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. 1998 Jun;106(Suppl 3):795–800. doi: 10.1289/ehp.98106795

Programming for responsiveness to environmental antigens that trigger allergic respiratory disease in adulthood is initiated during the perinatal period.

P G Holt 1
PMCID: PMC1533062  PMID: 9646039

Abstract

Allergy to airborne environmental antigens (allergens) is a major cause of asthma in children and adults. This review argues that the development of allergen-specific immunologic memory of the type that predisposes to allergy development is the end result of a T-cell selection process operative during infancy, which is triggered via encounters between the immature immune system and incoming airborne allergens from the environment. In normal individuals this process leads to the development of allergen-specific T-memory cells that secure the T helper (Th)-1 pattern of cytokines, which actively suppress the growth of their allergy-inducing Th-2 cytokine-secreting counterparts. However, these protective allergen-reactive Th-1 memory cells fail to develop in some individuals, permitting the subsequent proliferation of allergen-specific Th-2 cells that can trigger allergic reactions. Recent evidence suggests that genetic predisposition to allergy may be due in part to hyperactivity of control mechanisms operative in utero and which normally protect the fetoplacental unit against the toxic effect of Th-1 cytokines.

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Selected References

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  1. Aberg N., Hesselmar B., Aberg B., Eriksson B. Increase of asthma, allergic rhinitis and eczema in Swedish schoolchildren between 1979 and 1991. Clin Exp Allergy. 1995 Sep;25(9):815–819. doi: 10.1111/j.1365-2222.1995.tb00023.x. [DOI] [PubMed] [Google Scholar]
  2. Barrios C., Brawand P., Berney M., Brandt C., Lambert P. H., Siegrist C. A. Neonatal and early life immune responses to various forms of vaccine antigens qualitatively differ from adult responses: predominance of a Th2-biased pattern which persists after adult boosting. Eur J Immunol. 1996 Jul;26(7):1489–1496. doi: 10.1002/eji.1830260713. [DOI] [PubMed] [Google Scholar]
  3. Bentley A. M., Durham S. R., Kay A. B. Comparison of the immunopathology of extrinsic, intrinsic and occupational asthma. J Investig Allergol Clin Immunol. 1994 Sep-Oct;4(5):222–232. [PubMed] [Google Scholar]
  4. Björkstén B. Risk factors in early childhood for the development of atopic diseases. Allergy. 1994 Jul;49(6):400–407. doi: 10.1111/j.1398-9995.1994.tb00831.x. [DOI] [PubMed] [Google Scholar]
  5. Bråbäck L., Breborowicz A., Dreborg S., Knutsson A., Pieklik H., Björkstén B. Atopic sensitization and respiratory symptoms among Polish and Swedish school children. Clin Exp Allergy. 1994 Sep;24(9):826–835. doi: 10.1111/j.1365-2222.1994.tb01805.x. [DOI] [PubMed] [Google Scholar]
  6. Burrows B., Martinez F. D., Halonen M., Barbee R. A., Cline M. G. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med. 1989 Feb 2;320(5):271–277. doi: 10.1056/NEJM198902023200502. [DOI] [PubMed] [Google Scholar]
  7. Busse W. W. Role and contribution of viral respiratory infections to asthma. Allergy. 1993;48(17 Suppl):57–64. doi: 10.1111/j.1398-9995.1993.tb04700.x. [DOI] [PubMed] [Google Scholar]
  8. Chen N., Gao Q., Field E. H. Expansion of memory Th2 cells over Th1 cells in neonatal primed mice. Transplantation. 1995 Dec 15;60(11):1187–1193. [PubMed] [Google Scholar]
  9. Corrigan C. J., Kay A. B. T cells and eosinophils in the pathogenesis of asthma. Immunol Today. 1992 Dec;13(12):501–507. doi: 10.1016/0167-5699(92)90026-4. [DOI] [PubMed] [Google Scholar]
  10. Croner S., Kjellman N. I. Predictors of atopic disease: cord blood IgE and month of birth. Allergy. 1986 Jan;41(1):68–70. doi: 10.1111/j.1398-9995.1986.tb00277.x. [DOI] [PubMed] [Google Scholar]
  11. Demeure C. E., Yang L. P., Byun D. G., Ishihara H., Vezzio N., Delespesse G. Human naive CD4 T cells produce interleukin-4 at priming and acquire a Th2 phenotype upon repetitive stimulations in neutral conditions. Eur J Immunol. 1995 Sep;25(9):2722–2725. doi: 10.1002/eji.1830250950. [DOI] [PubMed] [Google Scholar]
  12. Devalia J. L., Rusznak C., Wang J., Khair O. A., Abdelaziz M. M., Calderón M. A., Davies R. J. Air pollutants and respiratory hypersensitivity. Toxicol Lett. 1996 Aug;86(2-3):169–176. doi: 10.1016/0378-4274(96)03687-9. [DOI] [PubMed] [Google Scholar]
  13. Finkelman F. D., Holmes J., Katona I. M., Urban J. F., Jr, Beckmann M. P., Park L. S., Schooley K. A., Coffman R. L., Mosmann T. R., Paul W. E. Lymphokine control of in vivo immunoglobulin isotype selection. Annu Rev Immunol. 1990;8:303–333. doi: 10.1146/annurev.iy.08.040190.001511. [DOI] [PubMed] [Google Scholar]
  14. Fuleihan R., Ahern D., Geha R. S. Decreased expression of the ligand for CD40 in newborn lymphocytes. Eur J Immunol. 1994 Aug;24(8):1925–1928. doi: 10.1002/eji.1830240832. [DOI] [PubMed] [Google Scholar]
  15. Hattevig G., Kjellman B., Björkstén B. Appearance of IgE antibodies to ingested and inhaled allergens during the first 12 years of life in atopic and non-atopic children. Pediatr Allergy Immunol. 1993 Nov;4(4):182–186. doi: 10.1111/j.1399-3038.1993.tb00089.x. [DOI] [PubMed] [Google Scholar]
  16. Heufler C., Koch F., Stanzl U., Topar G., Wysocka M., Trinchieri G., Enk A., Steinman R. M., Romani N., Schuler G. Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon-gamma production by T helper 1 cells. Eur J Immunol. 1996 Mar;26(3):659–668. doi: 10.1002/eji.1830260323. [DOI] [PubMed] [Google Scholar]
  17. Holt P. G. A potential vaccine strategy for asthma and allied atopic diseases during early childhood. Lancet. 1994 Aug 13;344(8920):456–458. doi: 10.1016/s0140-6736(94)91776-0. [DOI] [PubMed] [Google Scholar]
  18. Holt P. G., Clough J. B., Holt B. J., Baron-Hay M. J., Rose A. H., Robinson B. W., Thomas W. R. Genetic 'risk' for atopy is associated with delayed postnatal maturation of T-cell competence. Clin Exp Allergy. 1992 Dec;22(12):1093–1099. doi: 10.1111/j.1365-2222.1992.tb00135.x. [DOI] [PubMed] [Google Scholar]
  19. Holt P. G. Environmental factors and primary T-cell sensitisation to inhalant allergens in infancy: reappraisal of the role of infections and air pollution. Pediatr Allergy Immunol. 1995 Feb;6(1):1–10. doi: 10.1111/j.1399-3038.1995.tb00250.x. [DOI] [PubMed] [Google Scholar]
  20. Holt P. G., Haining S., Nelson D. J., Sedgwick J. D. Origin and steady-state turnover of class II MHC-bearing dendritic cells in the epithelium of the conducting airways. J Immunol. 1994 Jul 1;153(1):256–261. [PubMed] [Google Scholar]
  21. Holt P. G. Immunoprophylaxis of atopy: light at the end of the tunnel? Immunol Today. 1994 Oct;15(10):484–489. doi: 10.1016/0167-5699(94)90194-5. [DOI] [PubMed] [Google Scholar]
  22. Holt P. G., O'Keeffe P., Holt B. J., Upham J. W., Baron-Hay M. J., Suphioglu C., Knox B., Stewart G. A., Thomas W. R., Sly P. D. T-cell "priming" against environmental allergens in human neonates: sequential deletion of food antigen reactivity during infancy with concomitant expansion of responses to ubiquitous inhalant allergens. Pediatr Allergy Immunol. 1995 May;6(2):85–90. doi: 10.1111/j.1399-3038.1995.tb00264.x. [DOI] [PubMed] [Google Scholar]
  23. Holt P. G., Oliver J., Bilyk N., McMenamin C., McMenamin P. G., Kraal G., Thepen T. Downregulation of the antigen presenting cell function(s) of pulmonary dendritic cells in vivo by resident alveolar macrophages. J Exp Med. 1993 Feb 1;177(2):397–407. doi: 10.1084/jem.177.2.397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Holt P. G. Postnatal maturation of immune competence during infancy and childhood. Pediatr Allergy Immunol. 1995 May;6(2):59–70. doi: 10.1111/j.1399-3038.1995.tb00261.x. [DOI] [PubMed] [Google Scholar]
  25. Holt P. G., Schon-Hegrad M. A., Phillips M. J., McMenamin P. G. Ia-positive dendritic cells form a tightly meshed network within the human airway epithelium. Clin Exp Allergy. 1989 Nov;19(6):597–601. doi: 10.1111/j.1365-2222.1989.tb02752.x. [DOI] [PubMed] [Google Scholar]
  26. Janeway C. A., Jr The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol Today. 1992 Jan;13(1):11–16. doi: 10.1016/0167-5699(92)90198-G. [DOI] [PubMed] [Google Scholar]
  27. Johnston S. L., Pattemore P. K., Sanderson G., Smith S., Campbell M. J., Josephs L. K., Cunningham A., Robinson B. S., Myint S. H., Ward M. E. The relationship between upper respiratory infections and hospital admissions for asthma: a time-trend analysis. Am J Respir Crit Care Med. 1996 Sep;154(3 Pt 1):654–660. doi: 10.1164/ajrccm.154.3.8810601. [DOI] [PubMed] [Google Scholar]
  28. Kondo N., Kobayashi Y., Shinoda S., Kasahara K., Kameyama T., Iwasa S., Orii T. Cord blood lymphocyte responses to food antigens for the prediction of allergic disorders. Arch Dis Child. 1992 Aug;67(8):1003–1007. doi: 10.1136/adc.67.8.1003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Krishnan L., Guilbert L. J., Russell A. S., Wegmann T. G., Mosmann T. R., Belosevic M. Pregnancy impairs resistance of C57BL/6 mice to Leishmania major infection and causes decreased antigen-specific IFN-gamma response and increased production of T helper 2 cytokines. J Immunol. 1996 Jan 15;156(2):644–652. [PubMed] [Google Scholar]
  30. Lin H., Mosmann T. R., Guilbert L., Tuntipopipat S., Wegmann T. G. Synthesis of T helper 2-type cytokines at the maternal-fetal interface. J Immunol. 1993 Nov 1;151(9):4562–4573. [PubMed] [Google Scholar]
  31. Macatonia S. E., Hosken N. A., Litton M., Vieira P., Hsieh C. S., Culpepper J. A., Wysocka M., Trinchieri G., Murphy K. M., O'Garra A. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol. 1995 May 15;154(10):5071–5079. [PubMed] [Google Scholar]
  32. Martinez F. D. Role of viral infections in the inception of asthma and allergies during childhood: could they be protective? Thorax. 1994 Dec;49(12):1189–1191. doi: 10.1136/thx.49.12.1189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  34. Mosmann T. R., Moore K. W. The role of IL-10 in crossregulation of TH1 and TH2 responses. Immunol Today. 1991 Mar;12(3):A49–A53. doi: 10.1016/S0167-5699(05)80015-5. [DOI] [PubMed] [Google Scholar]
  35. Mosmann T. R., Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996 Mar;17(3):138–146. doi: 10.1016/0167-5699(96)80606-2. [DOI] [PubMed] [Google Scholar]
  36. Nelson D. J., Holt P. G. Defective regional immunity in the respiratory tract of neonates is attributable to hyporesponsiveness of local dendritic cells to activation signals. J Immunol. 1995 Oct 1;155(7):3517–3524. [PubMed] [Google Scholar]
  37. Nelson D. J., McMenamin C., McWilliam A. S., Brenan M., Holt P. G. Development of the airway intraepithelial dendritic cell network in the rat from class II major histocompatibility (Ia)-negative precursors: differential regulation of Ia expression at different levels of the respiratory tract. J Exp Med. 1994 Jan 1;179(1):203–212. doi: 10.1084/jem.179.1.203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Nilsson L., Björkstén B., Hattevig G., Kjellman B., Sigurs N., Kjellman N. I. Season of birth as predictor of atopic manifestations. Arch Dis Child. 1997 Apr;76(4):341–344. doi: 10.1136/adc.76.4.341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Peat J. K., van den Berg R. H., Green W. F., Mellis C. M., Leeder S. R., Woolcock A. J. Changing prevalence of asthma in Australian children. BMJ. 1994 Jun 18;308(6944):1591–1596. doi: 10.1136/bmj.308.6944.1591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Pepys J., Hutchcroft B. J. Bronchial provocation tests in etiologic diagnosis and analysis of asthma. Am Rev Respir Dis. 1975 Dec;112(6):829–859. doi: 10.1164/arrd.1975.112.6.829. [DOI] [PubMed] [Google Scholar]
  41. Piastra M., Stabile A., Fioravanti G., Castagnola M., Pani G., Ria F. Cord blood mononuclear cell responsiveness to beta-lactoglobulin: T-cell activity in 'atopy-prone' and 'non-atopy-prone' newborns. Int Arch Allergy Immunol. 1994 Aug;104(4):358–365. doi: 10.1159/000236692. [DOI] [PubMed] [Google Scholar]
  42. Piccinni M. P., Mecacci F., Sampognaro S., Manetti R., Parronchi P., Maggi E., Romagnani S. Aeroallergen sensitization can occur during fetal life. Int Arch Allergy Immunol. 1993;102(3):301–303. doi: 10.1159/000236541. [DOI] [PubMed] [Google Scholar]
  43. Prescott S. L., Macaubes C., Yabuhara A., Venaille T. J., Holt B. J., Habre W., Loh R., Sly P. D., Holt P. G. Developing patterns of T cell memory to environmental allergens in the first two years of life. Int Arch Allergy Immunol. 1997 May-Jul;113(1-3):75–79. doi: 10.1159/000237512. [DOI] [PubMed] [Google Scholar]
  44. Ridge J. P., Fuchs E. J., Matzinger P. Neonatal tolerance revisited: turning on newborn T cells with dendritic cells. Science. 1996 Mar 22;271(5256):1723–1726. doi: 10.1126/science.271.5256.1723. [DOI] [PubMed] [Google Scholar]
  45. Rinas U., Horneff G., Wahn V. Interferon-gamma production by cord-blood mononuclear cells is reduced in newborns with a family history of atopic disease and is independent from cord blood IgE-levels. Pediatr Allergy Immunol. 1993 May;4(2):60–64. doi: 10.1111/j.1399-3038.1993.tb00068.x. [DOI] [PubMed] [Google Scholar]
  46. Romagnani S. Induction of TH1 and TH2 responses: a key role for the 'natural' immune response? Immunol Today. 1992 Oct;13(10):379–381. doi: 10.1016/0167-5699(92)90083-J. [DOI] [PubMed] [Google Scholar]
  47. Roth I., Corry D. B., Locksley R. M., Abrams J. S., Litton M. J., Fisher S. J. Human placental cytotrophoblasts produce the immunosuppressive cytokine interleukin 10. J Exp Med. 1996 Aug 1;184(2):539–548. doi: 10.1084/jem.184.2.539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Saryan J. A., Bouras A. Month of birth and sensitization to dust mites in New England. Allergy Asthma Proc. 1996 Mar-Apr;17(2):65–69. doi: 10.2500/108854196778644994. [DOI] [PubMed] [Google Scholar]
  49. Schon-Hegrad M. A., Oliver J., McMenamin P. G., Holt P. G. Studies on the density, distribution, and surface phenotype of intraepithelial class II major histocompatibility complex antigen (Ia)-bearing dendritic cells (DC) in the conducting airways. J Exp Med. 1991 Jun 1;173(6):1345–1356. doi: 10.1084/jem.173.6.1345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Shaheen S. O. Changing patterns of childhood infection and the rise in allergic disease. Clin Exp Allergy. 1995 Nov;25(11):1034–1037. doi: 10.1111/j.1365-2222.1995.tb03248.x. [DOI] [PubMed] [Google Scholar]
  51. Singh R. R., Hahn B. H., Sercarz E. E. Neonatal peptide exposure can prime T cells and, upon subsequent immunization, induce their immune deviation: implications for antibody vs. T cell-mediated autoimmunity. J Exp Med. 1996 Apr 1;183(4):1613–1621. doi: 10.1084/jem.183.4.1613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Tang M. L., Kemp A. S., Thorburn J., Hill D. J. Reduced interferon-gamma secretion in neonates and subsequent atopy. Lancet. 1994 Oct 8;344(8928):983–985. doi: 10.1016/s0140-6736(94)91641-1. [DOI] [PubMed] [Google Scholar]
  53. Warner J. A., Miles E. A., Jones A. C., Quint D. J., Colwell B. M., Warner J. O. Is deficiency of interferon gamma production by allergen triggered cord blood cells a predictor of atopic eczema? Clin Exp Allergy. 1994 May;24(5):423–430. doi: 10.1111/j.1365-2222.1994.tb00930.x. [DOI] [PubMed] [Google Scholar]
  54. Wegmann T. G., Lin H., Guilbert L., Mosmann T. R. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today. 1993 Jul;14(7):353–356. doi: 10.1016/0167-5699(93)90235-D. [DOI] [PubMed] [Google Scholar]
  55. Wierenga E. A., Snoek M., de Groot C., Chrétien I., Bos J. D., Jansen H. M., Kapsenberg M. L. Evidence for compartmentalization of functional subsets of CD2+ T lymphocytes in atopic patients. J Immunol. 1990 Jun 15;144(12):4651–4656. [PubMed] [Google Scholar]
  56. Woolcock A. J. Asthma--disease of a modern lifestyle. Med J Aust. 1996 Oct 7;165(7):358–359. [PubMed] [Google Scholar]
  57. Wright A. L., Taussig L. M., Ray C. G., Harrison H. R., Holberg C. J. The Tucson Children's Respiratory Study. II. Lower respiratory tract illness in the first year of life. Am J Epidemiol. 1989 Jun;129(6):1232–1246. doi: 10.1093/oxfordjournals.aje.a115243. [DOI] [PubMed] [Google Scholar]

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