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. 1983 Nov;72(5):1650–1657. doi: 10.1172/JCI111124

Hyper IgM immunodeficiency. A primary dysfunction of B lymphocyte isotype switching.

D Levitt, P Haber, K Rich, M D Cooper
PMCID: PMC370453  PMID: 6605368

Abstract

Immunological evaluations (lymphocyte markers, B cell differentiation, T cell function) were performed on peripheral blood mononuclear cells from four individuals with hyper IgM immunodeficiency. Number, proportion, and proliferation of T lymphocytes and T lymphocyte subpopulations were relatively normal in affected individuals. The percentage and number of B cells expressing surface IgM and IgD were either normal or elevated in both blood and lymph nodes. However, surface IgG- and IgA-bearing B lymphocytes were completely absent. In vitro stimulation of blood lymphocytes with both T cell-dependent and T-cell independent polyclonal B cell activators resulted in normal numbers of IgM plasma cells and IgM secretion in cultures, but failed to induce any IgG- or IgA-producing cells. This failure of isotype switching was intrinsic to the B cell population and did not involve aberrant T cell help or suppression. Therefore, individuals with this disorder possess an intrinsic B cell dysfunction that is not related to abnormal T cell regulation.

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Selected References

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

  1. Abney E. R., Cooper M. D., Kearney J. F., Lawton A. R., Parkhouse R. M. Sequential expression of immunoglobulin on developing mouse B lymphocytes: a systematic survey that suggests a model for the generation of immunoglobulin isotype diversity. J Immunol. 1978 Jun;120(6):2041–2049. [PubMed] [Google Scholar]
  2. Armerding D., Katz D. H. Activation of T and B lymphocytes in vitro. II. Biological and biochemical properties of an allogeneic effect factor (AEF) active in triggering specific B lymphocytes. J Exp Med. 1974 Jul 1;140(1):19–37. doi: 10.1084/jem.140.1.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ashman R. F., Saxon A., Stevens R. H. Profile of multiple lymphocyte functional defects in acquired hypogrammaglobulinemia, derived from in vitro cell recombination analysis. J Allergy Clin Immunol. 1980 Apr;65(4):242–256. doi: 10.1016/0091-6749(80)90151-7. [DOI] [PubMed] [Google Scholar]
  4. Beall G. N., Ashman R. F., Miller M. E., Easwaran C., Raghunathan R., Louie J., Yoshikawa T. Hypogammaglobulinemia in mother and son. J Allergy Clin Immunol. 1980 Jun;65(6):471–481. doi: 10.1016/0091-6749(80)90242-0. [DOI] [PubMed] [Google Scholar]
  5. Cooper M. D. Pre-B cells; normal and abnormal development. J Clin Immunol. 1981 Apr;1(2):81–89. doi: 10.1007/BF00915383. [DOI] [PubMed] [Google Scholar]
  6. Coutinho A., Benner R., Björklund M., Forni L., Holmberg D., Ivars F., Martinez-A C., Pettersson S. A "trans" perspective on the control of immunoglobulin c gene expression. Immunol Rev. 1982;67:87–114. doi: 10.1111/j.1600-065x.1982.tb01057.x. [DOI] [PubMed] [Google Scholar]
  7. Falkoff R. J., Zhu L. P., Fauci A. S. Separate signals for human B cell proliferation and differentiation in response to Staphylococcus aureus: evidence for a two-signal model of B cell activation. J Immunol. 1982 Jul;129(1):97–102. [PubMed] [Google Scholar]
  8. Friedman S. M., Irigoyen O. H., Gay D., Chess L. MLC-derived human helper factor(s) that promote B cell differentiation: induction, functional characterization, and role of Ia antigens. J Immunol. 1980 Jun;124(6):2930–2935. [PubMed] [Google Scholar]
  9. Gathings W. E., Lawton A. R., Cooper M. D. Immunofluorescent studies of the development of pre-B cells, B lymphocytes and immunoglobulin isotype diversity in humans. Eur J Immunol. 1977 Nov;7(11):804–810. doi: 10.1002/eji.1830071112. [DOI] [PubMed] [Google Scholar]
  10. Geha R. S., Hyslop N., Alami S., Farah F., Schneeberger E. E., Rosen F. S. Hyper immunoglobulin M immunodeficiency. (Dysgammaglobulinemia). Presence of immunoglobulin M-secreting plasmacytoid cells in peripheral blood and failure of immunoglobulin M-immunoglobulin G switch in B-cell differentiation. J Clin Invest. 1979 Aug;64(2):385–391. doi: 10.1172/JCI109473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Herrod H. G., Buckley R. H. Use of a human plaque-forming cell assay to study peripheral blood bursa-equivalent cell activation and excessive suppressor cell activity in humoral immunodeficiency. J Clin Invest. 1979 May;63(5):868–876. doi: 10.1172/JCI109386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Isakson P. C., Puré E., Vitetta E. S., Krammer P. H. T cell-derived B cell differentiation factor(s). Effect on the isotype switch of murine B cells. J Exp Med. 1982 Mar 1;155(3):734–748. doi: 10.1084/jem.155.3.734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jerrells T. R., Dean J. H., Richardson G. L., Herberman R. B. Depletion of monocytes from human peripheral blood mononuclear leukocytes: comparison of the sephadex G-10 column method with other commonly used techniques. J Immunol Methods. 1980;32(1):11–29. doi: 10.1016/0022-1759(80)90113-1. [DOI] [PubMed] [Google Scholar]
  14. Kearney J. F., Abney E. R. Immunoglobulin isotype expression. Contemp Top Immunobiol. 1978;8:245–265. doi: 10.1007/978-1-4684-0922-2_8. [DOI] [PubMed] [Google Scholar]
  15. Keightley R. G., Cooper M. D., Lawton A. R. The T cell dependence of B cell differentiation induced by pokeweed mitogen. J Immunol. 1976 Nov;117(5 Pt 1):1538–1544. [PubMed] [Google Scholar]
  16. Krantman H. J., Stiehm E. R., Stevens R. H., Saxon A., Seeger R. C. Abnormal B cell differentiation and variable increased T cell suppression in immunodeficiency with hyper-IgM. Clin Exp Immunol. 1980 Apr;40(1):147–156. [PMC free article] [PubMed] [Google Scholar]
  17. Kubagawa H., Gathings W. E., Levitt D., Kearney J. F., Cooper M. D. Immunoglobulin isotype expression of normal pre-B cells as determined by immunofluorescence. J Clin Immunol. 1982 Oct;2(4):264–269. doi: 10.1007/BF00915065. [DOI] [PubMed] [Google Scholar]
  18. Kubagawa H., Mayumi M., Crist W. M., Cooper M. D. Immunoglobulin heavy-chain switching in pre-B leukaemias. Nature. 1983 Jan 27;301(5898):340–342. doi: 10.1038/301340a0. [DOI] [PubMed] [Google Scholar]
  19. Kuritani T., Cooper M. D. Human b-cell differentiation. I. Analysis of immunoglobulin heavy chain switching using monoclonal anti-immunoglobulin M, G, and A antibodies and pokeweed mitogen-induced plasma cell differentiation. J Exp Med. 1982 Mar 1;155(3):839–851. doi: 10.1084/jem.155.3.839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kyong C. U., Virella G., Fudenberg H. H., Darby C. P. X-linked immunodeficiency with increased IgM: clinical, ethnic, and immunologic heterogeneity. Pediatr Res. 1978 Oct;12(10):1024–1026. doi: 10.1203/00006450-197810000-00015. [DOI] [PubMed] [Google Scholar]
  21. Levitt D., Cooper M. D. Immunoregulatory defects in a family with selective IgA deficiency. J Pediatr. 1981 Jan;98(1):52–58. doi: 10.1016/s0022-3476(81)80532-x. [DOI] [PubMed] [Google Scholar]
  22. Levitt D., Cooper M. D. Mouse pre-B cells synthesize and secrete mu heavy chains but not light chains. Cell. 1980 Mar;19(3):617–625. doi: 10.1016/s0092-8674(80)80038-9. [DOI] [PubMed] [Google Scholar]
  23. Levitt D., Dagg M. K. Human B-lymphocyte subpopulations. II. Plasma cell differentiation of isotype-specific B lymphocytes from peripheral blood. Clin Immunol Immunopathol. 1981 Oct;21(1):50–61. doi: 10.1016/0090-1229(81)90194-x. [DOI] [PubMed] [Google Scholar]
  24. Levitt D., Duber-Stull D., Lawton A. R. T-cell-dependent and independent plasma cell differentiation induced by Escherichia coli Lipopolysaccharide in human peripheral blood lymphocytes. Clin Immunol Immunopathol. 1981 Mar;18(3):309–321. doi: 10.1016/0090-1229(81)90124-0. [DOI] [PubMed] [Google Scholar]
  25. Marcu K. B., Cooper M. D. New views of the immunoglobulin heavy-chain switch. Nature. 1982 Jul 22;298(5872):327–328. doi: 10.1038/298327a0. [DOI] [PubMed] [Google Scholar]
  26. Markham R. B., Reed N. D., Stashak P. W., Prescott B., Amsbaugh D. F., Baker P. J. Effect of concanavalin A on lymphocyte interactions involved in the antibody response to type III pneumococcal polysaccharide. II. Ability of suppressor T cells to act on both B cells and amplified T cells to limit the magnitude of the antibody response. J Immunol. 1977 Sep;119(3):1163–1168. [PubMed] [Google Scholar]
  27. Mongini P. K., Paul W. E., Metcalf E. S. T cell regulation of immunoglobulin class expression in the antibody response to trinitrophenyl-ficoll. Evidence for T cell enhancement of the immunoglobulin class switch. J Exp Med. 1982 Mar 1;155(3):884–902. doi: 10.1084/jem.155.3.884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Mongini P. K., Stein K. E., Paul W. E. T cell regulation of IgG subclass antibody production in response to T-independent antigens. J Exp Med. 1981 Jan 1;153(1):1–12. doi: 10.1084/jem.153.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Pascual-Salcedo D., de la Concha E. G., Garcia-Rodriguez M. C., Zabay J. M., Sainz T., Fontán G. Cellular basis of hyper IgM immunodeficiency. J Clin Lab Immunol. 1983 Jan;10(1):29–34. [PubMed] [Google Scholar]
  30. Pearl E. R., Vogler L. B., Okos A. J., Crist W. M., Lawton A. R., 3rd, Cooper M. D. B lymphocyte precursors in human bone marrow: an analysis of normal individuals and patients with antibody-deficiency states. J Immunol. 1978 Apr;120(4):1169–1175. [PubMed] [Google Scholar]
  31. Pellegrino M. A., Ferrone S., Dierich M. P., Reisfeld R. A. Enhancement of sheep red blood cell human lymphocyte rosette formation by the sulfhydryl compound 2-amino ethylisothiouronium bromide. Clin Immunol Immunopathol. 1975 Jan;3(3):324–333. doi: 10.1016/0090-1229(75)90019-7. [DOI] [PubMed] [Google Scholar]
  32. Pryjma J., Muñoz J., Galbraith R. M., Fudenberg H. H., Virella G. Induction and suppression of immunoglobulin synthesis in cultures of human lymphocytes: effects of pokeweed mitogen and Staphylococcus aureus Cowan I. J Immunol. 1980 Feb;124(2):656–661. [PubMed] [Google Scholar]
  33. Reinherz E. L., Cooper M. D., Schlossman S. F., Rosen F. S. Abnormalities of T cell maturation and regulation in human beings with immunodeficiency disorders. J Clin Invest. 1981 Sep;68(3):699–705. doi: 10.1172/JCI110305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Reinherz E. L., Geha R., Wohl M. E., Morimoto C., Rosen F. S., Schlossman S. F. Immunodeficiency associated with loss of T4+ inducer T-cell function. N Engl J Med. 1981 Apr 2;304(14):811–816. doi: 10.1056/NEJM198104023041403. [DOI] [PubMed] [Google Scholar]
  35. Reinherz E. L., Rubinstein A., Geha R. S., Strelkauskas A. J., Rosen F. S., Schlossman S. F. Abnormalities of immunoregulatory T cells in disorders of immune function. N Engl J Med. 1979 Nov 8;301(19):1018–1022. doi: 10.1056/NEJM197911083011902. [DOI] [PubMed] [Google Scholar]
  36. Reinherz E. L., Schlossman S. F. Current concepts in immunology: Regulation of the immune response--inducer and suppressor T-lymphocyte subsets in human beings. N Engl J Med. 1980 Aug 14;303(7):370–373. doi: 10.1056/NEJM198008143030704. [DOI] [PubMed] [Google Scholar]
  37. Rosen F. S., Janeway C. A. The gamma globulins. 3. The antibody deficiency syndromes. N Engl J Med. 1966 Sep 29;275(13):709–contd. doi: 10.1056/NEJM196609292751307. [DOI] [PubMed] [Google Scholar]
  38. Rosenberg Y. J. Isotype-specific T cell regulation of immunoglobulin expression. Immunol Rev. 1982;67:33–58. doi: 10.1111/j.1600-065x.1982.tb01054.x. [DOI] [PubMed] [Google Scholar]
  39. Shou L., Schwartz S. A., Good R. A. Suppressor cell activity after concanavalin A treatment of lymphocytes from normal donors. J Exp Med. 1976 May 1;143(5):1100–1110. doi: 10.1084/jem.143.5.1100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Siegal F. P., Siegal M., Good R. A. Role of helper, suppressor and B-cell defects in the pathogenesis of the hypogammaglobulinemias. N Engl J Med. 1978 Jul 27;299(4):172–178. doi: 10.1056/NEJM197807272990404. [DOI] [PubMed] [Google Scholar]
  41. Siegal F. P., Siegal M., Good R. A. Suppression of B-cell differentiation by leukocytes from hypogammaglobulinemic patients. J Clin Invest. 1976 Jul;58(1):109–122. doi: 10.1172/JCI108439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Stevens R. H., Macy E., Thiele C. J. Evidence that pokeweed-mitogen-reactive B cells are pre-committed in vivo to the high-rate secretion of a single immunoglobulin isotype in vitro. Scand J Immunol. 1981 Nov;14(5):449–457. doi: 10.1111/j.1365-3083.1981.tb00587.x. [DOI] [PubMed] [Google Scholar]
  43. Vogler L. B., Preud'homme J. L., Seligmann M., Gathings W. E., Crist W. M., Cooper M. D., Bollum F. J. Diversity of immunoglobulin expression in leukaemic cells resembling B-lymphocyte precursors. Nature. 1981 Mar 26;290(5804):339–341. doi: 10.1038/290339a0. [DOI] [PubMed] [Google Scholar]
  44. Waldmann T. A., Broder S., Krakauer R., Durm M., Meade B., Goldman C. Defect in IgA secretion and in IgA specific suppressor cells in patients with selective IgA deficiency. Trans Assoc Am Physicians. 1976;89:215–224. [PubMed] [Google Scholar]
  45. Waldmann T. A., Broder S. Polyclonal B-cell activators in the study of the regulation of immunoglobulin synthesis in the human system. Adv Immunol. 1982;32:1–63. doi: 10.1016/s0065-2776(08)60720-8. [DOI] [PubMed] [Google Scholar]
  46. Waldmann T. A., Broder S. Polyclonal B-cell activators in the study of the regulation of immunoglobulin synthesis in the human system. Adv Immunol. 1982;32:1–63. doi: 10.1016/s0065-2776(08)60720-8. [DOI] [PubMed] [Google Scholar]
  47. Waldmann T. A., Durm M., Broder S., Blackman M., Blaese R. M., Strober W. Role of suppressor T cells in pathogenesis of common variable hypogammaglobulinaemia. Lancet. 1974 Sep 14;2(7881):609–613. doi: 10.1016/s0140-6736(74)91940-0. [DOI] [PubMed] [Google Scholar]
  48. Watanabe T., Kimoto M., Maruyama S., Kishimoto T., Yamamura Y. Regulation of antibody response in different immunoglobulin classes. V. Establishment of T hybrid cell line secreting IgE class-specific suppressor factor. J Immunol. 1978 Nov;121(5):2113–2117. [PubMed] [Google Scholar]
  49. Yaoita Y., Kumagai Y., Okumura K., Honjo T. Expression of lymphocyte surface IgE does not require switch recombination. Nature. 1982 Jun 24;297(5868):697–699. doi: 10.1038/297697a0. [DOI] [PubMed] [Google Scholar]

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