Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Jan 1;177(1):99–107. doi: 10.1084/jem.177.1.99

Molecular evolution of the human immunoglobulin E response: high incidence of shared mutations and clonal relatedness among epsilon VH5 transcripts from three unrelated patients with atopic dermatitis

PMCID: PMC2190866  PMID: 8418213

Abstract

We have analyzed the nucleotide sequences of 19 epsilon VH5 transcripts derived from in vivo isotype switched peripheral blood B cells of three patients with atopic dermatitis. Comparison with the patients' own germline VH5 gene segments revealed that the epsilon transcripts were derived from both functional members of the human VH5 gene family and harbored numerous somatic mutations (range 5-36 per VH5 gene). In two patients, we detected clonally related but diverged transcripts, permitting the construction of a genealogical tree in one patient. We observed a high proportion of shared silent (S) and replacement (R) mutations among epsilon VH5 sequences derived from all three individuals, even among transcripts descending from the two different germline VH5 gene segments. A remarkably high number of these mutations is shared with previously reported VH5 genes encoding antibodies with defined specificities. The shared S mutations, and likely a fraction of the R mutations, appear to mark preferential sites ("hot spots") of somatic hypermutations in human VH5 genes. The distribution of R and S mutations over complementarity determining region and framework regions in the majority of VH regions deviated from that characteristic of antigen-driven immune response. We hypothesize that the V regions of immunoglobulin E-bearing B cells have accumulated "selectively neutral" mutations over extended periods of clonal expansion, resulting in unusual R/S ratios. We propose that the molecular characteristics of the epsilon VH regions in atopic dermatitis may be representative of antigens that recurrently or chronically stimulate the immune system.

Full Text

The Full Text of this article is available as a PDF (778.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adderson E. E., Shackelford P. G., Quinn A., Carroll W. L. Restricted Ig H chain V gene usage in the human antibody response to Haemophilus influenzae type b capsular polysaccharide. J Immunol. 1991 Sep 1;147(5):1667–1674. [PubMed] [Google Scholar]
  2. Alzari P. M., Spinelli S., Mariuzza R. A., Boulot G., Poljak R. J., Jarvis J. M., Milstein C. Three-dimensional structure determination of an anti-2-phenyloxazolone antibody: the role of somatic mutation and heavy/light chain pairing in the maturation of an immune response. EMBO J. 1990 Dec;9(12):3807–3814. doi: 10.1002/j.1460-2075.1990.tb07598.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Amit A. G., Mariuzza R. A., Phillips S. E., Poljak R. J. Three-dimensional structure of an antigen-antibody complex at 2.8 A resolution. Science. 1986 Aug 15;233(4765):747–753. doi: 10.1126/science.2426778. [DOI] [PubMed] [Google Scholar]
  4. Andris J. S., Johnson S., Zolla-Pazner S., Capra J. D. Molecular characterization of five human anti-human immunodeficiency virus type 1 antibody heavy chains reveals extensive somatic mutation typical of an antigen-driven immune response. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7783–7787. doi: 10.1073/pnas.88.17.7783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Berek C., Milstein C. Mutation drift and repertoire shift in the maturation of the immune response. Immunol Rev. 1987 Apr;96:23–41. doi: 10.1111/j.1600-065x.1987.tb00507.x. [DOI] [PubMed] [Google Scholar]
  6. Berman J. E., Mellis S. J., Pollock R., Smith C. L., Suh H., Heinke B., Kowal C., Surti U., Chess L., Cantor C. R. Content and organization of the human Ig VH locus: definition of three new VH families and linkage to the Ig CH locus. EMBO J. 1988 Mar;7(3):727–738. doi: 10.1002/j.1460-2075.1988.tb02869.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Clarke S., Rickert R., Wloch M. K., Staudt L., Gerhard W., Weigert M. The BALB/c secondary response to the Sb site of influenza virus hemagglutinin. Nonrandom silent mutation and unequal numbers of VH and Vk mutations. J Immunol. 1990 Oct 1;145(7):2286–2296. [PubMed] [Google Scholar]
  8. Hackett J., Jr, Rogerson B. J., O'Brien R. L., Storb U. Analysis of somatic mutations in kappa transgenes. J Exp Med. 1990 Jul 1;172(1):131–137. doi: 10.1084/jem.172.1.131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hanifin J. M. Atopic dermatitis. J Allergy Clin Immunol. 1984 Feb;73(2):211–226. doi: 10.1016/s0091-6749(84)80008-1. [DOI] [PubMed] [Google Scholar]
  10. Levy S., Mendel E., Kon S., Avnur Z., Levy R. Mutational hot spots in Ig V region genes of human follicular lymphomas. J Exp Med. 1988 Aug 1;168(2):475–489. doi: 10.1084/jem.168.2.475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Manser T. Evolution of antibody structure during the immune response. The differentiative potential of a single B lymphocyte. J Exp Med. 1989 Oct 1;170(4):1211–1230. doi: 10.1084/jem.170.4.1211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Manser T., Wysocki L. J., Margolies M. N., Gefter M. L. Evolution of antibody variable region structure during the immune response. Immunol Rev. 1987 Apr;96:141–162. doi: 10.1111/j.1600-065x.1987.tb00513.x. [DOI] [PubMed] [Google Scholar]
  13. McKean D., Huppi K., Bell M., Staudt L., Gerhard W., Weigert M. Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin. Proc Natl Acad Sci U S A. 1984 May;81(10):3180–3184. doi: 10.1073/pnas.81.10.3180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Parronchi P., Macchia D., Piccinni M. P., Biswas P., Simonelli C., Maggi E., Ricci M., Ansari A. A., Romagnani S. Allergen- and bacterial antigen-specific T-cell clones established from atopic donors show a different profile of cytokine production. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4538–4542. doi: 10.1073/pnas.88.10.4538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Pène J., Rousset F., Brière F., Chrétien I., Bonnefoy J. Y., Spits H., Yokota T., Arai N., Arai K., Banchereau J. IgE production by normal human lymphocytes is induced by interleukin 4 and suppressed by interferons gamma and alpha and prostaglandin E2. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6880–6884. doi: 10.1073/pnas.85.18.6880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Randen I., Brown D., Thompson K. M., Hughes-Jones N., Pascual V., Victor K., Capra J. D., Førre O., Natvig J. B. Clonally related IgM rheumatoid factors undergo affinity maturation in the rheumatoid synovial tissue. J Immunol. 1992 May 15;148(10):3296–3301. [PubMed] [Google Scholar]
  17. Rose D. R., Strong R. K., Margolies M. N., Gefter M. L., Petsko G. A. Crystal structure of the antigen-binding fragment of the murine anti-arsonate monoclonal antibody 36-71 at 2.9-A resolution. Proc Natl Acad Sci U S A. 1990 Jan;87(1):338–342. doi: 10.1073/pnas.87.1.338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Rudikoff S., Pawlita M., Pumphrey J., Heller M. Somatic diversification of immunoglobulins. Proc Natl Acad Sci U S A. 1984 Apr;81(7):2162–2166. doi: 10.1073/pnas.81.7.2162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Sampson H. A. Role of immediate hypersensitivity in the pathogenesis of atopic dermatitis. Allergy. 1989;44 (Suppl 9):52–58. [PubMed] [Google Scholar]
  20. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sanz I., Casali P., Thomas J. W., Notkins A. L., Capra J. D. Nucleotide sequences of eight human natural autoantibody VH regions reveals apparent restricted use of VH families. J Immunol. 1989 Jun 1;142(11):4054–4061. [PubMed] [Google Scholar]
  22. Sanz I., Kelly P., Williams C., Scholl S., Tucker P., Capra J. D. The smaller human VH gene families display remarkably little polymorphism. EMBO J. 1989 Dec 1;8(12):3741–3748. doi: 10.1002/j.1460-2075.1989.tb08550.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sharpe M. J., Milstein C., Jarvis J. M., Neuberger M. S. Somatic hypermutation of immunoglobulin kappa may depend on sequences 3' of C kappa and occurs on passenger transgenes. EMBO J. 1991 Aug;10(8):2139–2145. doi: 10.1002/j.1460-2075.1991.tb07748.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Shlomchik M. J., Aucoin A. H., Pisetsky D. S., Weigert M. G. Structure and function of anti-DNA autoantibodies derived from a single autoimmune mouse. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9150–9154. doi: 10.1073/pnas.84.24.9150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Shlomchik M. J., Marshak-Rothstein A., Wolfowicz C. B., Rothstein T. L., Weigert M. G. The role of clonal selection and somatic mutation in autoimmunity. 1987 Aug 27-Sep 2Nature. 328(6133):805–811. doi: 10.1038/328805a0. [DOI] [PubMed] [Google Scholar]
  26. Shlomchik M., Nemazee D., van Snick J., Weigert M. Variable region sequences of murine IgM anti-IgG monoclonal autoantibodies (rheumatoid factors). II. Comparison of hybridomas derived by lipopolysaccharide stimulation and secondary protein immunization. J Exp Med. 1987 Apr 1;165(4):970–987. doi: 10.1084/jem.165.4.970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wierenga E. A., Snoek M., Jansen H. M., Bos J. D., van Lier R. A., Kapsenberg M. L. Human atopen-specific types 1 and 2 T helper cell clones. J Immunol. 1991 Nov 1;147(9):2942–2949. [PubMed] [Google Scholar]
  28. Wysocki L. J., Gefter M. L. Gene conversion and the generation of antibody diversity. Annu Rev Biochem. 1989;58:509–531. doi: 10.1146/annurev.bi.58.070189.002453. [DOI] [PubMed] [Google Scholar]
  29. Wysocki L. J., Gefter M. L., Margolies M. N. Parallel evolution of antibody variable regions by somatic processes: consecutive shared somatic alterations in VH genes expressed by independently generated hybridomas apparently acquired by point mutation and selection rather than by gene conversion. J Exp Med. 1990 Jul 1;172(1):315–323. doi: 10.1084/jem.172.1.315. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES