Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Aug 15;102(4):688–694. doi: 10.1172/JCI3113

Immunoglobulin kappa chain receptor editing in systemic lupus erythematosus.

T Dörner 1, S J Foster 1, N L Farner 1, P E Lipsky 1
PMCID: PMC508930  PMID: 9710436

Abstract

To determine whether receptor editing of Vkappa genes was involved in the pathogenesis of systemic lupus erythematosus (SLE), the usage of Vkappa and Jkappa gene elements from individual peripheral CD19(+) B cells obtained from a patient with untreated SLE was examined. No differences in the Vkappa and Jkappa gene usage in the nonproductive gene repertoire of this SLE patient were noted compared with the distribution of genes found in normal adults. However, an increased usage of Jkappa5 segments, and a significant overrepresentation of the Vkappa1 and Vkappa4 families, especially the L15, O14/O4, and B3 genes characterized the productive Vkappa gene repertoire of the SLE patient. Furthermore, Jkappa5-containing Vkappa gene rearrangements in the productive but not the nonproductive repertoire manifested significantly fewer mutations compared with Vkappa genes recombined with Jkappa1-4. These data are consistent with the conclusion that receptor editing of Vkappa is much more apparent in this SLE patient than in normals and suggest that a deficiency in this means to counteract the emergence of autoimmunity is not an essential feature of SLE.

Full Text

The Full Text of this article is available as a PDF (174.3 KB).

Selected References

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

  1. Alt F. W., Oltz E. M., Young F., Gorman J., Taccioli G., Chen J. VDJ recombination. Immunol Today. 1992 Aug;13(8):306–314. doi: 10.1016/0167-5699(92)90043-7. [DOI] [PubMed] [Google Scholar]
  2. Bensimon C., Chastagner P., Zouali M. Human lupus anti-DNA autoantibodies undergo essentially primary V kappa gene rearrangements. EMBO J. 1994 Jul 1;13(13):2951–2962. doi: 10.1002/j.1460-2075.1994.tb06593.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brezinschek H. P., Brezinschek R. I., Lipsky P. E. Analysis of the heavy chain repertoire of human peripheral B cells using single-cell polymerase chain reaction. J Immunol. 1995 Jul 1;155(1):190–202. [PubMed] [Google Scholar]
  4. Brezinschek H. P., Foster S. J., Brezinschek R. I., Dörner T., Domiati-Saad R., Lipsky P. E. Analysis of the human VH gene repertoire. Differential effects of selection and somatic hypermutation on human peripheral CD5(+)/IgM+ and CD5(-)/IgM+ B cells. J Clin Invest. 1997 May 15;99(10):2488–2501. doi: 10.1172/JCI119433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen C., Prak E. L., Weigert M. Editing disease-associated autoantibodies. Immunity. 1997 Jan;6(1):97–105. doi: 10.1016/s1074-7613(00)80673-1. [DOI] [PubMed] [Google Scholar]
  6. Diamond B., Scharff M. D. Somatic mutation of the T15 heavy chain gives rise to an antibody with autoantibody specificity. Proc Natl Acad Sci U S A. 1984 Sep;81(18):5841–5844. doi: 10.1073/pnas.81.18.5841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dörner T., Brezinschek H. P., Brezinschek R. I., Foster S. J., Domiati-Saad R., Lipsky P. E. Analysis of the frequency and pattern of somatic mutations within nonproductively rearranged human variable heavy chain genes. J Immunol. 1997 Mar 15;158(6):2779–2789. [PubMed] [Google Scholar]
  8. Dörner T., Brezinschek H. P., Foster S. J., Brezinschek R. I., Farner N. L., Lipsky P. E. Comparable impact of mutational and selective influences in shaping the expressed repertoire of peripheral IgM+/CD5- and IgM+/CD5+ B cells. Eur J Immunol. 1998 Feb;28(2):657–668. doi: 10.1002/(SICI)1521-4141(199802)28:02<657::AID-IMMU657>3.0.CO;2-Z. [DOI] [PubMed] [Google Scholar]
  9. Dörner T., Brezinschek H. P., Foster S. J., Brezinschek R. I., Farner N. L., Lipsky P. E. Delineation of selective influences shaping the mutated expressed human Ig heavy chain repertoire. J Immunol. 1998 Mar 15;160(6):2831–2841. [PubMed] [Google Scholar]
  10. Foster S. J., Brezinschek H. P., Brezinschek R. I., Lipsky P. E. Molecular mechanisms and selective influences that shape the kappa gene repertoire of IgM+ B cells. J Clin Invest. 1997 Apr 1;99(7):1614–1627. doi: 10.1172/JCI119324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gay D., Saunders T., Camper S., Weigert M. Receptor editing: an approach by autoreactive B cells to escape tolerance. J Exp Med. 1993 Apr 1;177(4):999–1008. doi: 10.1084/jem.177.4.999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Han S., Dillon S. R., Zheng B., Shimoda M., Schlissel M. S., Kelsoe G. V(D)J recombinase activity in a subset of germinal center B lymphocytes. Science. 1997 Oct 10;278(5336):301–305. doi: 10.1126/science.278.5336.301. [DOI] [PubMed] [Google Scholar]
  13. Harada T., Suzuki N., Mizushima Y., Sakane T. Usage of a novel class of germ-line Ig variable region gene for cationic anti-DNA autoantibodies in human lupus nephritis and its role for the development of the disease. J Immunol. 1994 Nov 15;153(10):4806–4815. [PubMed] [Google Scholar]
  14. Ibrahim S. M., Weigert M., Basu C., Erikson J., Radic M. Z. Light chain contribution to specificity in anti-DNA antibodies. J Immunol. 1995 Sep 15;155(6):3223–3233. [PubMed] [Google Scholar]
  15. Kelsoe G. Life and death in germinal centers (redux). Immunity. 1996 Feb;4(2):107–111. doi: 10.1016/s1074-7613(00)80675-5. [DOI] [PubMed] [Google Scholar]
  16. Manheimer-Lory A. J., Zandman-Goddard G., Davidson A., Aranow C., Diamond B. Lupus-specific antibodies reveal an altered pattern of somatic mutation. J Clin Invest. 1997 Nov 15;100(10):2538–2546. doi: 10.1172/JCI119796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Manheimer-Lory A., Irigoyen M., Gaynor B., Monhian R., Splaver A., Diamond B. Analysis of V kappa I and V lambda II light chain genes in the expressed B-cell repertoire. Ann N Y Acad Sci. 1995 Sep 29;764:301–311. [PubMed] [Google Scholar]
  18. Manheimer-Lory A., Monhian R., Splaver A., Gaynor B., Diamond B. Analysis of the V kappa I family: germline genes from an SLE patient and expressed autoantibodies. Autoimmunity. 1995;20(4):259–265. doi: 10.3109/08916939508995703. [DOI] [PubMed] [Google Scholar]
  19. Nussenzweig M. C., Shaw A. C., Sinn E., Danner D. B., Holmes K. L., Morse H. C., 3rd, Leder P. Allelic exclusion in transgenic mice that express the membrane form of immunoglobulin mu. Science. 1987 May 15;236(4803):816–819. doi: 10.1126/science.3107126. [DOI] [PubMed] [Google Scholar]
  20. Papavasiliou F., Casellas R., Suh H., Qin X. F., Besmer E., Pelanda R., Nemazee D., Rajewsky K., Nussenzweig M. C. V(D)J recombination in mature B cells: a mechanism for altering antibody responses. Science. 1997 Oct 10;278(5336):298–301. doi: 10.1126/science.278.5336.298. [DOI] [PubMed] [Google Scholar]
  21. Prak E. L., Trounstine M., Huszar D., Weigert M. Light chain editing in kappa-deficient animals: a potential mechanism of B cell tolerance. J Exp Med. 1994 Nov 1;180(5):1805–1815. doi: 10.1084/jem.180.5.1805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Prak E. L., Weigert M. Light chain replacement: a new model for antibody gene rearrangement. J Exp Med. 1995 Aug 1;182(2):541–548. doi: 10.1084/jem.182.2.541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Radic M. Z., Weigert M. Origins of anti-DNA antibodies and their implications for B-cell tolerance. Ann N Y Acad Sci. 1995 Sep 29;764:384–396. doi: 10.1111/j.1749-6632.1995.tb55853.x. [DOI] [PubMed] [Google Scholar]
  24. Radic M. Z., Zouali M. Receptor editing, immune diversification, and self-tolerance. Immunity. 1996 Dec;5(6):505–511. doi: 10.1016/s1074-7613(00)80266-6. [DOI] [PubMed] [Google Scholar]
  25. Ray S. K., Putterman C., Diamond B. Pathogenic autoantibodies are routinely generated during the response to foreign antigen: a paradigm for autoimmune disease. Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):2019–2024. doi: 10.1073/pnas.93.5.2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Roben P., Barbas S. M., Sandoval L., Lecerf J. M., Stollar B. D., Solomon A., Silverman G. J. Repertoire cloning of lupus anti-DNA autoantibodies. J Clin Invest. 1996 Dec 15;98(12):2827–2837. doi: 10.1172/JCI119111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Russell D. M., Dembić Z., Morahan G., Miller J. F., Bürki K., Nemazee D. Peripheral deletion of self-reactive B cells. Nature. 1991 Nov 28;354(6351):308–311. doi: 10.1038/354308a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Schwartz R. S., Stollar B. D. Heavy-chain directed B-cell maturation: continuous clonal selection beginning at the pre-B cell stage. Immunol Today. 1994 Jan;15(1):27–32. doi: 10.1016/0167-5699(94)90022-1. [DOI] [PubMed] [Google Scholar]
  29. Schäble K. F., Zachau H. G. The variable genes of the human immunoglobulin kappa locus. Biol Chem Hoppe Seyler. 1993 Nov;374(11):1001–1022. [PubMed] [Google Scholar]
  30. Shlomchik M. J., Marshak-Rothstein A., Wolfowicz C. B., Rothstein T. L., Weigert M. G. The role of clonal selection and somatic mutation in autoimmunity. 1987 Aug 27-Sep 2Nature. 328(6133):805–811. doi: 10.1038/328805a0. [DOI] [PubMed] [Google Scholar]
  31. Shlomchik M., Mascelli M., Shan H., Radic M. Z., Pisetsky D., Marshak-Rothstein A., Weigert M. Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation. J Exp Med. 1990 Jan 1;171(1):265–292. doi: 10.1084/jem.171.1.265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Suzuki H., Takemura H., Suzuki M., Sekine Y., Kashiwagi H. Molecular cloning of anti-SS-A/Ro 60-kDa peptide Fab fragments from infiltrating salivary gland lymphocytes of a patient with Sjögren's syndrome. Biochem Biophys Res Commun. 1997 Mar 6;232(1):101–106. doi: 10.1006/bbrc.1997.6233. [DOI] [PubMed] [Google Scholar]
  33. Suzuki N., Harada T., Mihara S., Sakane T. Characterization of a germline Vk gene encoding cationic anti-DNA antibody and role of receptor editing for development of the autoantibody in patients with systemic lupus erythematosus. J Clin Invest. 1996 Oct 15;98(8):1843–1850. doi: 10.1172/JCI118985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Suzuki N., Mihara S., Sakane T. Development of pathogenic anti-DNA antibodies in patients with systemic lupus erythematosus. FASEB J. 1997 Oct;11(12):1033–1038. doi: 10.1096/fasebj.11.12.9337156. [DOI] [PubMed] [Google Scholar]
  35. Swanson P. C., Yung R. L., Blatt N. B., Eagan M. A., Norris J. M., Richardson B. C., Johnson K. J., Glick G. D. Ligand recognition by murine anti-DNA autoantibodies. II. Genetic analysis and pathogenicity. J Clin Invest. 1996 Apr 1;97(7):1748–1760. doi: 10.1172/JCI118602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Tan E. M. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol. 1989;44:93–151. doi: 10.1016/s0065-2776(08)60641-0. [DOI] [PubMed] [Google Scholar]
  37. Tan E. M., Cohen A. S., Fries J. F., Masi A. T., McShane D. J., Rothfield N. F., Schaller J. G., Talal N., Winchester R. J. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982 Nov;25(11):1271–1277. doi: 10.1002/art.1780251101. [DOI] [PubMed] [Google Scholar]
  38. Tiegs S. L., Russell D. M., Nemazee D. Receptor editing in self-reactive bone marrow B cells. J Exp Med. 1993 Apr 1;177(4):1009–1020. doi: 10.1084/jem.177.4.1009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Tonegawa S. Somatic generation of antibody diversity. Nature. 1983 Apr 14;302(5909):575–581. doi: 10.1038/302575a0. [DOI] [PubMed] [Google Scholar]
  40. Waisman A., Ruiz P. J., Mozes E. Variable regions of two murine antibodies that bind the SLE associated 16/6 idiotype. Lupus. 1996 Aug;5(4):279–287. doi: 10.1177/096120339600500407. [DOI] [PubMed] [Google Scholar]
  41. van Es J. H., Gmelig Meyling F. H., van de Akker W. R., Aanstoot H., Derksen R. H., Logtenberg T. Somatic mutations in the variable regions of a human IgG anti-double-stranded DNA autoantibody suggest a role for antigen in the induction of systemic lupus erythematosus. J Exp Med. 1991 Feb 1;173(2):461–470. doi: 10.1084/jem.173.2.461. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES