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. 1990 Oct;87(20):7907–7911. doi: 10.1073/pnas.87.20.7907

Possible deletion of a developmentally regulated heavy-chain variable region gene in autoimmune diseases.

P M Yang 1, N J Olsen 1, K A Siminovitch 1, T Olee 1, F Kozin 1, D A Carson 1, P P Chen 1
PMCID: PMC54860  PMID: 2122448

Abstract

Several autoantibody-associated variable region (V) genes are preferentially expressed during early ontogenic development, suggesting strongly that they are of developmental and physiological importance. As such, it is possible that polymorphisms in one or more of these genes may alter susceptibility to autoimmune disease. We have searched extensively for a probe related to a developmentally regulated V gene that has the power to differentiate among highly homologous V genes in human populations. Using such a probe (i.e., Humhv3005/P1) related to both anti-DNA and anti-IgG autoantibodies, we studied restriction fragment length polymorphisms in patients with rheumatoid arthritis and systemic lupus erythematosus and found an apparent heavy-chain V (VH) gene deletion that was nearly restricted to the autoimmune patients. These data suggest that deletions of physiologically important VH genes may increase the risk of autoimmunity through indirect effects on the development and homeostasis of the B-cell repertoire.

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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. Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
  3. Avrameas S., Guilbert B., Mahana W., Matsiota P., Ternynck T. Recognition of self and non-self constituents by polyspecific autoreceptors. Int Rev Immunol. 1988 Mar;3(1-2):1–15. doi: 10.3109/08830188809051179. [DOI] [PubMed] [Google Scholar]
  4. Bell J. I., Todd J. A., McDevitt H. O. The molecular basis of HLA-disease association. Adv Hum Genet. 1989;18:1–41. [PubMed] [Google Scholar]
  5. 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]
  6. Bona C. A. V genes encoding autoantibodies: molecular and phenotypic characteristics. Annu Rev Immunol. 1988;6:327–358. doi: 10.1146/annurev.iy.06.040188.001551. [DOI] [PubMed] [Google Scholar]
  7. Cairns E., Kwong P. C., Misener V., Ip P., Bell D. A., Siminovitch K. A. Analysis of variable region genes encoding a human anti-DNA antibody of normal origin. Implications for the molecular basis of human autoimmune responses. J Immunol. 1989 Jul 15;143(2):685–691. [PubMed] [Google Scholar]
  8. 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]
  9. Casali P., Notkins A. L. Probing the human B-cell repertoire with EBV: polyreactive antibodies and CD5+ B lymphocytes. Annu Rev Immunol. 1989;7:513–535. doi: 10.1146/annurev.iy.07.040189.002501. [DOI] [PubMed] [Google Scholar]
  10. Chen P. P., Albrandt K., Orida N. K., Radoux V., Chen E. Y., Schrantz R., Liu F. T., Carson D. A. Genetic basis for the cross-reactive idiotypes on the light chains of human IgM anti-IgG autoantibodies. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8318–8322. doi: 10.1073/pnas.83.21.8318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chen P. P., Fong S., Carson D. A. Rheumatoid factor. Rheum Dis Clin North Am. 1987 Dec;13(3):545–568. [PubMed] [Google Scholar]
  12. Chen P. P., Fong S., Goni F., Silverman G. J., Fox R. I., Liu M. F., Frangione B., Carson D. A. Cross-reacting idiotypes on cryoprecipitating rheumatoid factor. Springer Semin Immunopathol. 1988;10(1):35–55. doi: 10.1007/BF02054022. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. 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]
  16. Chen P. P. Structural analyses of human developmentally regulated Vh3 genes. Scand J Immunol. 1990 Mar;31(3):257–267. doi: 10.1111/j.1365-3083.1990.tb02767.x. [DOI] [PubMed] [Google Scholar]
  17. Chen P. P., Yang P. M. A segment of human Vh gene locus is duplicated. Scand J Immunol. 1990 May;31(5):593–599. doi: 10.1111/j.1365-3083.1990.tb02810.x. [DOI] [PubMed] [Google Scholar]
  18. Coutinho A., Grandien A., Faro-Rivas J., Mota-Santos T. A. Idiotypes, tailors and networks. Ann Inst Pasteur Immunol. 1988 Nov-Dec;139(6):599–607. doi: 10.1016/0769-2625(88)90049-9. [DOI] [PubMed] [Google Scholar]
  19. Crowley J. J., Mageed R. A., Silverman G. J., Chen P. P., Kozin F., Erger R. A., Jefferis R., Carson D. A. The incidence of a new human cross-reactive idiotype linked to subgroup VHIII heavy chains. Mol Immunol. 1990 Jan;27(1):87–94. doi: 10.1016/0161-5890(90)90063-6. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Goñi F. R., Chen P. P., McGinnis D., Arjonilla M. L., Fernandez J., Carson D., Solomon A., Mendez E., Frangione B. Structural and idiotypic characterization of the L chains of human IgM autoantibodies with different specificities. J Immunol. 1989 May 1;142(9):3158–3163. [PubMed] [Google Scholar]
  22. Guilbert B., Dighiero G., Avrameas S. Naturally occurring antibodies against nine common antigens in human sera. I. Detection, isolation and characterization. J Immunol. 1982 Jun;128(6):2779–2787. [PubMed] [Google Scholar]
  23. Kocks C., Rajewsky K. Stable expression and somatic hypermutation of antibody V regions in B-cell developmental pathways. Annu Rev Immunol. 1989;7:537–559. doi: 10.1146/annurev.iy.07.040189.002541. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Lundkvist I., Coutinho A., Varela F., Holmberg D. Evidence for a functional idiotypic network among natural antibodies in normal mice. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5074–5078. doi: 10.1073/pnas.86.13.5074. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Morel P. A., Dorman J. S., Todd J. A., McDevitt H. O., Trucco M. Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8111–8115. doi: 10.1073/pnas.85.21.8111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nepom G. T., Hansen J. A., Nepom B. S. The molecular basis for HLA class II associations with rheumatoid arthritis. J Clin Immunol. 1987 Jan;7(1):1–7. doi: 10.1007/BF00915418. [DOI] [PubMed] [Google Scholar]
  28. Pennell C. A., Mercolino T. J., Grdina T. A., Arnold L. W., Haughton G., Clarke S. H. Biased immunoglobulin variable region gene expression by Ly-1 B cells due to clonal selection. Eur J Immunol. 1989 Jul;19(7):1289–1295. doi: 10.1002/eji.1830190721. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. 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]
  31. 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]
  32. Siminovitch K. A., Chen P. P. The biologic significance of human natural autoimmune responses: relationship to the germline, early immune and malignant B cell variable gene repertoire. Int Rev Immunol. 1990;5(3-4):265–277. doi: 10.3109/08830189009056734. [DOI] [PubMed] [Google Scholar]
  33. Siminovitch K. A., Misener V., Kwong P. C., Song Q. L., Chen P. P. A natural autoantibody is encoded by germline heavy and lambda light chain variable region genes without somatic mutation. J Clin Invest. 1989 Nov;84(5):1675–1678. doi: 10.1172/JCI114347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. 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]
  35. Zouali M., Stollar B. D., Schwartz R. S. Origin and diversification of anti-DNA antibodies. Immunol Rev. 1988 Oct;105:137–159. doi: 10.1111/j.1600-065x.1988.tb00770.x. [DOI] [PubMed] [Google Scholar]

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