Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Jun;91(6):2358–2367. doi: 10.1172/JCI116468

A fetally expressed immunoglobulin VH1 gene belongs to a complex set of alleles.

E H Sasso 1, K Willems van Dijk 1, A P Bull 1, E C Milner 1
PMCID: PMC443293  PMID: 8099917

Abstract

The immunoglobulin VH gene 51p1, a member of the large VH1 gene family, is preferentially expressed by B cells in the fetus and in chronic lymphocytic leukemia (CLL) and appears to be the source for many cryoglobulin rheumatoid factors. Polymorphism of 51p1 may therefore be functionally important. We have studied the germline representation of 51p1 and closely related VH elements to establish their prevalence and allelic relationship. A panel of oligonucleotide probes directed to the complementarity determining regions (CDR1 and CDR2) of 51p1 and a similar gene, hv1263, was used in restriction fragment polymorphism analysis of 48 unrelated individuals and six families. 13 VH alleles to the 51p1 locus were identified, each distinguished by its restriction fragment size, hybridization profile, or both. On some haplotypes the locus was duplicated. Null alleles were not seen. The 13 alleles were cloned, yielding nine distinct nucleotide sequences that were > 98.2% identical and included 51p1 and hv1263. These germline variations could influence specificity for antigen, because the corresponding protein sequences differed by up to five amino acids, including three nonconservative changes in the CDR. Two of the most prevalent variants contained 51p1. These findings expand the spectrum of polymorphism seen among human VH genes and elucidate the germline origin of VH1 sequences frequently expressed in autoantibodies and CLL. We conclude that the 51p1 locus is polymorphic, and that the 51p1 element is the predominant member of a complex set of alleles.

Full text

PDF
2358

Images in this article

2361Image
on p.2361
2361Image
on p.2361
2361Image
on p.2361
2361Image
on p.2361
2365Image
on p.2365
2365Image
on p.2365

Selected References

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

  1. Berman J. E., Mellis S. J., Pollock R., Smith C. L., Suh H., Heinke B., Kowal C., Surti U., Chess L., Cantor C. R. Content and organization of the human Ig VH locus: definition of three new VH families and linkage to the Ig CH locus. EMBO J. 1988 Mar;7(3):727–738. doi: 10.1002/j.1460-2075.1988.tb02869.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Buluwela L., Rabbitts T. H. A VH gene is located within 95 Kb of the human immunoglobulin heavy chain constant region genes. Eur J Immunol. 1988 Nov;18(11):1843–1845. doi: 10.1002/eji.1830181130. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Chen P. P., Liu M. F., Sinha S., Carson D. A. A 16/6 idiotype-positive anti-DNA antibody is encoded by a conserved VH gene with no somatic mutation. Arthritis Rheum. 1988 Nov;31(11):1429–1431. doi: 10.1002/art.1780311113. [DOI] [PubMed] [Google Scholar]
  5. Chen P. P., Siminovitch K. A., Olsen N. J., Erger R. A., Carson D. A. A highly informative probe for two polymorphic Vh gene regions that contain one or more autoantibody-associated Vh genes. J Clin Invest. 1989 Aug;84(2):706–710. doi: 10.1172/JCI114218. [DOI] [PMC free article] [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. Dunning A. M., Talmud P., Humphries S. E. Errors in the polymerase chain reaction. Nucleic Acids Res. 1988 Nov 11;16(21):10393–10393. doi: 10.1093/nar/16.21.10393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. 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]
  9. Johnson M. J., Natali A. M., Cann H. M., Honjo T., Cavalli-Sforza L. L. Polymorphisms of a human variable heavy chain gene show linkage with constant heavy chain genes. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7840–7844. doi: 10.1073/pnas.81.24.7840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Keohavong P., Thilly W. G. Fidelity of DNA polymerases in DNA amplification. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9253–9257. doi: 10.1073/pnas.86.23.9253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kipps T. J., Robbins B. A., Carson D. A. Uniform high frequency expression of autoantibody-associated crossreactive idiotypes in the primary B cell follicles of human fetal spleen. J Exp Med. 1990 Jan 1;171(1):189–196. doi: 10.1084/jem.171.1.189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. Kipps T. J., Tomhave E., Pratt L. F., Duffy S., Chen P. P., Carson D. A. Developmentally restricted immunoglobulin heavy chain variable region gene expressed at high frequency in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5913–5917. doi: 10.1073/pnas.86.15.5913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kodaira M., Kinashi T., Umemura I., Matsuda F., Noma T., Ono Y., Honjo T. Organization and evolution of variable region genes of the human immunoglobulin heavy chain. J Mol Biol. 1986 Aug 20;190(4):529–541. doi: 10.1016/0022-2836(86)90239-1. [DOI] [PubMed] [Google Scholar]
  15. Lee K. H., Matsuda F., Kinashi T., Kodaira M., Honjo T. A novel family of variable region genes of the human immunoglobulin heavy chain. J Mol Biol. 1987 Jun 20;195(4):761–768. doi: 10.1016/0022-2836(87)90482-7. [DOI] [PubMed] [Google Scholar]
  16. Logtenberg T., Young F. M., Van Es J. H., Gmelig-Meyling F. H., Alt F. W. Autoantibodies encoded by the most Jh-proximal human immunoglobulin heavy chain variable region gene. J Exp Med. 1989 Oct 1;170(4):1347–1355. doi: 10.1084/jem.170.4.1347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. Matsuda F., Shin E. K., Nagaoka H., Matsumura R., Haino M., Fukita Y., Taka-ishi S., Imai T., Riley J. H., Anand R. Structure and physical map of 64 variable segments in the 3'0.8-megabase region of the human immunoglobulin heavy-chain locus. Nat Genet. 1993 Jan;3(1):88–94. doi: 10.1038/ng0193-88. [DOI] [PubMed] [Google Scholar]
  19. Matthyssens G., Rabbitts T. H. Structure and multiplicity of genes for the human immunoglobulin heavy chain variable region. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6561–6565. doi: 10.1073/pnas.77.11.6561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mortari F., Newton J. A., Wang J. Y., Schroeder H. W., Jr The human cord blood antibody repertoire. Frequent usage of the VH7 gene family. Eur J Immunol. 1992 Jan;22(1):241–245. doi: 10.1002/eji.1830220135. [DOI] [PubMed] [Google Scholar]
  21. Olee T., Yang P. M., Siminovitch K. A., Olsen N. J., Hillson J., Wu J., Kozin F., Carson D. A., Chen P. P. Molecular basis of an autoantibody-associated restriction fragment length polymorphism that confers susceptibility to autoimmune diseases. J Clin Invest. 1991 Jul;88(1):193–203. doi: 10.1172/JCI115277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pincus S. H. Human immunoglobulin heavy-chain-variable (VH) region gene families defined by hybridization with cloned human and murine VH-genes. Hum Immunol. 1988 Jul;22(3):199–215. doi: 10.1016/0198-8859(88)90029-8. [DOI] [PubMed] [Google Scholar]
  23. Rechavi G., Bienz B., Ram D., Ben-Neriah Y., Cohen J. B., Zakut R., Givol D. Organization and evolution of immunoglobulin VH gene subgroups. Proc Natl Acad Sci U S A. 1982 Jul;79(14):4405–4409. doi: 10.1073/pnas.79.14.4405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rechavi G., Ram D., Glazer L., Zakut R., Givol D. Evolutionary aspects of immunoglobulin heavy chain variable region (VH) gene subgroups. Proc Natl Acad Sci U S A. 1983 Feb;80(3):855–859. doi: 10.1073/pnas.80.3.855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sam M., Walter M. A., Cox D. W. RsaI polymorphism of a human immunoglobulin VH5 subclass locus. Nucleic Acids Res. 1988 Sep 12;16(17):8748–8748. doi: 10.1093/nar/16.17.8748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sanz I., Dang H., Takei M., Talal N., Capra J. D. VH sequence of a human anti-Sm autoantibody. Evidence that autoantibodies can be unmutated copies of germline genes. J Immunol. 1989 Feb 1;142(3):883–887. [PubMed] [Google Scholar]
  27. Sanz I., Kelly P., Williams C., Scholl S., Tucker P., Capra J. D. The smaller human VH gene families display remarkably little polymorphism. EMBO J. 1989 Dec 1;8(12):3741–3748. doi: 10.1002/j.1460-2075.1989.tb08550.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sasso E. H., Van Dijk K. W., Milner E. C. Prevalence and polymorphism of human VH3 genes. J Immunol. 1990 Oct 15;145(8):2751–2757. [PubMed] [Google Scholar]
  29. Sasso E. H., Willems van Dijk K., Bull A., van der Maarel S. M., Milner E. C. VH genes in tandem array comprise a repeated germline motif. J Immunol. 1992 Aug 15;149(4):1230–1236. [PubMed] [Google Scholar]
  30. 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]
  31. Schroeder H. W., Jr, Walter M. A., Hofker M. H., Ebens A., Willems van Dijk K., Liao L. C., Cox D. W., Milner E. C., Perlmutter R. M. Physical linkage of a human immunoglobulin heavy chain variable region gene segment to diversity and joining region elements. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8196–8200. doi: 10.1073/pnas.85.21.8196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Schroeder H. W., Jr, Wang J. Y. Preferential utilization of conserved immunoglobulin heavy chain variable gene segments during human fetal life. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6146–6150. doi: 10.1073/pnas.87.16.6146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Shen A., Humphries C., Tucker P., Blattner F. Human heavy-chain variable region gene family nonrandomly rearranged in familial chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8563–8567. doi: 10.1073/pnas.84.23.8563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Shin E. K., Matsuda F., Nagaoka H., Fukita Y., Imai T., Yokoyama K., Soeda E., Honjo T. Physical map of the 3' region of the human immunoglobulin heavy chain locus: clustering of autoantibody-related variable segments in one haplotype. EMBO J. 1991 Dec;10(12):3641–3645. doi: 10.1002/j.1460-2075.1991.tb04930.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sikder S. K., Borden P., Gruezo F., Akolkar P. N., Bhattacharya S. B., Morrison S. L., Kabat E. A. Amino acid substitutions in VH CDR2 change the idiotype but not the antigen-binding of monoclonal antibodies to alpha(1----6)dextrans. J Immunol. 1989 Feb 1;142(3):888–893. [PubMed] [Google Scholar]
  36. 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]
  37. Siminovitch K. A., Misener V., Kwong P. C., Yang P. M., Laskin C. A., Cairns E., Bell D., Rubin L. A., Chen P. P. A human anti-cardiolipin autoantibody is encoded by developementally restricted heavy and light chain variable region genes. Autoimmunity. 1990;8(2):97–105. doi: 10.3109/08916939008995727. [DOI] [PubMed] [Google Scholar]
  38. Souroujon M. C., Rubinstein D. B., Schwartz R. S., Barrett K. J. Polymorphisms in human H chain V region genes from the VHIII gene family. J Immunol. 1989 Jul 15;143(2):706–711. [PubMed] [Google Scholar]
  39. Turnbull I. F., Bernard O., Sriprakash K. S., Mathews J. D. Human immunoglobulin variable region genes: a new VH sequence used to detect polymorphism. Immunogenetics. 1987;25(3):184–192. doi: 10.1007/BF00344033. [DOI] [PubMed] [Google Scholar]
  40. Van Dijk K. W., Milner L. A., Milner E. C. Mapping of human H chain V region genes (VH4) using deletional analysis and pulsed field gel electrophoresis. J Immunol. 1992 May 1;148(9):2923–2931. [PubMed] [Google Scholar]
  41. Walter M. A., Cox D. W. Analysis of genetic variation reveals human immunoglobulin VH-region gene organization. Am J Hum Genet. 1988 Mar;42(3):446–451. [PMC free article] [PubMed] [Google Scholar]
  42. Walter M. A., Cox D. W. Nonuniform linkage disequilibrium within a 1,500-kb region of the human immunoglobulin heavy-chain complex. Am J Hum Genet. 1991 Nov;49(5):917–931. [PMC free article] [PubMed] [Google Scholar]
  43. Walter M. A., Dosch H. M., Cox D. W. A deletion map of the human immunoglobulin heavy chain variable region. J Exp Med. 1991 Aug 1;174(2):335–349. doi: 10.1084/jem.174.2.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Walter M. A., Gibson W. T., Ebers G. C., Cox D. W. Susceptibility to multiple sclerosis is associated with the proximal immunoglobulin heavy chain variable region. J Clin Invest. 1991 Apr;87(4):1266–1273. doi: 10.1172/JCI115128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Walter M. A., Linsley P. S., Cox D. W. Apa I polymorphism of a human immunoglobin VH3 subclass locus. Nucleic Acids Res. 1987 Jun 11;15(11):4697–4697. doi: 10.1093/nar/15.11.4697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Willems van Dijk K., Milner L. A., Sasso E. H., Milner E. C. Chromosomal organization of the heavy chain variable region gene segments comprising the human fetal antibody repertoire. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10430–10434. doi: 10.1073/pnas.89.21.10430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Willems van Dijk K., Schroeder H. W., Jr, Perlmutter R. M., Milner E. C. Heterogeneity in the human Ig VH locus. J Immunol. 1989 Apr 1;142(7):2547–2554. [PubMed] [Google Scholar]
  48. Wood W. I., Gitschier J., Lasky L. A., Lawn R. M. Base composition-independent hybridization in tetramethylammonium chloride: a method for oligonucleotide screening of highly complex gene libraries. Proc Natl Acad Sci U S A. 1985 Mar;82(6):1585–1588. doi: 10.1073/pnas.82.6.1585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. van Dijk K. W., Sasso E. H., Milner E. C. Polymorphism of the human Ig VH4 gene family. J Immunol. 1991 May 15;146(10):3646–3651. [PubMed] [Google Scholar]

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

RESOURCES