Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1982 Mar 1;155(3):839–851. doi: 10.1084/jem.155.3.839

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

PMCID: PMC2186621  PMID: 6801181

Abstract

Monoclonal antibodies were used to examine the immunoglobulin isotypes expressed by B lymphocyte precursors of IgM, IgG, IgA, and IgA2 plasma cells. Plasma-cell differentiation was induced by the addition of pokeweed mitogen to cultures of blood mononuclear cells. Anti-mu, - gamma, -alpha, and -alpha 1 antibodies were used in some experiments to inhibit differentiation of B lymphocytes bearing these heavy chain isotypes, and for selective removal of B lymphocyte precursors before culture with pokeweed mitogen in other experiments. Three major subpopulations of B lymphocyte precursors were identified: (a) a subpopulation of surface (s) IgM+ precursors of IgM plasma cells that did not express IgG or IgA isotypes, (b) a subpopulation of sIgG+ precursors of IgG plasma cells of which approximately one-half bore some IgM and none had detectable IgA receptors, and (c) a subpopulation of sIgA+ precursors of IgA plasma cells; one half of these precursors could be shown to express functional IgM receptors but none were found to express IgG receptors. The sIgA subpopulation could be further subdivided into sIgA1+ precursors of IgA1 plasma cells and IgA1- negative precursors of IgA2 plasma cells. These results suggest that normal human B cells can switch from mu directly to each of the other heavy chain isotypes, and that these represent the main switch pathways.

Full Text

The Full Text of this article is available as a PDF (934.3 KB).

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. Ault K. A., Towle M. Human B lymphocyte subsets. I. IgG-bearing B cell response to pokeweed mitogen. J Exp Med. 1981 Feb 1;153(2):339–351. doi: 10.1084/jem.153.2.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chiorazzi N., Fu S. M., Kunkel H. G. Stimulation of human B lymphocytes by antibodies to IgM and IgG: functional evidence for the expression of IgG on B-lymphocyte surface membranes. Clin Immunol Immunopathol. 1980 Mar;15(3):301–313. doi: 10.1016/0090-1229(80)90042-2. [DOI] [PubMed] [Google Scholar]
  4. Conley M. E., Kearney J. F., Lawton A. R., 3rd, Cooper M. D. Differentiation of human B cells expressing the IgA subclasses as demonstrated by monoclonal hybridoma antibodies. J Immunol. 1980 Nov;125(5):2311–2316. [PubMed] [Google Scholar]
  5. Cooper M. D., Lawton A. R., 3rd The development of the immune system. Sci Am. 1974 Nov;231(5):58–72. doi: 10.1038/scientificamerican1174-58. [DOI] [PubMed] [Google Scholar]
  6. Cooper M. D., Lawton A. R., Kincade P. W. A two-stage model for development of antibody-producing cells. Clin Exp Immunol. 1972 May;11(1):143–149. [PMC free article] [PubMed] [Google Scholar]
  7. Cory S., Adams J. M. Deletions are associated with somatic rearrangement of immunoglobulin heavy chain genes. Cell. 1980 Jan;19(1):37–51. doi: 10.1016/0092-8674(80)90386-4. [DOI] [PubMed] [Google Scholar]
  8. Davis M. M., Kim S. K., Hood L. E. DNA sequences mediating class switching in alpha-immunoglobulins. Science. 1980 Sep 19;209(4463):1360–1365. doi: 10.1126/science.6774415. [DOI] [PubMed] [Google Scholar]
  9. Finkelman F. D., Lipsky P. E. Immunoglobulin secretion by human splenic lymphocytes in vitro: the effects of antibodies to IgM and IgD. J Immunol. 1978 May;120(5):1465–1472. [PubMed] [Google Scholar]
  10. 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]
  11. Gearhart P. J., Cebra J. J. Most B cells that have switched surface immunoglobulin isotypes generate clones of cells that do not secrete IgM. J Immunol. 1981 Sep;127(3):1030–1034. [PubMed] [Google Scholar]
  12. Gearhart P. J., Hurwitz J. L., Cebra J. J. Successive switching of antibody isotypes expressed within the lines of a B-cell clone. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5424–5428. doi: 10.1073/pnas.77.9.5424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hengartner H., Meo T., Müller E. Assignment of genes for immunoglobulin kappa and heavy chains to chromosomes 6 and 12 in mouse. Proc Natl Acad Sci U S A. 1978 Sep;75(9):4494–4498. doi: 10.1073/pnas.75.9.4494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kataoka T., Kawakami T., Takahashi N., Honjo T. Rearrangement of immunoglobulin gamma 1-chain gene and mechanism for heavy-chain class switch. Proc Natl Acad Sci U S A. 1980 Feb;77(2):919–923. doi: 10.1073/pnas.77.2.919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kearney J. F., Cooper M. D., Lawton A. R. B lymphocyte differentiation induced by lipopolysaccharide. III. Suppression of B cell maturation by anti-mouse immunoglobulin antibodies. J Immunol. 1976 Jun;116(6):1664–1668. [PubMed] [Google Scholar]
  16. 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]
  17. Kincade P. W., Lawton A. R., Bockman D. E., Cooper M. D. Suppression of immunoglobulin G synthesis as a result of antibody-mediated suppression of immunoglobulin M synthesis in chickens. Proc Natl Acad Sci U S A. 1970 Dec;67(4):1918–1925. doi: 10.1073/pnas.67.4.1918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lawton A. R., 3rd, Asofsky R., Hylton M. B., Cooper M. D. Suppression of immunoglobulin class synthesis in mice. I. Effects of treatment with antibody to -chain. J Exp Med. 1972 Feb 1;135(2):277–297. doi: 10.1084/jem.135.2.277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lawton A. R., 3rd, Cooper M. D. Modification of B lymphocyte differentiation by anti-immunoglobulins. Contemp Top Immunobiol. 1974;3:193–225. doi: 10.1007/978-1-4684-3045-5_8. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Liu C. P., Tucker P. W., Mushinski J. F., Blattner F. R. Mapping of heavy chain genes for mouse immunoglobulins M and D. Science. 1980 Sep 19;209(4463):1348–1353. doi: 10.1126/science.6774414. [DOI] [PubMed] [Google Scholar]
  22. Mage M. G., McHugh L. L., Rothstein T. L. Mouse lymphocytes with and without surface immunoglobulin: preparative scale separation in polystyrene tissue culture dishes coated with specifically purified anti-immunoglobulin. J Immunol Methods. 1977;15(1):47–56. doi: 10.1016/0022-1759(77)90016-3. [DOI] [PubMed] [Google Scholar]
  23. Maki R., Traunecker A., Sakano H., Roeder W., Tonegawa S. Exon shuffling generates an immunoglobulin heavy chain gene. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2138–2142. doi: 10.1073/pnas.77.4.2138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Manning D. D., Jutila J. W. Immunosuppression in mice injected with heterologous anti-immunoglobulin antisera. J Immunol. 1972 Jan;108(1):282–285. [PubMed] [Google Scholar]
  25. Manning D. D. Recovery from anti-IG induced immunosuppression: implications for a model of Ig-secreting cell development. J Immunol. 1974 Aug;113(2):455–463. [PubMed] [Google Scholar]
  26. NOSSAL G. J., SZENBERG A., ADA G. L., AUSTIN C. M. SINGLE CELL STUDIES ON 19S ANTIBODY PRODUCTION. J Exp Med. 1964 Mar 1;119:485–502. doi: 10.1084/jem.119.3.485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nishida Y., Kataoka T., Ishida N., Nakai S., Kishimoto T., Böttcher I., Honjo T. Cloning of mouse immunoglobulin epsilon gene and its location within the heavy chain gene cluster. Proc Natl Acad Sci U S A. 1981 Mar;78(3):1581–1585. doi: 10.1073/pnas.78.3.1581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Obata M., Kataoka T., Nakai S., Yamagishi H., Takahashi N., Yamawaki-Kataoka Y., Nikaido T., Shimizu A., Honjo T. Structure of a rearranged gamma 1 chain gene and its implication to immunoglobulin class-switch mechanism. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2437–2441. doi: 10.1073/pnas.78.4.2437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Pierce C. W., Solliday S. M., Asofsky R. Immune responses in vitro. IV. Suppression of primary M, G, and A plaque-forming cell responses in mouse spleen cell cultures by class-specific antibody to mouse immunoglobulins. J Exp Med. 1972 Mar 1;135(3):675–697. doi: 10.1084/jem.135.3.675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Radbruch A., Liesegang B., Rajewsky K. Isolation of variants of mouse myeloma X63 that express changed immunoglobulin class. Proc Natl Acad Sci U S A. 1980 May;77(5):2909–2913. doi: 10.1073/pnas.77.5.2909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rosenberg S. A., Lipsky P. E. Monocyte dependence of pokeweed mitogen-induced differentiation of immunoglobulin-secreting cells from human peripheral blood mononuclear cells. J Immunol. 1979 Mar;122(3):926–931. [PubMed] [Google Scholar]
  32. Sakano H., Maki R., Kurosawa Y., Roeder W., Tonegawa S. Two types of somatic recombination are necessary for the generation of complete immunoglobulin heavy-chain genes. Nature. 1980 Aug 14;286(5774):676–683. doi: 10.1038/286676a0. [DOI] [PubMed] [Google Scholar]
  33. Shimizu A., Takahashi N., Yamawaki-Kataoka Y., Nishida Y., Kataoka T., Honjo T. Ordering of mouse immunoglobulin heavy chain genes by molecular cloning. Nature. 1981 Jan 15;289(5794):149–153. doi: 10.1038/289149a0. [DOI] [PubMed] [Google Scholar]
  34. Teale J. M., Lafrenz D., Klinman N. R., Strober S. Immunoglobulin class commitment exhibited by B lymphocytes separated according to surface isotype. J Immunol. 1981 May;126(5):1952–1957. [PubMed] [Google Scholar]
  35. Thiele C. J., Stevens R. H. Antibody potential of human peripheral blood lymphocytes differentially expressing surface membrane IgM. J Immunol. 1980 Apr;124(4):1898–1904. [PubMed] [Google Scholar]
  36. Thiele C. J., Stevens R. H. Expression of surface membrane IgG on pokeweed mitogen-reactive anti-tetanus toxoid antibody-producing cells. J Clin Immunol. 1981 Jul;1(3):174–180. doi: 10.1007/BF00922760. [DOI] [PubMed] [Google Scholar]
  37. Wang A. C., Wilson K. S., Hopper J. E., Fudenberg H. H., Nisonoff A. Evidence for control of synthesis of the varible regions of the heavy chains of immunoglobulins G and M by the same gene. Proc Natl Acad Sci U S A. 1970 Jun;66(2):337–343. doi: 10.1073/pnas.66.2.337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Warrington R. J., Sauder P. J., Rutherford W. J. Suppression of mitogen-induced human immunoglobulin (Ig)-A synthesis by heterologous antibody to IgA. Clin Immunol Immunopathol. 1981 Jun;19(3):372–382. doi: 10.1016/0090-1229(81)90080-5. [DOI] [PubMed] [Google Scholar]
  39. Wysocki L. J., Sato V. L. "Panning" for lymphocytes: a method for cell selection. Proc Natl Acad Sci U S A. 1978 Jun;75(6):2844–2848. doi: 10.1073/pnas.75.6.2844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Yaoita Y., Honjo T. Deletion of immunoglobulin heavy chain genes from expressed allelic chromosome. Nature. 1980 Aug 28;286(5776):850–853. doi: 10.1038/286850a0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES