Skip to main content

Thank you for visiting nature.com. 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.

  • Article
  • Published:

Association between atopy and variants of the β subunit of the high–affinity immunoglobulin E receptor

Abstract

The β–subunit of the high–affinity IgE receptor (FcεRI–β) on chromosome 11 is maternally linked to atopy, the state of enhanced IgE responsiveness underlying allergic asthma and rhinitis. We have identified a common variant of FcεRI–β, lle181Leu within the 4th transmembrane domain. Leu181 shows significant association with positive IgE responses in a random patient sample. Amongst 60 unrelated nuclear families with allergic asthmatic probands, Leu181 is identified in 10 (17%), is maternally inherited in each, and shows a strong association with atopy. Our data indicate that FcεRI–β, subject to maternal modification, may be the atopy–causing locus on chromosome 11q.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Stenius, B., Wide, L., Seymour, W.M., Holford-Strevens, V. & Pepys, J. Clinical significance of specific IgE to common allergens. I. Relationship of specific IgE against Dermatophagoides spp. and grass pollen to skin and nasal tests and history. Clin. Allergy 1, 37–55 (1971).

    Article  CAS  Google Scholar 

  2. Ishizaka, K. Mechanisms of reaginic hypersensitivity. Clin. Allergy 1, 9–24 (1971).

    Article  CAS  Google Scholar 

  3. Dombrowicz, D., Flamand, V., Brigman, K.K., Koller, B.H. & Kinet, J.-P. Abolition of anaphylaxis by targeted disruption of the high affinity immunoglobulin E receptor a chain gene. Cell 75, 969–976 (1993).

    Article  CAS  Google Scholar 

  4. Galli, S.J. New concepts about the mast cell. New Engl. J. Med. 328, 257–265 (1993).

    Article  CAS  Google Scholar 

  5. Tollerund, D.J., O'Connor, G.T., Sparrow, D. & Weiss, S.T. Asthma, hay fever, and phlegm production associated with distinct patterns of allergy skin test reactivity, eosinophilia, and serum IgE levels. The Normative Aging Study. Am. Rev. respir. Dis. 144, 776–781 (1991).

    Article  Google Scholar 

  6. Backer, V. et al. Distribution of serum IgE in children and adolescents aged 7 to 16 years in Copenhagen, in relation to factors of importance. Allergy 47, 484–489 (1992).

    Article  CAS  Google Scholar 

  7. Cline, M.G. & Burrows, B. Distributions of allergy in a population sample residing in Tuscon, Arizona. Thorax 44, 425–431 (1989).

    Article  CAS  Google Scholar 

  8. Holford-Strevens, V. et al. Serum total IgE levels in Canadian adults. J. Allergy clin. Immunol. 73, 516–522 (1984).

    Article  CAS  Google Scholar 

  9. Woolcock, A.J., Peat, J.K. & Salome, C.M. Prevalence of bronchial hyperresponsiveness and asthma in a rural adult population. Thorax 42, 361–368 (1987).

    Article  CAS  Google Scholar 

  10. Young, R.P., Hart, B.J., Merret, T.G., Read, A.F. & Hopkin, J.M. House dust mite allergy: interaction of genetic factors and dosage of allergen exposure. Clin. exp. Allergy 22, 205–211 (1992).

    Article  CAS  Google Scholar 

  11. Sporik, R., Chapman, M.D. & Platts-Mills, T.A. House dust mite exposure as a cause of asthma. Clin. Exp. Allergy 22, 897–906 (1992).

    Article  CAS  Google Scholar 

  12. Marsh, D.G. et al. HLA-Dw2: a genetic marker for human immune response to short ragweed pollen allergen Ra5.1. Response resulting primarily from natural antigenic exposure. J. exp. Med. 155, 1439–1451 (1982).

    Article  CAS  Google Scholar 

  13. Young, R.P. et al. HLA-DR and HLA-DP genotypes and immunoglobulin E responses to common major allergens. Clin. Allergy (in the press).

  14. Moffatt, M.F. et al. Genetic linkage of the TCR-α/δ region to specific Immunogulobulin E responses. Lancet (in the press).

  15. Cookson, W.O.C.M., Sharp, P.A., Faux, J.A. & Hopkin, J.M. Linkage between immunoglobulin E responses underlying asthma and rhinitis and chromosome 11q. Lancet, 1, 1292–1295 (1989).

    Article  CAS  Google Scholar 

  16. Young, R.P. et al. Confirmation of genetic linkage between atopic IgE responses and chromosome 11q13. J. med. Genet. 29, 236–238 (1992).

    Article  CAS  Google Scholar 

  17. Cookson, W.O.C.M. et al. Maternal inheritance of atopic IgE responsiveness on chromosome 11q. Lancet 340, 381–384 (1992).

    Article  CAS  Google Scholar 

  18. Sandford, A.J. et al. Localisation of atopy and β-subunit of high-affinity IgE receptor (FcεR1) on chromosome 11q. Lancet 341, 332–334 (1993).

    Article  CAS  Google Scholar 

  19. Moffatt, M.F., Sharp, P.A., Faux, J.A., Young, R.P., Cookson, W.O.C. & Hopkin, J.M. Factors confounding genetic linkage between atopy and chromosome 11q. Clin. exp. Allergy 22, 1046–1051 (1992).

    Article  CAS  Google Scholar 

  20. Magnusson, C.G. Cord serum IgE in relation to family history and as predictor of atopy disease in early infancy. Allergy 43, 241–251 (1988).

    Article  CAS  Google Scholar 

  21. Arshad, S.H., Matthews, S., Gant, C. & Hide, D.W. Effect of allergen avoidance on development of allergic disorders in infancy. Lancet 339, 1493–1497 (1992).

    Article  CAS  Google Scholar 

  22. Halonen, M., Stern, D., Taussig, L.M., Wright, A., Ray, C.G. & Martinez, F.D. The predictive relationship between serum IgE levels at birth and subsequent incidences of lower respiratory illnesses and eczema in infants. Am. Rev. respir. Dis. 146, 866–870 (1992).

    Article  CAS  Google Scholar 

  23. Lympany, P., Welsh, K.I., Cochrane, G.M., Kemeny, D.M. & Lee, T.H. Genetic analysis of the linkage between chromosome 11 q and atopy. Clin. exp. Allergy 22, 1085–92 (1992).

    Article  CAS  Google Scholar 

  24. Hizawa, N. et al. Lack of linkage between atopy and locus 11q13. Clin. exp. Allergy 22, 1065–1069 (1992).

    Article  CAS  Google Scholar 

  25. Rich, S.S., Roitman-Johnson, B., Greenberg, B., Roberts, S. & Blumenthal, M.N. Genetic analysis of atopy in three large kindreds: no evidence of linkage to D11S97. Clin. exp. Allergy 22, 1070–1076 (1992).

    Article  CAS  Google Scholar 

  26. Amelung, P.J. et al. Atopy and bronchial hyperresponsiveness: exclusion of linkage to markers on chromosomes 11 and 6p. Clin. exp. Allergy 22, 1077–1084 (1992).

    Article  CAS  Google Scholar 

  27. Shirakawa, T. et al. Linkage between atopic IgE reponses and chromosome 11q in Japanese families. Clin. Genet, (in the press).

  28. Collee, J.M., de Vries, H.G. & Gerritsen, J. Allele sharing on chromosome 11q13 in sibs with asthma. Lancet 342, 936 (1993).

    Article  CAS  Google Scholar 

  29. Tedder, T.F., Streuli, M., Schlossman, S.F. & Saito, H. Isolation and structure of a cDNA encoding the B1 (CD20) cell-surface antigen of human B lymphocytes. Proc. natn. Acad. Sci. U.S.A. 85, 208–212 (1988).

    Article  CAS  Google Scholar 

  30. Charmley, P., Nguyen, J., Tedder, T.F. & Gatti, R. A frequent human CD20 (B1) differentiation antigen DNA polymorphism detected with Mspl is located near 11q12–13. Nucl. Acids Res. 18, 207 (1990).

    Article  CAS  Google Scholar 

  31. Kuster, H., Zhang, L., Brini, A.T., MacGlashan, D.W.J. & Kinet, J.P. The gene and cDNA for the human high affinity imujnoglobulin E receptor β chain and expression of the complete human receptor. J. biol. Chem. 267, 12782–12787 (1992).

    CAS  PubMed  Google Scholar 

  32. Feme, R.M. et al. Development, multiplexing, and application of ARMS tests for common mutations in the CFTR gene. Am. J. hum. Genet. 51, 251–262 (1992).

    Google Scholar 

  33. Cookson, W.O.C.M. & Hopkin, J.M. Dominant inheritance of atopic immunoglobulin-E responsiveness. Lancet i, 86–88 (1989).

    Google Scholar 

  34. Metzger, H. The high affinity receptor for IgE on mast cells. Clin. exp. Allergy 21, 269–279 (1991).

    Article  CAS  Google Scholar 

  35. Blank, U. et al. Complete structure and expression in tranfected cells of high affinity IgE receptor. Nature 337, 187–189 (1989).

    Article  CAS  Google Scholar 

  36. Ra, C., Jouvin, M.H.E. & Kinet, J.P. Complete structure of the mouse mast cell receptor for IgE (FcεRI) and surface expression of chimeric receptors (rat-mouse-human) on transfected cells. J. biol. Chem. 264, 15323–15327 (1989).

    CAS  PubMed  Google Scholar 

  37. Bieber, T. et al. Human epidermal Langerhans cells express the high affinity receptor for immunoglobulin E (FcεRI). J. exp. Med. 175, 1285–1290 (1992).

    Article  CAS  Google Scholar 

  38. Maurer, D. et al. Expression of functional high affinity Immunoglobulin E receptors (FcεRI) on monocytes of atopic individuals. J. exp. Med. 179, 745–750 (1994).

    Article  CAS  Google Scholar 

  39. Oliver, J.M., Seagrave, J., Stump, R.F., Pfeiffer, J.R. & Deanin, G.G. Signal transduction and cellular response in RBL-2H3 mast cells. Prog. Allergy 42, 185–245 (1988).

    CAS  PubMed  Google Scholar 

  40. Helm, B. et al. The mast cell binding site on human immunoglobulin E. Nature 331, 180–183 (1988).

    Article  CAS  Google Scholar 

  41. Plaut, M. et al. Mast cell lines produce lymphokines in response to cross linkage of FcεRI to calcium ionophores. Nature 339, 64–67 (1989).

    Article  CAS  Google Scholar 

  42. Ben-Sasson, S.Z., Le Gros, G., Conrad, D.H. & Finkelman, F.D. Cross-linking Fc receptors stimulate splenic non-B, non-T cells to secrete interleukin 4 and other lymphokines. Proc. natn. Acad. Sci. U.S.A. 87, 1421–1425 (1990).

    Article  CAS  Google Scholar 

  43. Thompson, H.L., Metcalfe, D.D. & Kinet, J.P. Early expression of high-affinity receptor for immunoglobulin E (FcεRI) during differentiation of mouse mast cells and human basophils. J. clin. Invest. 85, 1227–1233 (1990).

    Article  CAS  Google Scholar 

  44. Wodnar-Filipowicz, A., Heusser, C.H. & Moroni, C. Production of the haemopoietic growth factors GM-CSF and interleukin-3 by mast ceils in response to IgE receptor-mediated activation. Nature 339, 150–152 (1989).

    Article  CAS  Google Scholar 

  45. Paul, W.E., Seder, R.A. & Plant, M. Lymphokine and cytokine production by Fc_RI+ cells. Adv. Immunol. 53, 1–29 (1992).

    Google Scholar 

  46. Gascan, H. et al. Human B cell clones can be induced to proliferate and to switch to IgE and lgG4 synthesis by Interleukin 4 and a signal provided by activated CD4+ T cell clones. J. exp. Med. 17, 747–750 (1991).

    Article  Google Scholar 

  47. Gaucnat, J.-F. et al. Induction of human IgE synthesis in B cells by mast cells and basophils. Nature 365, 340–343 (1993).

    Article  Google Scholar 

  48. Kinet, J.-P., Quarto, R., Perez-Montfort, R. & Metzger, H. Non covalently and covalently bound lipid on the receptor for immunoglobulin E. Biochemistry 24, 7342–7348 (1985).

    Article  CAS  Google Scholar 

  49. Dohlman, H.G., Caron, M.G. & Lefkowitz, R. A family of receptors coupled to guanine nucleotide regulatory proteins. Biochemistry 26, 2657–2663 (1987).

    Article  CAS  Google Scholar 

  50. Rees, D.C., DeAntonio, L. & Eisenberg, D. Hydrophobic organization of membrane proteins. Science 245, 510–513 (1989).

    Article  CAS  Google Scholar 

  51. Varin-Blank, N. & Metzger, H. Surface expression of mutated subunits of the high affinity mast cell receptor for IgE. J. biol. Chem. 265, 15685–15694 (1990).

    CAS  PubMed  Google Scholar 

  52. Oksenberg, D. et al. A single amino-acid difference confers major pharmacological variation between human and rodent 5-HT1B receptors. Nature 360, 161–163 (1992).

    Article  CAS  Google Scholar 

  53. Shenker, A. et al. A constitutively activating mutation of the leuteinizing hormone receptor in familial male precocious puberty. Nature 365, 652–654 (1993).

    Article  CAS  Google Scholar 

  54. Beinborn, M., Lee, Y.-M., McBride, E.W., Quinn, S.M. & Kopin, A.S. A single amino acid of the cholecystokinin-B/gastin receptor determines specificity for non-peptide antagonists. Nature 362, 348–350 (1993).

    Article  CAS  Google Scholar 

  55. Eccleston, E., Leonard, B.J., Loee, J.S. & Wellford, H.J. Basophilic leukaemia in the albino rat and a demonstration of basoprotein. Nature new Biology 244, 73–76 (1973).

    Article  CAS  Google Scholar 

  56. Kinet, J.P., Blank, U., Ra, C., White, K., Metzger, H. & Kochan, J. Isolation and characterisation of cDNAs coding for the beta subunit of the high affinity receptor for immunoglobulin E. Proc. natn. Acad. Sci. U.S.A. 85, 6483–6487 (1988).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shirakawa, T., Li, A., Dubowitz, M. et al. Association between atopy and variants of the β subunit of the high–affinity immunoglobulin E receptor. Nat Genet 7, 125–130 (1994). https://doi.org/10.1038/ng0694-125

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0694-125

This article is cited by

Search

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