Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1982 Oct 1;156(4):975–985. doi: 10.1084/jem.156.4.975

Normal human B cells display ordered light chain gene rearrangements and deletions

PMCID: PMC2186822  PMID: 6818320

Abstract

Human kappa-producing B cell lines and leukemias retain their excluded lambda light chain genes in the germ line configuration, whereas transformed lambda-producing B cells uniformly rearrange or delete their kappa genes (12). Whether the unexpected lambda gene recombinations within malignant lambda-producing B cells reflect a normal developmental process or are secondary to transformation and specific chromosomal translocations was uncertain. To resolve this issue, we purified circulating lambda-bearing B cells from a normal individual to 97% purity by using a series of negative selection steps and a final positive selection on a cell sorter. Over 95% of the collective kappa genes in these lambda B cells were no longer in their germ line form, with the majority (60%) deleted and the remainder present but in a rearranged state. The chromosomal loss of the germ line kappa genes included the joining (J kappa) segments as well as the constant (C kappa) region, yet the particular variable (V kappa) gene family studied was spared. In addition, the incidence of kappa gene deletions was higher in long-term than in freshly transformed lambda B cell lines. This implies that the deletion of aberrantly rearranged kappa genes may occur as a second event. Such a mechanism would serve to eliminate aberrant transcripts and light chain fragments that might interfere with the synthesis and assembly of effective immunoglobulin molecules. Thus, despite the nearly equal usage of kappa and lambda light chain genes in man, there appears to be a sequential order to their expression during normal B cell ontogeny in which kappa gene rearrangements precede those of lambda.

Full Text

The Full Text of this article is available as a PDF (966.3 KB).

Selected References

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

  1. Alt F. W., Enea V., Bothwell A. L., Baltimore D. Activity of multiple light chain genes in murine myeloma cells producing a single, functional light chain. Cell. 1980 Aug;21(1):1–12. doi: 10.1016/0092-8674(80)90109-9. [DOI] [PubMed] [Google Scholar]
  2. Breard J., Reinherz E. L., Kung P. C., Goldstein G., Schlossman S. F. A monoclonal antibody reactive with human peripheral blood monocytes. J Immunol. 1980 Apr;124(4):1943–1948. [PubMed] [Google Scholar]
  3. Coleclough C., Perry R. P., Karjalainen K., Weigert M. Aberrant rearrangements contribute significantly to the allelic exclusion of immunoglobulin gene expression. Nature. 1981 Apr 2;290(5805):372–378. doi: 10.1038/290372a0. [DOI] [PubMed] [Google Scholar]
  4. Erikson J., Martinis J., Croce C. M. Assignment of the genes for human lambda immunoglobulin chains to chromosome 22. Nature. 1981 Nov 12;294(5837):173–175. doi: 10.1038/294173a0. [DOI] [PubMed] [Google Scholar]
  5. Ginsburg W. W., Finkelman F. D., Lipsky P. E. Circulating and mitogen-induced immunoglobulin-secreting cells in human peripheral blood: evaluation by a modified reverse hemolytic plaque assay. J Immunol. 1978 Jan;120(1):33–39. [PubMed] [Google Scholar]
  6. Hieter P. A., Hollis G. F., Korsmeyer S. J., Waldmann T. A., Leder P. Clustered arrangement of immunoglobulin lambda constant region genes in man. Nature. 1981 Dec 10;294(5841):536–540. doi: 10.1038/294536a0. [DOI] [PubMed] [Google Scholar]
  7. Hieter P. A., Korsmeyer S. J., Waldmann T. A., Leder P. Human immunoglobulin kappa light-chain genes are deleted or rearranged in lambda-producing B cells. Nature. 1981 Apr 2;290(5805):368–372. doi: 10.1038/290368a0. [DOI] [PubMed] [Google Scholar]
  8. Hieter P. A., Max E. E., Seidman J. G., Maizel J. V., Jr, Leder P. Cloned human and mouse kappa immunoglobulin constant and J region genes conserve homology in functional segments. Cell. 1980 Nov;22(1 Pt 1):197–207. doi: 10.1016/0092-8674(80)90168-3. [DOI] [PubMed] [Google Scholar]
  9. Hozumi N., Tonegawa S. Evidence for somatic rearrangement of immunoglobulin genes coding for variable and constant regions. Proc Natl Acad Sci U S A. 1976 Oct;73(10):3628–3632. doi: 10.1073/pnas.73.10.3628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Joho R., Weissman I. L. V-J joining of immunoglobulin kappa genes only occurs on one homologous chromosome. Nature. 1980 Mar 13;284(5752):179–181. doi: 10.1038/284179a0. [DOI] [PubMed] [Google Scholar]
  11. Kessler S., Kim K. J., Scher I. Surface membrane kappa and lambda light chain expression on spleen cells of neonatal and maturing normal and immune-defective CBA/NB mice: the kappa:lambda ratio is constant. J Immunol. 1981 Oct;127(4):1674–1678. [PubMed] [Google Scholar]
  12. Klein G. The role of gene dosage and genetic transpositions in carcinogenesis. Nature. 1981 Nov 26;294(5839):313–318. doi: 10.1038/294313a0. [DOI] [PubMed] [Google Scholar]
  13. Korsmeyer S. J., Hieter P. A., Ravetch J. V., Poplack D. G., Waldmann T. A., Leder P. Developmental hierarchy of immunoglobulin gene rearrangements in human leukemic pre-B-cells. Proc Natl Acad Sci U S A. 1981 Nov;78(11):7096–7100. doi: 10.1073/pnas.78.11.7096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Leder P., Max E. E., Seidman J. G., Kwan S. P., Scharff M., Nau M., Norman B. Recombination events that activate, diversify, and delete immunoglobulin genes. Cold Spring Harb Symp Quant Biol. 1981;45(Pt 2):859–865. doi: 10.1101/sqb.1981.045.01.103. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Martial J. A., Hallewell R. A., Baxter J. D., Goodman H. M. Human growth hormone: complementary DNA cloning and expression in bacteria. Science. 1979 Aug 10;205(4406):602–607. doi: 10.1126/science.377496. [DOI] [PubMed] [Google Scholar]
  17. Max E. E., Seidman J. G., Leder P. Sequences of five potential recombination sites encoded close to an immunoglobulin kappa constant region gene. Proc Natl Acad Sci U S A. 1979 Jul;76(7):3450–3454. doi: 10.1073/pnas.76.7.3450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Max E. E., Seidman J. G., Miller H., Leder P. Variation in the crossover point of kappa immunoglobulin gene V-J recombination: evidence from a cryptic gene. Cell. 1980 Oct;21(3):793–799. doi: 10.1016/0092-8674(80)90442-0. [DOI] [PubMed] [Google Scholar]
  19. McBride O. W., Hieter P. A., Hollis G. F., Swan D., Otey M. C., Leder P. Chromosomal location of human kappa and lambda immunoglobulin light chain constant region genes. J Exp Med. 1982 May 1;155(5):1480–1490. doi: 10.1084/jem.155.5.1480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. McGuire K. L., Vitetta E. S. kappa/lambda Shifts do not occur during maturation of murine B cells. J Immunol. 1981 Oct;127(4):1670–1673. [PubMed] [Google Scholar]
  21. Nelson D. L., Bundy B. M., Pitchon H. E., Blaese R. M., Strober W. The effector cells in human peripheral blood mediating mitogen-induced cellular cytotoxicity and antibody-dependent cellular cytotoxicity. J Immunol. 1976 Nov;117(5 Pt 1):1472–1481. [PubMed] [Google Scholar]
  22. Nilsson K., Klein G., Henle W., Henle G. The establishment of lymphoblastoid lines from adult and fetal human lymphoid tissue and its dependence on EBV. Int J Cancer. 1971 Nov 15;8(3):443–450. doi: 10.1002/ijc.2910080312. [DOI] [PubMed] [Google Scholar]
  23. Polsky F., Edgell M. H., Seidman J. G., Leder P. High capacity gel preparative electrophoresis for purification of fragments of genomic DNA. Anal Biochem. 1978 Jul 1;87(2):397–410. doi: 10.1016/0003-2697(78)90689-9. [DOI] [PubMed] [Google Scholar]
  24. Quintáns J., Lefkovits I. Precursor cells specific to sheep red cells in nude mice. Estimation of frequency in the microculture system. Eur J Immunol. 1973 Jul;3(7):392–397. doi: 10.1002/eji.1830030704. [DOI] [PubMed] [Google Scholar]
  25. Rigby P. W., Dieckmann M., Rhodes C., Berg P. Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase I. J Mol Biol. 1977 Jun 15;113(1):237–251. doi: 10.1016/0022-2836(77)90052-3. [DOI] [PubMed] [Google Scholar]
  26. Sakano H., Hüppi K., Heinrich G., Tonegawa S. Sequences at the somatic recombination sites of immunoglobulin light-chain genes. Nature. 1979 Jul 26;280(5720):288–294. doi: 10.1038/280288a0. [DOI] [PubMed] [Google Scholar]
  27. Sakano H., Hüppi K., Heinrich G., Tonegawa S. Sequences at the somatic recombination sites of immunoglobulin light-chain genes. Nature. 1979 Jul 26;280(5720):288–294. doi: 10.1038/280288a0. [DOI] [PubMed] [Google Scholar]
  28. Schwartz B. D., Kask A. M., Sharrow S. O., David C. S., Schwartz R. H. Partial chemical characterization of Ia antigens derived from murine thymocytes. Proc Natl Acad Sci U S A. 1977 Mar;74(3):1195–1199. doi: 10.1073/pnas.74.3.1195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Seidman J. G., Max E. E., Leder P. A kappa-immunoglobulin gene is formed by site-specific recombination without further somatic mutation. Nature. 1979 Aug 2;280(5721):370–375. doi: 10.1038/280370a0. [DOI] [PubMed] [Google Scholar]
  30. Seidman J. G., Max E. E., Leder P. A kappa-immunoglobulin gene is formed by site-specific recombination without further somatic mutation. Nature. 1979 Aug 2;280(5721):370–375. doi: 10.1038/280370a0. [DOI] [PubMed] [Google Scholar]
  31. Siden E., Alt F. W., Shinefeld L., Sato V., Baltimore D. Synthesis of immunoglobulin mu chain gene products precedes synthesis of light chains during B-lymphocyte development. Proc Natl Acad Sci U S A. 1981 Mar;78(3):1823–1827. doi: 10.1073/pnas.78.3.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Zatz M. M., Mathieson B. J., Kanellopoulos-Langevin C., Sharrow S. O. Separation and characterization of two component tumor lines within the AKR lymphoma, AKTB-1, by fluorescence-activated cell sorting and flow microfluorometry analysis. I. the coexistence of sIg+ and sIg- sublines. J Immunol. 1981 Feb;126(2):608–613. [PubMed] [Google Scholar]

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

RESOURCES