Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1989 Aug;86(15):5913–5917. doi: 10.1073/pnas.86.15.5913

Developmentally restricted immunoglobulin heavy chain variable region gene expressed at high frequency in chronic lymphocytic leukemia.

T J Kipps 1, E Tomhave 1, L F Pratt 1, S Duffy 1, P P Chen 1, D A Carson 1
PMCID: PMC297741  PMID: 2503826

Abstract

During fetal development, murine and human B-lineage cells rearrange and express a highly restricted set of immunoglobulin heavy chain variable region genes (VH genes). We noted that a VH gene of the restricted human fetal repertoire, designated 51p1, potentially could encode the VH region of two human IgM rheumatoid factor proteins. These rheumatoid factors share a cross-reactive idiotype (CRI) defined by reactivity with G6, a murine monoclonal antibody that recognizes an antibody heavy chain determinant present on many human IgM autoantibodies, particularly rheumatoid factors. Recently, we found that the G6 CRI also is expressed frequently by neoplastic CD5 (Leu1) B cells from patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. However, neoplastic CD5-negative B cells from patients with lymphomas of follicular center cell origin rarely express this CRI. Here, we report that G6-reactive leukemic cells from two unrelated CLL patients express a VH gene that shares greater than 99% homology with a rearranged VH gene previously isolated from the leukemic cell DNA of another CLL patient and that is identical to VH 51p1. Using the polymerase chain reaction, we find that this VH gene is rearranged, and presumably expressed, in the genomic DNA of all examined cases of G6-reactive CLL or small lymphocytic lymphoma. Thus these data indicate that the autoantibody-associated G6 CRI is a serologic marker for a conserved and developmentally restricted VH1 gene that is expressed at high frequency in CD5 B-cell malignancies and early B-cell ontogeny.

Full text

PDF
5913

Images in this article

5916Image
on p.5916
5916Image
on p.5916

Selected References

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

  1. Alt F. W., Blackwell T. K., Yancopoulos G. D. Development of the primary antibody repertoire. Science. 1987 Nov 20;238(4830):1079–1087. doi: 10.1126/science.3317825. [DOI] [PubMed] [Google Scholar]
  2. Antin J. H., Emerson S. G., Martin P., Gadol N., Ault K. A. Leu-1+ (CD5+) B cells. A major lymphoid subpopulation in human fetal spleen: phenotypic and functional studies. J Immunol. 1986 Jan;136(2):505–510. [PubMed] [Google Scholar]
  3. Bofill M., Janossy G., Janossa M., Burford G. D., Seymour G. J., Wernet P., Kelemen E. Human B cell development. II. Subpopulations in the human fetus. J Immunol. 1985 Mar;134(3):1531–1538. [PubMed] [Google Scholar]
  4. Caligaris-Cappio F., Gobbi M., Bofill M., Janossy G. Infrequent normal B lymphocytes express features of B-chronic lymphocytic leukemia. J Exp Med. 1982 Feb 1;155(2):623–628. doi: 10.1084/jem.155.2.623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Carson D. A., Chen P. P., Fox R. I., Kipps T. J., Jirik F., Goldfien R. D., Silverman G., Radoux V., Fong S. Rheumatoid factor and immune networks. Annu Rev Immunol. 1987;5:109–126. doi: 10.1146/annurev.iy.05.040187.000545. [DOI] [PubMed] [Google Scholar]
  6. Carson D. A., Chen P. P., Kipps T. J., Radoux V., Jirik F. R., Goldfien R. D., Fox R. I., Silverman G. J., Fong S. Idiotypic and genetic studies of human rheumatoid factors. Arthritis Rheum. 1987 Dec;30(12):1321–1325. doi: 10.1002/art.1780301201. [DOI] [PubMed] [Google Scholar]
  7. Carson D. A., Fong S. A common idiotope on human rheumatoid factors identified by a hybridoma antibody. Mol Immunol. 1983 Oct;20(10):1081–1087. doi: 10.1016/0161-5890(83)90116-5. [DOI] [PubMed] [Google Scholar]
  8. Casali P., Burastero S. E., Nakamura M., Inghirami G., Notkins A. L. Human lymphocytes making rheumatoid factor and antibody to ssDNA belong to Leu-1+ B-cell subset. Science. 1987 Apr 3;236(4797):77–81. doi: 10.1126/science.3105056. [DOI] [PubMed] [Google Scholar]
  9. Chen P. P., Liu M. F., Glass C. A., Sinha S., Kipps T. J., Carson D. A. Characterization of two immunoglobulin VH genes that are homologous to human rheumatoid factors. Arthritis Rheum. 1989 Jan;32(1):72–76. doi: 10.1002/anr.1780320112. [DOI] [PubMed] [Google Scholar]
  10. Dersimonian H., Schwartz R. S., Barrett K. J., Stollar B. D. Relationship of human variable region heavy chain germ-line genes to genes encoding anti-DNA autoantibodies. J Immunol. 1987 Oct 1;139(7):2496–2501. [PubMed] [Google Scholar]
  11. Desiderio S. V., Yancopoulos G. D., Paskind M., Thomas E., Boss M. A., Landau N., Alt F. W., Baltimore D. Insertion of N regions into heavy-chain genes is correlated with expression of terminal deoxytransferase in B cells. Nature. 1984 Oct 25;311(5988):752–755. doi: 10.1038/311752a0. [DOI] [PubMed] [Google Scholar]
  12. Dildrop R., Krawinkel U., Winter E., Rajewsky K. VH-gene expression in murine lipopolysaccharide blasts distributes over the nine known VH-gene groups and may be random. Eur J Immunol. 1985 Nov;15(11):1154–1156. doi: 10.1002/eji.1830151117. [DOI] [PubMed] [Google Scholar]
  13. Förster I., Gu H., Rajewsky K. Germline antibody V regions as determinants of clonal persistence and malignant growth in the B cell compartment. EMBO J. 1988 Dec 1;7(12):3693–3703. doi: 10.1002/j.1460-2075.1988.tb03251.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gadol N., Ault K. A. Phenotypic and functional characterization of human Leu1 (CD5) B cells. Immunol Rev. 1986 Oct;93:23–34. doi: 10.1111/j.1600-065x.1986.tb01500.x. [DOI] [PubMed] [Google Scholar]
  15. Hardy R. R., Hayakawa K. Development and physiology of Ly-1 B and its human homolog, Leu-1 B. Immunol Rev. 1986 Oct;93:53–79. doi: 10.1111/j.1600-065x.1986.tb01502.x. [DOI] [PubMed] [Google Scholar]
  16. Hardy R. R., Hayakawa K., Shimizu M., Yamasaki K., Kishimoto T. Rheumatoid factor secretion from human Leu-1+ B cells. Science. 1987 Apr 3;236(4797):81–83. doi: 10.1126/science.3105057. [DOI] [PubMed] [Google Scholar]
  17. Hayakawa K., Hardy R. R., Honda M., Herzenberg L. A., Steinberg A. D., Herzenberg L. A. Ly-1 B cells: functionally distinct lymphocytes that secrete IgM autoantibodies. Proc Natl Acad Sci U S A. 1984 Apr;81(8):2494–2498. doi: 10.1073/pnas.81.8.2494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hayakawa K., Hardy R. R., Parks D. R., Herzenberg L. A. The "Ly-1 B" cell subpopulation in normal immunodefective, and autoimmune mice. J Exp Med. 1983 Jan 1;157(1):202–218. doi: 10.1084/jem.157.1.202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Heitzmann J. G., Cohn M. The WI-L2-729-HF2 human hybridoma system. Stable hybrids at high frequency. Mol Biol Med. 1983 Sep;1(2):235–243. [PubMed] [Google Scholar]
  20. Herzenberg L. A., Stall A. M., Lalor P. A., Sidman C., Moore W. A., Parks D. R., Herzenberg L. A. The Ly-1 B cell lineage. Immunol Rev. 1986 Oct;93:81–102. doi: 10.1111/j.1600-065x.1986.tb01503.x. [DOI] [PubMed] [Google Scholar]
  21. Humphries C. G., Shen A., Kuziel W. A., Capra J. D., Blattner F. R., Tucker P. W. A new human immunoglobulin VH family preferentially rearranged in immature B-cell tumours. Nature. 1988 Feb 4;331(6155):446–449. doi: 10.1038/331446a0. [DOI] [PubMed] [Google Scholar]
  22. Ichihara Y., Abe M., Yasui H., Matsuoka H., Kurosawa Y. At least five DH genes of human immunoglobulin heavy chains are encoded in 9-kilobase DNA fragments. Eur J Immunol. 1988 Apr;18(4):649–652. doi: 10.1002/eji.1830180426. [DOI] [PubMed] [Google Scholar]
  23. Kearney J. F., Vakil M. Idiotype-directed interactions during ontogeny play a major role in the establishment of the adult B cell repertoire. Immunol Rev. 1986 Dec;94:39–50. doi: 10.1111/j.1600-065x.1986.tb01163.x. [DOI] [PubMed] [Google Scholar]
  24. Kipps T. J., Fong S., Tomhave E., Chen P. P., Goldfien R. D., Carson D. A. High-frequency expression of a conserved kappa light-chain variable-region gene in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 1987 May;84(9):2916–2920. doi: 10.1073/pnas.84.9.2916. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kipps T. J., Robbins B. A., Kuster P., Carson D. A. Autoantibody-associated cross-reactive idiotypes expressed at high frequency in chronic lymphocytic leukemia relative to B-cell lymphomas of follicular center cell origin. Blood. 1988 Aug;72(2):422–428. [PubMed] [Google Scholar]
  26. Kipps T. J., Tomhave E., Chen P. P., Carson D. A. Autoantibody-associated kappa light chain variable region gene expressed in chronic lymphocytic leukemia with little or no somatic mutation. Implications for etiology and immunotherapy. J Exp Med. 1988 Mar 1;167(3):840–852. doi: 10.1084/jem.167.3.840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kipps T. J., Vaughan J. H. Genetic influence on the levels of circulating CD5 B lymphocytes. J Immunol. 1987 Aug 15;139(4):1060–1064. [PubMed] [Google Scholar]
  28. Mageed R. A., Dearlove M., Goodall D. M., Jefferis R. Immunogenic and antigenic epitopes of immunoglobulins. XVII--Monoclonal antibodies reactive with common and restricted idiotopes to the heavy chain of human rheumatoid factors. Rheumatol Int. 1986;6(4):179–183. doi: 10.1007/BF00541285. [DOI] [PubMed] [Google Scholar]
  29. Martinez C., Pereira P., Toribio M. L., Marcos M. A., Bandeira A., de la Hera A., Marquez C., Cazenave P. A., Coutinho A. The participation of B cells and antibodies in the selection and maintenance of T cell repertoires. Immunol Rev. 1988 Jan;101:191–215. doi: 10.1111/j.1600-065x.1988.tb00738.x. [DOI] [PubMed] [Google Scholar]
  30. Newkirk M. M., Mageed R. A., Jefferis R., Chen P. P., Capra J. D. Complete amino acid sequences of variable regions of two human IgM rheumatoid factors, BOR and KAS of the Wa idiotypic family, reveal restricted use of heavy and light chain variable and joining region gene segments. J Exp Med. 1987 Aug 1;166(2):550–564. doi: 10.1084/jem.166.2.550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pennell C. A., Arnold L. W., Haughton G., Clarke S. H. Restricted Ig variable region gene expression among Ly-1+ B cell lymphomas. J Immunol. 1988 Oct 15;141(8):2788–2796. [PubMed] [Google Scholar]
  32. Perlmutter R. M., Kearney J. F., Chang S. P., Hood L. E. Developmentally controlled expression of immunoglobulin VH genes. Science. 1985 Mar 29;227(4694):1597–1601. doi: 10.1126/science.3975629. [DOI] [PubMed] [Google Scholar]
  33. Preud'homme J. L., Seligmann M. Anti-human immunoglobulin G activity of membrane-bound monoclonal immunoglobulin M in lymphoproliferative disorders. Proc Natl Acad Sci U S A. 1972 Aug;69(8):2132–2135. doi: 10.1073/pnas.69.8.2132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Radoux V., Chen P. P., Sorge J. A., Carson D. A. A conserved human germline V kappa gene directly encodes rheumatoid factor light chains. J Exp Med. 1986 Dec 1;164(6):2119–2124. doi: 10.1084/jem.164.6.2119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ravetch J. V., Siebenlist U., Korsmeyer S., Waldmann T., Leder P. Structure of the human immunoglobulin mu locus: characterization of embryonic and rearranged J and D genes. Cell. 1981 Dec;27(3 Pt 2):583–591. doi: 10.1016/0092-8674(81)90400-1. [DOI] [PubMed] [Google Scholar]
  36. Saiki R. K., Bugawan T. L., Horn G. T., Mullis K. B., Erlich H. A. Analysis of enzymatically amplified beta-globin and HLA-DQ alpha DNA with allele-specific oligonucleotide probes. Nature. 1986 Nov 13;324(6093):163–166. doi: 10.1038/324163a0. [DOI] [PubMed] [Google Scholar]
  37. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  38. Schroeder H. W., Jr, Hillson J. L., Perlmutter R. M. Early restriction of the human antibody repertoire. Science. 1987 Nov 6;238(4828):791–793. doi: 10.1126/science.3118465. [DOI] [PubMed] [Google Scholar]
  39. Silverman G. J., Goldfien R. D., Chen P., Mageed R. A., Jefferis R., Goñi F., Frangione B., Fong S., Carson D. A. Idiotypic and subgroup analysis of human monoclonal rheumatoid factors. Implications for structural and genetic basis of autoantibodies in humans. J Clin Invest. 1988 Aug;82(2):469–475. doi: 10.1172/JCI113620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Tarlinton D., Stall A. M., Herzenberg L. A. Repetitive usage of immunoglobulin VH and D gene segments in CD5+ Ly-1 B clones of (NZB x NZW)F1 mice. EMBO J. 1988 Dec 1;7(12):3705–3710. doi: 10.1002/j.1460-2075.1988.tb03253.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Tonegawa S. Somatic generation of antibody diversity. Nature. 1983 Apr 14;302(5909):575–581. doi: 10.1038/302575a0. [DOI] [PubMed] [Google Scholar]
  42. Yancopoulos G. D., Alt F. W. Regulation of the assembly and expression of variable-region genes. Annu Rev Immunol. 1986;4:339–368. doi: 10.1146/annurev.iy.04.040186.002011. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES