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The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1995 Feb;95(2):510–514. doi: 10.1172/JCI117692

Signaling through CD40 rescues IgE but not IgG or IgA secretion in X-linked immunodeficiency with hyper-IgM.

O Saiki 1, T Tanaka 1, Y Wada 1, H Uda 1, A Inoue 1, Y Katada 1, M Izeki 1, M Iwata 1, H Nunoi 1, I Matsuda 1, et al.
PMCID: PMC295502  PMID: 7532185

Abstract

The ligand for CD40 (CD40L) is a membrane protein on activated T cells that induces B cell proliferation and differentiation. Several mutations of the CD40L gene were reported responsible for defective class switching of B cells in an X-linked immunodeficiency with hyper IgM (X-HIM). We studied four affected males from three families and found three independent mutations including new mutations of CD40L gene. In every X-HIM patient tested, however, anti-CD40 plus IL-10 did not induce class switching from IgM to IgG or IgA, even in the presence of Staphylococcus aureus Cowan I strain (SAC). CD4+ T cell clones, expressing CD40L on their surface, also did not rescue IgG or IgA induction by X-HIM peripheral blood B cells in vitro. But signaling through CD40 induced both B cell proliferation and IgE secretion when IL-4 was added to the culture. Taken together, these results show that in vitro signaling through CD40 rescues IgE but not IgG or IgA secretion by peripheral blood X-HIM B cells and suggest that in vivo CD40 and CD40L interaction might be necessary for IgG and IgA differentiation in X-HIM.

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Selected References

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

  1. Allen R. C., Armitage R. J., Conley M. E., Rosenblatt H., Jenkins N. A., Copeland N. G., Bedell M. A., Edelhoff S., Disteche C. M., Simoneaux D. K. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science. 1993 Feb 12;259(5097):990–993. doi: 10.1126/science.7679801. [DOI] [PubMed] [Google Scholar]
  2. Armitage R. J., Fanslow W. C., Strockbine L., Sato T. A., Clifford K. N., Macduff B. M., Anderson D. M., Gimpel S. D., Davis-Smith T., Maliszewski C. R. Molecular and biological characterization of a murine ligand for CD40. Nature. 1992 May 7;357(6373):80–82. doi: 10.1038/357080a0. [DOI] [PubMed] [Google Scholar]
  3. Armitage R. J., Macduff B. M., Spriggs M. K., Fanslow W. C. Human B cell proliferation and Ig secretion induced by recombinant CD40 ligand are modulated by soluble cytokines. J Immunol. 1993 May 1;150(9):3671–3680. [PubMed] [Google Scholar]
  4. 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]
  5. Banchereau J., de Paoli P., Vallé A., Garcia E., Rousset F. Long-term human B cell lines dependent on interleukin-4 and antibody to CD40. Science. 1991 Jan 4;251(4989):70–72. doi: 10.1126/science.1702555. [DOI] [PubMed] [Google Scholar]
  6. Clark E. A., Ledbetter J. A. Activation of human B cells mediated through two distinct cell surface differentiation antigens, Bp35 and Bp50. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4494–4498. doi: 10.1073/pnas.83.12.4494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. 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]
  9. Forsgren A., Svedjelund A., Wigzell H. Lymphocyte stimulation by protein A of Staphylococcus aureus. Eur J Immunol. 1976 Mar;6(3):207–213. doi: 10.1002/eji.1830060312. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. Graf D., Korthäuer U., Mages H. W., Senger G., Kroczek R. A. Cloning of TRAP, a ligand for CD40 on human T cells. Eur J Immunol. 1992 Dec;22(12):3191–3194. doi: 10.1002/eji.1830221226. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. Hollenbaugh D., Grosmaire L. S., Kullas C. D., Chalupny N. J., Braesch-Andersen S., Noelle R. J., Stamenkovic I., Ledbetter J. A., Aruffo A. The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity. EMBO J. 1992 Dec;11(12):4313–4321. doi: 10.1002/j.1460-2075.1992.tb05530.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. 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]
  18. Luzi G., Businco L., Aiuti F. Primary immunodeficiency syndromes in Italy: a report of the national register in children and adults. J Clin Immunol. 1983 Oct;3(4):316–320. doi: 10.1007/BF00915792. [DOI] [PubMed] [Google Scholar]
  19. Mayer L., Kwan S. P., Thompson C., Ko H. S., Chiorazzi N., Waldmann T., Rosen F. Evidence for a defect in "switch" T cells in patients with immunodeficiency and hyperimmunoglobulinemia M. N Engl J Med. 1986 Feb 13;314(7):409–413. doi: 10.1056/NEJM198602133140703. [DOI] [PubMed] [Google Scholar]
  20. Notarangelo L. D., Duse M., Ugazio A. G. Immunodeficiency with hyper-IgM (HIM). Immunodefic Rev. 1992;3(2):101–121. [PubMed] [Google Scholar]
  21. Puck J. M. X-linked immunodeficiencies. Adv Hum Genet. 1993;21:107–144. doi: 10.1007/978-1-4615-3010-7_2. [DOI] [PubMed] [Google Scholar]
  22. Ramesh N., Fuleihan R., Ramesh V., Lederman S., Yellin M. J., Sharma S., Chess L., Rosen F. S., Geha R. S. Deletions in the ligand for CD40 in X-linked immunoglobulin deficiency with normal or elevated IgM (HIGMX-1). Int Immunol. 1993 Jul;5(7):769–773. doi: 10.1093/intimm/5.7.769. [DOI] [PubMed] [Google Scholar]
  23. Rousset F., Garcia E., Defrance T., Péronne C., Vezzio N., Hsu D. H., Kastelein R., Moore K. W., Banchereau J. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1890–1893. doi: 10.1073/pnas.89.5.1890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Saiki O., Kawamoto M., Fukuzumi M., Kanou M., Utsumi S. Staphylococcus aureus Wood 46 strain activates human B cells without affecting DNA synthesis or tyrosine phosphorylation. J Immunol. 1993 Apr 15;150(8 Pt 1):3224–3229. [PubMed] [Google Scholar]
  25. Saiki O., Ralph P., Cunningham-Rundles C., Good R. A. Three distinct stages of B-cell defects in common varied immunodeficiency. Proc Natl Acad Sci U S A. 1982 Oct;79(19):6008–6012. doi: 10.1073/pnas.79.19.6008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Saiki O., Ralph P. IgM- and IgD-bearing peripheral blood lymphocytes differentiate to IgM but not IgG or IgA immunoglobulin-secreting cells. Eur J Immunol. 1982 Jun;12(6):506–510. doi: 10.1002/eji.1830120611. [DOI] [PubMed] [Google Scholar]
  27. Schwaber J., Rosen F. S. X chromosome linked immunodeficiency. Immunodefic Rev. 1990;2(3):233–251. [PubMed] [Google Scholar]
  28. Shapira S. K., Vercelli D., Jabara H. H., Fu S. M., Geha R. S. Molecular analysis of the induction of immunoglobulin E synthesis in human B cells by interleukin 4 and engagement of CD40 antigen. J Exp Med. 1992 Jan 1;175(1):289–292. doi: 10.1084/jem.175.1.289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Spriggs M. K., Armitage R. J., Strockbine L., Clifford K. N., Macduff B. M., Sato T. A., Maliszewski C. R., Fanslow W. C. Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion. J Exp Med. 1992 Dec 1;176(6):1543–1550. doi: 10.1084/jem.176.6.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Stamenkovic I., Clark E. A., Seed B. A B-lymphocyte activation molecule related to the nerve growth factor receptor and induced by cytokines in carcinomas. EMBO J. 1989 May;8(5):1403–1410. doi: 10.1002/j.1460-2075.1989.tb03521.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Suemura M., Kishimoto T. Regulation of human IgE response by T cells and their products. Int Arch Allergy Appl Immunol. 1985;77(1-2):26–31. doi: 10.1159/000233748. [DOI] [PubMed] [Google Scholar]
  32. Thorley-Lawson D. A. The suppression of Epstein-Barr virus infection in vitro occurs after infection but before transformation of the cell. J Immunol. 1980 Feb;124(2):745–751. [PubMed] [Google Scholar]
  33. Torres R. M., Clark E. A. Differential increase of an alternatively polyadenylated mRNA species of murine CD40 upon B lymphocyte activation. J Immunol. 1992 Jan 15;148(2):620–626. [PubMed] [Google Scholar]

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