliomaki, M. et al. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 357, 1076–1079 (2001).

    CAS  PubMed  Google Scholar 

  19. 19

    Gehring, U. et al. Exposure to endotoxin decreases the risk of atopic eczema in infancy: a cohort study. J. Allergy Clin. Immunol. 108, 847–854 (2001).

    CAS  PubMed  Google Scholar 

  20. 20

    Lorenz, E. et al. Genes other than TLR4 are involved in the response to inhaled LPS. Am. J. Physiol. Lung Cell. Mol. Physiol. 281, (Suppl. 2) L1106–1114 (2001).

    CAS  PubMed  Google Scholar 

  21. 21

    Matricardi, P.M. et al. Cross sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus. Brit. Med. J. 314, 999–1003 (1997).

    CAS  PubMed  Google Scholar 

  22. 22

    Matricardi, P. et al. Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma: epidemiological study. Brit. Med. J. 320, 412–417 (2000).

    CAS  PubMed  Google Scholar 

  23. 23

    McIntire, J.J. et al. Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nature Immunol. 2, 1109–1116 (2001).

    CAS  Google Scholar 

  24. 24

    Mosmann, T.R. & Coffman, R.L. Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).

    CAS  PubMed  Google Scholar 

  25. 25

    Prescott, S.L. et al. Developing patterns of T cell memory to environmental allergens in the first two years of life. Int. Arch. Allergy Immunol. 113, 75–79 (1997).

    CAS  PubMed  Google Scholar 

  26. 26

    Abbas, A.K., Murphy, K.M. & Sher, A. Functional diversity of helper T lymphocytes. Nature 383, 787–793 (1996).

    CAS  Google Scholar 

  27. 27

    Coffman, R.L. et al. The role of helper T cell products in mouse B cell differentiation and isotype regulation. Immunol. Rev. 102, 5–28 (1988).

    CAS  PubMed  Google Scholar 

  28. 28

    Iwamoto, I., Nakajima, H., Endo, H. & Yoshida, S. Interferon γ regulates antigen-induced eosinophil recruitment into the mouse airways by inhibiting the infiltration of CD4+ T cells. J. Exp. Med. 177, 573–576 (1993).

    CAS  PubMed  Google Scholar 

  29. 29

    Corrigan, C.J. & Kay, A.B. CD4 T-lymphocyte activation in acute severe asthma. Relationship to disease severity and atopic status. Am. Rev. Respir. Dis. 141, 970–977 (1990).

    CAS  PubMed  Google Scholar 

  30. 30

    Cembrzynska-Nowak, M., Szklarz, E., Inglot, A.D. & Teodorczyk-Injeyan, J.A. Elevated release of tumor necrosis factor-α and interferon-γ by bronchoalveolar leukocytes from patients with bronchial asthma. Am. Rev. Respir. Dis. 147, 291–295 (1993).

    CAS  PubMed  Google Scholar 

  31. 31

    Hansen, G., Berry, G., DeKruyff, R.H. & Umetsu, D.T. Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J. Clin. Invest. 103, 175–183 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Lafaille, J.J. et al. Myelin basic protein-specific T helper 2 (Th2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease. J. Exp. Med. 186, 307–312 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Pakala, S.V., Kurrer, M.O. & Katz, J.D. T helper 2 cells induce acute pancreatitis and diabetes in immune-compromised nonobese diabetic mice. J. Exp. Med. 186, 299–206 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Genain, C.P. et al. Late complications of immune deviation therapy in a nonhuman primate. Science 274, 2054–2056 (1996).

    CAS  PubMed  Google Scholar 

  35. 35

    Seymour, B.W., Gershwin, L.J. & Coffman, R.L. Aerosol-induced immunoglobulin (Ig)-E unresponsiveness to ovalbumin does not require CD8+ or T cell receptor (TCR)-γ/δ+ T cells or interferon (IFN)-γ in a murine model of allergen sensitization. J. Exp. Med. 187, 721–731 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Tsitoura, D.C., DeKruyff, R.H., Lamb, J.R. & Umetsu, D.T. Intranasal exposure to protein antigen induces immunological tolerance mediated by functionally disabled CD4+ T cells. J. Immunol. 163, 2592–2600 (1999).

    CAS  PubMed  Google Scholar 

  37. 37

    Tsitoura, D.C., Blumenthal, R.L., Berry, G., DeKruyff, R.H. & Umetsu, D.T. Mechanisms preventing allergen-induced airways hyperreactivity: Role of immune deviation and tolerance. J. Allergy Clin. Immunol. 106, 239–246 (2000).

    CAS  PubMed  Google Scholar 

  38. 38

    Chen, Y., Kuchroo, V.K., Inobe, J., Hafler, D.A. & Weiner, H.L. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265, 1237–1240 (1994).

    CAS  PubMed  Google Scholar 

  39. 39

    Chen, Y. et al. Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature 376, 177–180 (1995).

    CAS  PubMed  Google Scholar 

  40. 40

    Hansen, G. et al. CD4+ Th cells engineered to produce latent TGF-β1 reverse allergen-induced airway hyperreactivity and inflammation. J. Clin. Invest. 11, 89–96 (2000).

    Google Scholar 

  41. 41

    McWilliam, A.S. et al. Dendritic cells are recruited into the airway epithelium during the inflammatory response to a broad spectrum of stimuli. J. Exp. Med. 184, 2429–2432 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Akbari, O., DeKruyff, R.H. & Umetsu, D.T. Pulmonary dendritic cells secreting IL-10 mediate T cell tolerance induced by respiratory exposure to antigen. Nature Immunol. 2, 725–731 (2001).

    CAS  Google Scholar 

  43. 43

    Tsitoura, D.C., Yeung, V.P., DeKruyff, R.H. & Umetsu, D.T. Critical role of B cells in the development of T cell tolerance to aeroallergens. Int. Immunol. 14, 513–523 (2002).

    Google Scholar 

  44. 44

    Akbari, O. et al. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nature Med. (in the press, 2002).

  45. 45

    McAdam, A.J. et al. ICOS is critical for CD40-mediated antibody class switching. Nature 409, 102–105 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Nakajima, A. et al. Requirement of CD28-CD86 co-stimulation in the interaction between antigen-primed T helper type 2 and B cells. Int. Immunol. 9, 637–644 (1997).

    CAS  PubMed  Google Scholar 

  47. 47

    Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).

    CAS  PubMed  Google Scholar 

  48. 48

    Barrat, F.J. et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J. Exp. Med. 195, 603–616 (2002).

    CAS  Article  Google Scholar 

  49. 49

    Jonuleit, H. et al. Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood. J. Exp. Med. 193, 1285–1294 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Huang, F.P. et al. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J. Exp. Med. 191, 435–444 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Sauter, B. et al. Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J. Exp. Med. 191, 423–434 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). J. Immunol. 160, 1151–1164 (1995).

    Google Scholar 

  53. 53

    Thornton, A. & Shevach, E.M. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188, 287–296 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Tivol, E.A. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multi-organ tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3, 541–547 (1995).

    CAS  PubMed  Google Scholar 

  55. 55

    Zuany-Amorim C et al. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nature Med. 8, 8625–8629 (2002).

    Google Scholar 

  56. 56

    Weiner, H.L. The mucosal milieu creates tolerogenic dendritic cells and Tr1 and Th3 regulatory cells. Nature Immunol. 2, 671–672 (2001).

    CAS  Google Scholar 

  57. 57

    Coffman, R.L., Varkila, K., Scott, P. & Chatelain, R. Role of cytokines in the differentiation of CD4+ T-cell subsets in vivo. Immunol. Rev. 123, 189–207 (1991).

    CAS  PubMed  Google Scholar 

  58. 58

    Makela, M.J. et al. IL-10 is necessary for the expression of airway hyperresponsiveness but not pulmonary inflammation after allergic sensitization. Proc. Natl. Acad. Sci. USA 97, 6007–6012 (2000).

    CAS  PubMed  Google Scholar 

  59. 59

    Levings, M.K. & Roncarolo, M.G. T-regulatory 1 cells: a novel subset of CD4 T cells with immunoregulatory properties. J. Allergy Clin. Immunol. 106, (Suppl. S) 109–112 (2000).

    Google Scholar 

  60. 60

    Akdis, C.A., Blesken, T., Akdis, M., Wuthrich, B. & Blaser, K. Role of interleukin 10 in specific immunotherapy. J. Clin. Invest. 102, 98–106 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Oh, J.W. et al. CD4 T helper cells engineered to produce IL-10 reverse allergen-induced airway hyperreactivity and inflammation. J. Allergy Clin. Immunol. (in the press, 2002).

  62. 62

    Hutloff, A. et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397, 263–266 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Aicher, A. et al. Characterization of human inducible costimulator ligand expression and function. J. Immunol. 164, 4689–4696 (2000).

    CAS  PubMed  Google Scholar 

  64. 64

    Mages, H.W. et al. Molecular cloning and characterization of murine ICOS and identification of B7h as ICOS ligand. Eur. J. Immunol. 30, 1040–1047 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Swallow, M.M., Wallin, J.J. & Sha, W.C. B7h, a novel costimulatory homolog of B7. 1 and B7. 2, is induced by TNFα. Immunity 11, 423–432 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Gonzalo, J.A. et al. ICOS is critical for T helper cell-mediated lung mucosal inflammatory responses. Nature Immunol. 2, 597–604 (2001).

    CAS  Google Scholar 

  67. 67

    Coyle, A.J. et al. The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. Immunity 13, 95–105 (2000).

    CAS  PubMed  Google Scholar 

  68. 68

    Dong, C. et al. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 409, 97–101 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Rottman, J.B. et al. The costimulatory molecule ICOS plays an important role in the immunopathogenesis of EAE. Nature Immunol. 2, 605–611 (2001).

    CAS  Google Scholar 

  70. 70

    Umetsu, D.T. & DeKruyff, R.H. Th1 and Th2 CD4+ cells in human allergic diseases. J. Allergy Clin. Immunol. 100, 1–6 (1997).

    CAS  PubMed  Google Scholar 

  71. 71

    Haneda, K. et al. TGF-β induced by oral tolerance ameliorates experimental tracheal eosinophilia. J. Immunol. 159, 4484–4490 (1997).

    CAS  PubMed  Google Scholar 

  72. 72

    Russo, M. et al. Suppression of asthma-like responses in different mouse strains by oral tolerance. Am. J. Respir. Cell. Mol. Biol. 24, 518–526 (2001).

    CAS  PubMed  Google Scholar 

  73. 73

    Gerosa, F. et al. Interleukin-12 primes human CD4 and CD8 T cell clones for high production of both interferon-γ and interleukin-10. J. Exp. Med. 183, 2559–2569 (1996).

    CAS  PubMed  Google Scholar 

  74. 74

    Tsitoura, D.C. et al. Respiratory infection with influenza A virus interferes with the induction of tolerance to aeroallergens. J. Immunol. 165, 3484–3491 (2000).

    CAS  PubMed  Google Scholar 

  75. 75

    Hurst, S.D., Seymour, B.W., Muchamuel, T., Kurup, V.P. & Coffman, R.L. Modulation of inhaled antigen-induced IgE tolerance by ongoing Th2 responses in the lung. J. Immunol. 166, 4922–4930 (2001).

    CAS  PubMed  Google Scholar 

  76. 76

    Wannemuehler, M.J., Kiyono, H., Babb, J.L., Michalek, S.M. & McGhee, J.R. Lipopolysaccharide (LPS) regulation of the immune response: LPS converts germfree mice to sensitivity to oral tolerance induction. J. Immunol. 129, 959–965 (1982).

    CAS  PubMed  Google Scholar 

  77. 77

    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  PubMed  Google Scholar 

  78. 78

    Ogura, Y. et al. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-κB. J. Biol. Chem. 276, 4812–4818 (2001).

    CAS  PubMed  Google Scholar 

  79. 79

    Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).

    CAS  Google Scholar 

  80. 80

    Hugot, J.P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).

    CAS  Google Scholar 

  81. 81

    Neish, A.S. et al. Prokaryotic regulation of epithelial responses by inhibition of IκBα ubiquitination. Science 289, 1560–1563 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Mahanty, S. et al. High levels of spontaneous and parasite antigen-driven interleukin-10 production are associated with antigen-specific hyporesponsiveness in human lymphatic filariasis. J. Infect. Dis. 173, 769–773 (1996).

    CAS  PubMed  Google Scholar 

  83. 83

    Yazdanbakhsh, M., Kremsner, P.G. & van Ree, R. Allergy, parasites, and the hygiene hypothesis. Science 296, 490–494 (2002).

    CAS  PubMed  Google Scholar 

  84. 84

    Diez-Gonzalez, F., Callaway, T.R., Kizoulis, M.G. & Russell, J.B. Grain feeding and the dissemination of acid-resistant Escherichia coli from cattle. Science 281, 1666–1668 (1998).

    CAS  PubMed  Google Scholar 

  85. 85

    Passalacqua, G. et al. Clinical and immunologic effects of a rush sublingual immunotherapy to Parietaria species: A double-blind, placebo-controlled trial. J. Allergy Clin. Immunol. 104, 964–968 (1999).

    CAS  PubMed  Google Scholar 

  86. 86

    Moller, C. et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J. Allergy Clin. Immunol. 109, 251–256 (2002).

    Google Scholar 

  87. 87

    Secrist, H., Chelen, C.J., Wen, Y., Marshall, J.D. & Umetsu, D.T. Allergen immunotherapy decreases interleukin 4 production in CD4+ T cells from allergic individuals. J. Exp. Med. 178, 2123–2130 (1993).

    CAS  PubMed  Google Scholar 

  88. 88

    Durham, S.R. et al. Long-term clinical efficacy of grass-pollen immunotherapy. New Engl. J. Med. 341, 468–475 (1999).

    CAS  PubMed  Google Scholar 

  89. 89

    Tighe, H. et al. Conjugation of immunostimulatory DNA to the short ragweed allergen amb a 1 enhances its immunogenicity and reduces its allergenicity. J. Allergy Clin. Immunol. 106, 124–134 (2000).

    CAS  Google Scholar 

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Correspondence to Dale T. Umetsu.

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Umetsu, D., McIntire, J., Akbari, O. et al. Asthma: an epidemic of dysregulated immunity. Nat Immunol 3, 715–720 (2002). https://doi.org/10.1038/ni0802-715

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