Immunoglobulin heavy chain variable region gene usage in human autoimmune diseases

  • Virginia Pascual
  • J. Donald Capra
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 386)

Abstract

The variable regions of immunoglobulin heavy and light chains are assembled in pre-B cells by the somatic joining of genetic elements which, in the chromosome, are separated by thousands of base pairs. The repertoire of germline variable region genes represents the substrate upon which diversity is generated in the antibody system, since the recombination of one among different available VH, D, and JH, as well as VL and JL gene segments, provides each B lymphocyte with a unique immunoglobulin receptor molecule. Diversity is enhanced several orders of magnitude by the generation of junctional amino acids during the process of rearrangement and the combinatorial association of heavy and light chains. Somatic mutation and gene conversion are additional mechanisms which, working upon the already assembled antibody molecule, lead to a practically unlimited number of antibody specificities (reviewed in Reference 1).

Keywords

Arthritis Carbohydrate Recombination Germinal Pyruvate 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    V. Pascual, and J. D. Capra, Human immunoglobulin heavy chain variable region genes:Organization, polymorphism, and expression, Adv. Immunol 49:1 (1991).CrossRefGoogle Scholar
  2. 2.
    F. Matsuda, E. K. Shin, H. Nagaoka, R. Matsumura, M. Haino, Y. Fukita, S. Taka-ishi, T. Imai, J. H. Riley, R. Anand, E. Soeda, and T. Honjo, Structure and physical map of 64 variable segments in the 3’ 0.8 megabase region of the human immunoglobulin heavy chain locus, Nature Genet. 3:88 (1993).PubMedCrossRefGoogle Scholar
  3. 3.
    G. D. Yancopoulos, S. V. Desiderio, M. Paskind, J. F. Kearney, D. Baltimore, and F. W. Alt, Preferential utilization of the most JH proximal VH segments in pre-B cell lines, Nature 311:727 (1984).PubMedCrossRefGoogle Scholar
  4. 4.
    R. M. Perlmutter, J. F. Kearney, S. P. Chang, and L. H. Hood, Developmentally controlled expression of immunoglobulin VH genes, Science 227:1597 (1985).PubMedCrossRefGoogle Scholar
  5. 5.
    H. W. Schroeder, J. L. Hillson, and R. M. Perlmutter, Early restriction in the human antibody repertoire, Science 238:791 (1987).PubMedCrossRefGoogle Scholar
  6. 6.
    H. W. Schroeder, and J. Y. Wang, Preferential utilization of conserved immunoglobulin heavy chain variable gene segments during human fetal life, Proc. Natl. Acad. Sci U.S.A. 87:6146 (1990).PubMedCrossRefGoogle Scholar
  7. 7.
    K. W. Van Dijk, L. A. Milner, E. H. Sasso, and E. C. B. Milner, Chromosomal organization of the heavy chain variable region gene segments comprising the human fetal antibody repertoire, Proc. Natl. Acad. Sci. U.S.A. 89:10430 (1992).CrossRefGoogle Scholar
  8. 8.
    V. Pascual, L. Verkruyse, M. L. Casey, and J. D. Capra, Analysis of Ig H chain gene segment utilization in human fetal liver, J. Immunol. 151:4164 (1993).PubMedGoogle Scholar
  9. 9.
    V. Pascual, and J. D. Capra, VH4–21, a human VH gene segment overrepresented in the autoimmune repertoire, Arthritis Rheum. 35:11 (1992).PubMedCrossRefGoogle Scholar
  10. 10.
    H. G. Kunkel, V. Agnello, F. G. Joslin, R.J. Winchester, and J. D. Capra, Cross-idiotypic specificity among monoclonal IgM proteins with anti-gamma globulin activity, J. Exp. Med. 137:331 (1973).PubMedCrossRefGoogle Scholar
  11. 11.
    I. Randen, K. M. Thompson, V. Pascual, K. Victor, D. Beale, J. Coadwell, O. Forre, J. D. Capra, and J. B. Natvig, Rheumatoid factor V genes from patients with rheumatoid arthritis are diverse and show evidence of an antigen-driven response, Immunol. Rev. 128:49 (1992).Google Scholar
  12. 12.
    K. D. Victor,V. Pascual, A. K. Levfert, and J. D. Capra, Human anti-acetylcholine antibodies use variable gene segments analogous to those used in autoantibodies of various specificities. Mol. Immunol. 29:1501 (1992).CrossRefGoogle Scholar
  13. 13.
    K. D. Victor, V. Pascual, C. L. Williams, V. A. Lennon, and J. D. Capra, Human monoclonal striational autoantibodies isolated from thymic B lymphocytes of patients with myasthenia gravis use VH and VL gene segments associated with the autoimmune repertoire, Eur. J. Immunol. 22:2231 (1992).PubMedCrossRefGoogle Scholar
  14. 14.
    D. Vazquez-Abad, V. Pascual, M. Zanetti, and N. F. Rothfield, Analysis of human anti-topoisomerase-I idiotypes, J. Clin. Invest. 92:1302 (1993).PubMedCrossRefGoogle Scholar
  15. 15.
    I. Randen, D. Brown, K. M. Thompson, N. Hughes-Jones, V. Pascual, K. Victor, J. D. Capra, O. Forre, and J. B. Natvig, Clonally related IgM rheumatoid factors undergo affinity maturation in the rheumatoid synovial tissue, J. Immunol. 148:3296 (1992).PubMedGoogle Scholar
  16. 16.
    M. E. Gershwin, and I. R. Mackay. Primary biliary cirrhosis:Paradigm or paradox for autoimmunity, Gastroenterol. 100:822 (1991).Google Scholar
  17. 17.
    V. Pascual, S. Cha, M. E. Gershwin, J. D. Capra, and P. S. C. Leung, Nucleotide sequence analysis of natural and combinatorial anti-PDC-E2 antibodies in patients with primary biliary cirrhosis:Recapitulating immune selection with molecular biology. J. Immunol. In press.Google Scholar
  18. 18.
    V. Pascual, K. Victor, D. Leslz, M. B. Spellerberg, T. J. Hamblin, K. M. Thompson, I. Randen, J. B. Natvig, J. D. Capra, and F. K. Stevenson, Nucleotide sequence analysis of the V regions of two IgM cold agglutinins:Evidence that the VH4–21 gene segment is responsible for the major cross-reactive idiotype, J. Immunol. 146:4385 (1991).PubMedGoogle Scholar
  19. 19.
    J. Leoni, J. Ghiso, F. Goni, and B. Frangione, The primary structure of the Fab fragment of protein KAU, a monoclonal immunoglobulin M cold agglutinin, J. Biol Chem. 266:2836 (1991).PubMedGoogle Scholar
  20. 20.
    L. E. Silberstein, L. C. Jefferies, J. Goldman, D. Friedman, J. S. Moore, P. C. Nowell, D. Roelcke, W. Pruzanski, J. Roudier, and G. J. Silverman, Variable region gene analysis of pathologic human autoantibodies to the related i and I red blood cell antigens, Blood 78:2372 (1991).PubMedGoogle Scholar
  21. 21.
    K. M. Thompson, J. Sutherland, G. Bardem, M. D. Melamed, I. Randen, J. B. Natvig, V.Pascual, J. D. Capra, and F. K. Stevenson, Human monoclonal antibodies against blood group antigens preferentially express a VH4-21 variable region gene-associated epitope, Scand. J. Immunol. 34:509 (1991).Google Scholar
  22. 22.
    R. Baer, A. Foster, I. Lavenir, and T. Rabbitts, Immunoglobulin VH genes are transcribed in T cells in association with a new 5’ exon, J. Exp. Med. 167:2011 (1988).PubMedCrossRefGoogle Scholar
  23. 23.
    E. Timmers, M. Kenter, A. Thompson, A. E. M. Kraakman, J. E. Berman, F. W. Alt, and R. K. B. Schuurman, Diversity of immunoglobulin heavy chain gene segment rearrangement in B lymphoblastoid cell lines from X-linked agammaglobulinemia patients, Eur. J. Immunol. 21:2355 (1991).PubMedCrossRefGoogle Scholar
  24. 24.
    V. Pascual, and J. D. Capra, B-cell superantigens? Current Biol. 1:315 (1991).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1995

Authors and Affiliations

  • Virginia Pascual
    • 1
  • J. Donald Capra
    • 1
  1. 1.Department of MicrobiologyUT Southwestern Medical CenterDallasUSA

Personalised recommendations