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. 1994 Aug 1;180(2):663–671. doi: 10.1084/jem.180.2.663

Disodium cromoglycate inhibits S mu-->S epsilon deletional switch recombination and IgE synthesis in human B cells

PMCID: PMC2191587  PMID: 8046339

Abstract

IgE synthesis requires interleukin 4 (IL-4) and a T-B cell interaction that involves the B cell antigen CD40 and its ligand expressed on activated T cells. IL-4 induces epsilon germline transcription whereas ligation of CD40 results in deletional S mu-->S epsilon switch recombination, expression of mature epsilon transcripts, and IgE synthesis and secretion. We demonstrate that disodium cromoglycate (DSCG), a drug commonly used for the prophylactic treatment of allergic disease, inhibits T cell-driven IgE synthesis by human B cells at concentrations readily achievable in the course of inhaled therapy for asthma. Inhibition of IgE synthesis by DSCG was not the result of drug toxicity because DSCG did not affect the viability of T and B cells or their proliferation to mitogens. DSCG did not interfere with CD40 ligand expression by T cells but clearly targeted the B cells because it inhibited IgE synthesis induced by anti-CD40 and IL-4 in populations of highly purified B cells. DSCG had no effect on the induction of epsilon germline transcripts by IL-4 but strongly inhibited CD40 mediated S mu-->S epsilon deletional switch recombination in IL-4- treated B cells as assayed by nested primer PCR. The effect of DSCG was not specific for CD40-mediated induction of IgE isotype switching because DSCG inhibited IgE synthesis as well as S mu-->S epsilon deletional switch recombination induced by hydrocortisone and IL-4 in B cells. Moreover, the effect of DSCG was not specific for IgE isotype switching because DSCG inhibited the synthesis of IgG4 by B cells sorted for lack of surface expression of IgG4 and stimulated with anti- CD40 and IL-4. DSCG caused only minimal inhibition (< 15%) of spontaneous IgE synthesis by lymphocytes from patients with the hyper- IgE syndrome and did not affect pokeweed mitogen-induced IgG and IgA synthesis by lymphocytes suggesting that it has little effect on B cells that have already undergone isotype switching. These results indicate that DSCG inhibits switching to IgE in B cells and suggest a novel potential mechanism for the prevention of allergic disease by DSCG.

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Selected References

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  1. Church M. K., Hiroi J. Inhibition of IgE-dependent histamine release from human dispersed lung mast cells by anti-allergic drugs and salbutamol. Br J Pharmacol. 1987 Feb;90(2):421–429. doi: 10.1111/j.1476-5381.1987.tb08972.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Clark E. A., Shu G. Association between IL-6 and CD40 signaling. IL-6 induces phosphorylation of CD40 receptors. J Immunol. 1990 Sep 1;145(5):1400–1406. [PubMed] [Google Scholar]
  3. Cox J. S. Disodium cromoglycate (FPL 670) ('Intal'): a specific inhibitor of reaginic antibody-antigen mechanisms. Nature. 1967 Dec 30;216(5122):1328–1329. doi: 10.1038/2161328a0. [DOI] [PubMed] [Google Scholar]
  4. Esser C., Radbruch A. Immunoglobulin class switching: molecular and cellular analysis. Annu Rev Immunol. 1990;8:717–735. doi: 10.1146/annurev.iy.08.040190.003441. [DOI] [PubMed] [Google Scholar]
  5. Fanslow W. C., Anderson D. M., Grabstein K. H., Clark E. A., Cosman D., Armitage R. J. Soluble forms of CD40 inhibit biologic responses of human B cells. J Immunol. 1992 Jul 15;149(2):655–660. [PubMed] [Google Scholar]
  6. Flint K. C., Leung K. B., Pearce F. L., Hudspith B. N., Brostoff J., Johnson N. M. Human mast cells recovered by bronchoalveolar lavage: their morphology, histamine release and the effects of sodium cromoglycate. Clin Sci (Lond) 1985 Apr;68(4):427–432. doi: 10.1042/cs0680427. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Gauchat J. F., Lebman D. A., Coffman R. L., Gascan H., de Vries J. E. Structure and expression of germline epsilon transcripts in human B cells induced by interleukin 4 to switch to IgE production. J Exp Med. 1990 Aug 1;172(2):463–473. doi: 10.1084/jem.172.2.463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gruber M. F., Bjorndahl J. M., Nakamura S., Fu S. M. Anti-CD45 inhibition of human B cell proliferation depends on the nature of activation signals and the state of B cell activation. A study with anti-IgM and anti-CDw40 antibodies. J Immunol. 1989 Jun 15;142(12):4144–4152. [PubMed] [Google Scholar]
  10. Jabara H. H., Ahern D. J., Vercelli D., Geha R. S. Hydrocortisone and IL-4 induce IgE isotype switching in human B cells. J Immunol. 1991 Sep 1;147(5):1557–1560. [PubMed] [Google Scholar]
  11. Jabara H. H., Fu S. M., Geha R. S., Vercelli D. CD40 and IgE: synergism between anti-CD40 monoclonal antibody and interleukin 4 in the induction of IgE synthesis by highly purified human B cells. J Exp Med. 1990 Dec 1;172(6):1861–1864. doi: 10.1084/jem.172.6.1861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jabara H. H., Loh R., Ramesh N., Vercelli D., Geha R. S. Sequential switching from mu to epsilon via gamma 4 in human B cells stimulated with IL-4 and hydrocortisone. J Immunol. 1993 Nov 1;151(9):4528–4533. [PubMed] [Google Scholar]
  13. Jabara H. H., Schneider L. C., Shapira S. K., Alfieri C., Moody C. T., Kieff E., Geha R. S., Vercelli D. Induction of germ-line and mature C epsilon transcripts in human B cells stimulated with rIL-4 and EBV. J Immunol. 1990 Nov 15;145(10):3468–3473. [PubMed] [Google Scholar]
  14. Kay A. B., Walsh G. M., Moqbel R., MacDonald A. J., Nagakura T., Carroll M. P., Richerson H. B. Disodium cromoglycate inhibits activation of human inflammatory cells in vitro. J Allergy Clin Immunol. 1987 Jul;80(1):1–8. doi: 10.1016/s0091-6749(87)80183-5. [DOI] [PubMed] [Google Scholar]
  15. Kimata H., Yoshida A., Ishioka C., Mikawa H. Disodium cromoglycate (DSCG) selectively inhibits IgE production and enhances IgG4 production by human B cell in vitro. Clin Exp Immunol. 1991 Jun;84(3):395–399. [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. Mazurek N., Berger G., Pecht I. A binding site on mast cells and basophils for the anti-allergic drug cromolyn. Nature. 1980 Aug 14;286(5774):722–723. doi: 10.1038/286722a0. [DOI] [PubMed] [Google Scholar]
  18. Mills F. C., Thyphronitis G., Finkelman F. D., Max E. E. Ig mu-epsilon isotype switch in IL-4-treated human B lymphoblastoid cells. Evidence for a sequential switch. J Immunol. 1992 Aug 1;149(3):1075–1085. [PubMed] [Google Scholar]
  19. Neale M. G., Brown K., Hodder R. W., Auty R. M. The pharmacokinetics of sodium cromoglycate in man after intravenous and inhalation administration. Br J Clin Pharmacol. 1986 Oct;22(4):373–382. doi: 10.1111/j.1365-2125.1986.tb02905.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. Ren C. L., Morio T., Fu S. M., Geha R. S. Signal transduction via CD40 involves activation of lyn kinase and phosphatidylinositol-3-kinase, and phosphorylation of phospholipase C gamma 2. J Exp Med. 1994 Feb 1;179(2):673–680. doi: 10.1084/jem.179.2.673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Shapira S. K., Jabara H. H., Thienes C. P., Ahern D. J., Vercelli D., Gould H. J., Geha R. S. Deletional switch recombination occurs in interleukin-4-induced isotype switching to IgE expression by human B cells. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7528–7532. doi: 10.1073/pnas.88.17.7528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Stamenkovic I., Amiot M., Pesando J. M., Seed B. A lymphocyte molecule implicated in lymph node homing is a member of the cartilage link protein family. Cell. 1989 Mar 24;56(6):1057–1062. doi: 10.1016/0092-8674(89)90638-7. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Thyphronitis G., Tsokos G. C., June C. H., Levine A. D., Finkelman F. D. IgE secretion by Epstein-Barr virus-infected purified human B lymphocytes is stimulated by interleukin 4 and suppressed by interferon gamma. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5580–5584. doi: 10.1073/pnas.86.14.5580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Uckun F. M., Schieven G. L., Dibirdik I., Chandan-Langlie M., Tuel-Ahlgren L., Ledbetter J. A. Stimulation of protein tyrosine phosphorylation, phosphoinositide turnover, and multiple previously unidentified serine/threonine-specific protein kinases by the Pan-B-cell receptor CD40/Bp50 at discrete developmental stages of human B-cell ontogeny. J Biol Chem. 1991 Sep 15;266(26):17478–17485. [PubMed] [Google Scholar]
  28. Umetsu D. T., Leung D. Y., Siraganian R., Jabara H. H., Geha R. S. Differential requirements of B cells from normal and allergic subjects for the induction of IgE synthesis by an alloreactive T cell clone. J Exp Med. 1985 Jul 1;162(1):202–214. doi: 10.1084/jem.162.1.202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Vercelli D., Jabara H. H., Arai K., Geha R. S. Induction of human IgE synthesis requires interleukin 4 and T/B cell interactions involving the T cell receptor/CD3 complex and MHC class II antigens. J Exp Med. 1989 Apr 1;169(4):1295–1307. doi: 10.1084/jem.169.4.1295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Vercelli D., Jabara H. H., Arai K., Yokota T., Geha R. S. Endogenous interleukin 6 plays an obligatory role in interleukin 4-dependent human IgE synthesis. Eur J Immunol. 1989 Aug;19(8):1419–1424. doi: 10.1002/eji.1830190811. [DOI] [PubMed] [Google Scholar]
  31. Vercelli D., Jabara H. H., Cunningham-Rundles C., Abrams J. S., Lewis D. B., Meyer J., Schneider L. C., Leung D. Y., Geha R. S. Regulation of immunoglobulin (Ig)E synthesis in the hyper-IgE syndrome. J Clin Invest. 1990 May;85(5):1666–1671. doi: 10.1172/JCI114618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Vercelli D., Jabara H. H., Lauener R. P., Geha R. S. IL-4 inhibits the synthesis of IFN-gamma and induces the synthesis of IgE in human mixed lymphocyte cultures. J Immunol. 1990 Jan 15;144(2):570–573. [PubMed] [Google Scholar]
  33. Walker S. R., Evans M. E., Richards A. J., Paterson J. W. The fate of ( 14 C)disodium cromoglycate in man. J Pharm Pharmacol. 1972 Jul;24(7):525–531. doi: 10.1111/j.2042-7158.1972.tb09051.x. [DOI] [PubMed] [Google Scholar]
  34. Wells E., Mann J. Phosphorylation of a mast cell protein in response to treatment with anti-allergic compounds. Implications for the mode of action of sodium cromoglycate. Biochem Pharmacol. 1983 Mar 1;32(5):837–842. doi: 10.1016/0006-2952(83)90585-3. [DOI] [PubMed] [Google Scholar]
  35. Zhang K., Clark E. A., Saxon A. CD40 stimulation provides an IFN-gamma-independent and IL-4-dependent differentiation signal directly to human B cells for IgE production. J Immunol. 1991 Mar 15;146(6):1836–1842. [PubMed] [Google Scholar]

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