Skip to main content
NCBI home page
Clinical and Diagnostic Laboratory Immunology logoLink to Clinical and Diagnostic Laboratory Immunology
. 1995 Jul;2(4):412–416. doi: 10.1128/cdli.2.4.412-416.1995

Intrinsic defect in B cells of patients with hyper-immunoglobulin M syndrome.

Y B Porat 1, D Levy 1, J Levy 1, I Zan-Bar 1
PMCID: PMC170171  PMID: 7583916

Abstract

We challenge the theory that the CD40-CD40 ligand is the only explanation for X-linked immunodeficiency in patients with hyper-immunoglobulin M (IgM) syndrome (HIGM1), and we demonstrate an intrinsic defect in the patients' B cells. Patients with HIGM1 have a defective CD40 ligand on their activated T-helper cells; therefore, they cannot receive signals for isotype switching when the cells are activated by T cell-dependent antigens. We activated mononuclear cells from three patients with HIGM1 and from three healthy blood donors with T cell-independent mitogens and studied their proliferative responses and Ig secretion. Normal murine plasma membrane fragments were implanted into peripheral blood mononuclear cells, and the cells were activated with Staphylococcus aureus Cowan I, pokeweed mitogen, and lipopolysaccharide. This implantation significantly augmented the proliferative responses to the mitogens in two patients. However, it augmented IGM secretion in response to B-cell mitogens in only one patient. No IgG or IgA response could be detected in the implanted mononuclear cells that originated from patients with HIGM1, unlike implanted mononuclear cells from healthy donors, which responded by IgM, IgG, and IgA antibody secretion following their stimulation with B-cell mitogens. The data suggest that the B cells of patients with HIGM1 possess an additional defect which prevents Ig isotype switching in response to T cell-independent mitogens. This defect is not located in the membrane receptors or within the membrane enzymes.

Full Text

The Full Text of this article is available as a PDF (229.7 KB).

Selected References

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

  1. Abramovitz B., Altboum I., Lapidot M., Loyter A., Zan-Bar I. Induction of serotonin release from mast cells by lymphocyte activators is dependent upon implantation of lymphocyte plasma membrane components. Exp Cell Res. 1991 Jun;194(2):228–231. doi: 10.1016/0014-4827(91)90358-2. [DOI] [PubMed] [Google Scholar]
  2. Aruffo A., Farrington M., Hollenbaugh D., Li X., Milatovich A., Nonoyama S., Bajorath J., Grosmaire L. S., Stenkamp R., Neubauer M. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell. 1993 Jan 29;72(2):291–300. doi: 10.1016/0092-8674(93)90668-g. [DOI] [PubMed] [Google Scholar]
  3. Bartlett W. C., Michael A., McCann J., Yuan D., Claassen E., Noelle R. J. Cognate interactions between helper T cells and B cells. II. Dissection of cognate help by using a class II-restricted, antigen-specific, IL-2-dependent helper T cell clone. J Immunol. 1989 Sep 15;143(6):1745–1754. [PubMed] [Google Scholar]
  4. Ben-Anat Porat Y., Zan-Bar I. Repair of immunoglobulin response in B cell line (JK32.1) originating from immunodeficient patient via implantation of functional plasma membranes. Clin Immunol Immunopathol. 1995 Feb;74(2):151–155. doi: 10.1006/clin.1995.1022. [DOI] [PubMed] [Google Scholar]
  5. Callard R. E., Smith S. H., Herbert J., Morgan G., Padayachee M., Lederman S., Chess L., Kroczek R. A., Fanslow W. C., Armitage R. J. CD40 ligand (CD40L) expression and B cell function in agammaglobulinemia with normal or elevated levels of IgM (HIM). Comparison of X-linked, autosomal recessive, and non-X-linked forms of the disease, and obligate carriers. J Immunol. 1994 Oct 1;153(7):3295–3306. [PubMed] [Google Scholar]
  6. Coffman R. L., Ohara J., Bond M. W., Carty J., Zlotnik A., Paul W. E. B cell stimulatory factor-1 enhances the IgE response of lipopolysaccharide-activated B cells. J Immunol. 1986 Jun 15;136(12):4538–4541. [PubMed] [Google Scholar]
  7. Conley M. E., Larché M., Bonagura V. R., Lawton A. R., 3rd, Buckley R. H., Fu S. M., Coustan-Smith E., Herrod H. G., Campana D. Hyper IgM syndrome associated with defective CD40-mediated B cell activation. J Clin Invest. 1994 Oct;94(4):1404–1409. doi: 10.1172/JCI117476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Defrance T., Vanbervliet B., Brière F., Durand I., Rousset F., Banchereau J. Interleukin 10 and transforming growth factor beta cooperate to induce anti-CD40-activated naive human B cells to secrete immunoglobulin A. J Exp Med. 1992 Mar 1;175(3):671–682. doi: 10.1084/jem.175.3.671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. DiSanto J. P., Bonnefoy J. Y., Gauchat J. F., Fischer A., de Saint Basile G. CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. Nature. 1993 Feb 11;361(6412):541–543. doi: 10.1038/361541a0. [DOI] [PubMed] [Google Scholar]
  10. Durandy A., Schiff C., Bonnefoy J. Y., Forveille M., Rousset F., Mazzei G., Milili M., Fischer A. Induction by anti-CD40 antibody or soluble CD40 ligand and cytokines of IgG, IgA and IgE production by B cells from patients with X-linked hyper IgM syndrome. Eur J Immunol. 1993 Sep;23(9):2294–2299. doi: 10.1002/eji.1830230936. [DOI] [PubMed] [Google Scholar]
  11. Foy T. M., Shepherd D. M., Durie F. H., Aruffo A., Ledbetter J. A., Noelle R. J. In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. II. Prolonged suppression of the humoral immune response by an antibody to the ligand for CD40, gp39. J Exp Med. 1993 Nov 1;178(5):1567–1575. doi: 10.1084/jem.178.5.1567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fuleihan R., Ramesh N., Loh R., Jabara H., Rosen R. S., Chatila T., Fu S. M., Stamenkovic I., Geha R. S. Defective expression of the CD40 ligand in X chromosome-linked immunoglobulin deficiency with normal or elevated IgM. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2170–2173. doi: 10.1073/pnas.90.6.2170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gascan H., Gauchat J. F., Aversa G., Van Vlasselaer P., de Vries J. E. Anti-CD40 monoclonal antibodies or CD4+ T cell clones and IL-4 induce IgG4 and IgE switching in purified human B cells via different signaling pathways. J Immunol. 1991 Jul 1;147(1):8–13. [PubMed] [Google Scholar]
  14. 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]
  15. Gougeon M. L., Morelet L., Doussau M., Theze J., Griscelli C., Fischer A. Hyper-IgM immunodeficiency syndrome: influence of lymphokines on in vitro maturation of peripheral B cells. J Clin Immunol. 1992 Mar;12(2):92–100. doi: 10.1007/BF00918138. [DOI] [PubMed] [Google Scholar]
  16. Hendriks R. W., Kraakman M. E., Craig I. W., Espanol T., Schuurman R. K. Evidence that in X-linked immunodeficiency with hyperimmunoglobulinemia M the intrinsic immunoglobulin heavy chain class switch mechanism is intact. Eur J Immunol. 1990 Dec;20(12):2603–2608. doi: 10.1002/eji.1830201212. [DOI] [PubMed] [Google Scholar]
  17. Jakobovits A., Sharon N., Zan-Bar I. Acquisition of mitogenic responsiveness by nonresponding lymphocytes upon insertion of appropriate membrane components. J Exp Med. 1982 Oct 1;156(4):1274–1279. doi: 10.1084/jem.156.4.1274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Katz D. H., Hamaoka T., Dorf M. E., Benacerraf B. Cell interactions between histoincompatible T and B lymphocytes. The H-2 gene complex determines successful physiologic lymphocyte interactions. Proc Natl Acad Sci U S A. 1973 Sep;70(9):2624–2628. doi: 10.1073/pnas.70.9.2624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Korthäuer U., Graf D., Mages H. W., Brière F., Padayachee M., Malcolm S., Ugazio A. G., Notarangelo L. D., Levinsky R. J., Kroczek R. A. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature. 1993 Feb 11;361(6412):539–541. doi: 10.1038/361539a0. [DOI] [PubMed] [Google Scholar]
  20. Kroczek R. A., Graf D., Brugnoni D., Giliani S., Korthüer U., Ugazio A., Senger G., Mages H. W., Villa A., Notarangelo L. D. Defective expression of CD40 ligand on T cells causes "X-linked immunodeficiency with hyper-IgM (HIGM1)". Immunol Rev. 1994 Apr;138:39–59. doi: 10.1111/j.1600-065x.1994.tb00846.x. [DOI] [PubMed] [Google Scholar]
  21. Levitt D., Haber P., Rich K., Cooper M. D. Hyper IgM immunodeficiency. A primary dysfunction of B lymphocyte isotype switching. J Clin Invest. 1983 Nov;72(5):1650–1657. doi: 10.1172/JCI111124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Levy D., Porat Y., Pick I., Handzel Z. T., Schlesinger M., Tanay A., Zan-Bar I. Induction of responsiveness in lymphocytes of immunodeficient patients' cells implanted with foreign plasma membranes. Immunodeficiency. 1993;4(1-4):43–46. [PubMed] [Google Scholar]
  23. Marshall L. S., Aruffo A., Ledbetter J. A., Noelle R. J. The molecular basis for T cell help in humoral immunity: CD40 and its ligand, gp39. J Clin Immunol. 1993 May;13(3):165–174. doi: 10.1007/BF00919969. [DOI] [PubMed] [Google Scholar]
  24. Mayer L., Posnett D. N., Kunkel H. G. Human malignant T cells capable of inducing an immunoglobulin class switch. J Exp Med. 1985 Jan 1;161(1):134–144. doi: 10.1084/jem.161.1.134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mitchison N. A. The carrier effect in the secondary response to hapten-protein conjugates. II. Cellular cooperation. Eur J Immunol. 1971 Jan;1(1):18–27. doi: 10.1002/eji.1830010104. [DOI] [PubMed] [Google Scholar]
  26. Noelle R. J., Roy M., Shepherd D. M., Stamenkovic I., Ledbetter J. A., Aruffo A. A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6550–6554. doi: 10.1073/pnas.89.14.6550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nonoyama S., Hollenbaugh D., Aruffo A., Ledbetter J. A., Ochs H. D. B cell activation via CD40 is required for specific antibody production by antigen-stimulated human B cells. J Exp Med. 1993 Sep 1;178(3):1097–1102. doi: 10.1084/jem.178.3.1097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Peretz H., Toister Z., Laster Y., Loyter A. Fusion of intact human erythrocytes and erythrocyte ghosts. J Cell Biol. 1974 Oct;63(1):1–11. doi: 10.1083/jcb.63.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Prujansky-Jakobovits A., Volsky D. J., Loyter A., Sharon N. Alteration of lymphocyte surface properties by insertion of foreign functional components of plasma membrane. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7247–7251. doi: 10.1073/pnas.77.12.7247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Puck J. M. Molecular and genetic basis of X-linked immunodeficiency disorders. J Clin Immunol. 1994 Mar;14(2):81–89. doi: 10.1007/BF01541340. [DOI] [PubMed] [Google Scholar]
  31. ROSEN F. S., KEVY S. V., MERLER E., JANEWAY C. A., GITLIN D. Recurrent bacterial infections and dysgamma-globulinemia: deficiency of 7S gamma-globulins in the presence of elevated 19S gamma-globulins. Report of two cases. Pediatrics. 1961 Aug;28:182–195. [PubMed] [Google Scholar]
  32. Sherr E., Adelman D. C., Saxon A., Gilly M., Wall R., Sidell N. Retinoic acid induces the differentiation of B cell hybridomas from patients with common variable immunodeficiency. J Exp Med. 1988 Jul 1;168(1):55–71. doi: 10.1084/jem.168.1.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Snapper C. M., Finkelman F. D., Paul W. E. Differential regulation of IgG1 and IgE synthesis by interleukin 4. J Exp Med. 1988 Jan 1;167(1):183–196. doi: 10.1084/jem.167.1.183. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Clinical and Diagnostic Laboratory Immunology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES