Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Dec;92(6):2821–2833. doi: 10.1172/JCI116902

Naturally occurring anti-i/I cold agglutinins may be encoded by different VH3 genes as well as the VH4.21 gene segment.

L C Jefferies 1, C M Carchidi 1, L E Silberstein 1
PMCID: PMC288483  PMID: 8254037

Abstract

In the current study, we wished to determine if the V regions encoding the naturally occurring anti-i/I Cold Agglutinins (anti-i/I CA) differ from pathogenic anti-i/I CA that are exclusively encoded by the VH4.21 gene. After EBV transformation of B lymphocytes, we generated one anti-I secreting clone from each of two individuals; clone 4G (individual CM, PBL) and clone Sp1 (individual SC, spleen). Clone 4G expresses a VH3 gene sequence that is 92% homologous to the germline gene WHG26. Clone Sp1 also expresses a VH3 gene that is 98% homologous to the fetally rearranged M85/20P1 gene. Another clone, Sp2 (anti-i specificity), from individual SC is 98% homologous to the germline gene VH4.21. For correlation, we studied anti-i/I CA fractions purified from 15 normal sera and found no or relatively small amounts of 9G4 (VH4.21 related idiotype) reactive IgM. Five cold agglutinin fractions contained large amounts of VH3-encoded IgM (compared to pooled normal IgM) by virtue of their binding to modified protein Staph A (SPA), and absorption of three CA fractions with modified SPA specifically removed anti-i/I binding specificity entirely. Collectively, the data indicate that naturally occurring anti-i/I CA may be encoded to a large extent by non-VH4.21-related genes, and that the VH4.21 gene is not uniquely required for anti-i/I specificity.

Full text

PDF
2821

Images in this article

2828Image
on p.2828
2828Image
on p.2828
2830Image
on p.2830

Selected References

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

  1. Adderson E. E., Shackelford P. G., Quinn A., Wilson P. M., Cunningham M. W., Insel R. A., Carroll W. L. Restricted immunoglobulin VH usage and VDJ combinations in the human response to Haemophilus influenzae type b capsular polysaccharide. Nucleotide sequences of monospecific anti-Haemophilus antibodies and polyspecific antibodies cross-reacting with self antigens. J Clin Invest. 1993 Jun;91(6):2734–2743. doi: 10.1172/JCI116514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. COSTEA N., YAKULIS V., HELLER P. EXPERIMENTAL PRODUCTION OF COLD AGGLUTININS IN RABBITS. Blood. 1965 Sep;26:323–340. [PubMed] [Google Scholar]
  3. 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]
  4. Friedman D. F., Cho E. A., Goldman J., Carmack C. E., Besa E. C., Hardy R. R., Silberstein L. E. The role of clonal selection in the pathogenesis of an autoreactive human B cell lymphoma. J Exp Med. 1991 Sep 1;174(3):525–537. doi: 10.1084/jem.174.3.525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Goldberg L. S., Barnett E. V. Mixed gamma G-gamma M cold agglutinin. J Immunol. 1967 Oct;99(4):803–809. [PubMed] [Google Scholar]
  6. Ichihara Y., Matsuoka H., Kurosawa Y. Organization of human immunoglobulin heavy chain diversity gene loci. EMBO J. 1988 Dec 20;7(13):4141–4150. doi: 10.1002/j.1460-2075.1988.tb03309.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Jefferies L. C., Silverman G. J., Carchidi C. M., Silberstein L. E. Idiotypic heterogeneity of VKIII autoantibodies to red blood cell antigens. Clin Immunol Immunopathol. 1992 Nov;65(2):119–128. doi: 10.1016/0090-1229(92)90214-9. [DOI] [PubMed] [Google Scholar]
  8. Küppers R., Fischer U., Rajewsky K., Gause A. Immunoglobulin heavy and light chain gene sequences of a human CD5 positive immunocytoma and sequences of four novel VHIII germline genes. Immunol Lett. 1992 Sep;34(1):57–62. doi: 10.1016/0165-2478(92)90027-l. [DOI] [PubMed] [Google Scholar]
  9. Leoni J., Ghiso J., Goñi F., Frangione B. The primary structure of the Fab fragment of protein KAU, a monoclonal immunoglobulin M cold agglutinin. J Biol Chem. 1991 Feb 15;266(5):2836–2842. [PubMed] [Google Scholar]
  10. Madaio M. P., Schattner A., Shattner M., Schwartz R. S. Lupus serum and normal human serum contain anti-DNA antibodies with the same idiotypic marker. J Immunol. 1986 Oct 15;137(8):2535–2540. [PubMed] [Google Scholar]
  11. Olee T., Lu E. W., Huang D. F., Soto-Gil R. W., Deftos M., Kozin F., Carson D. A., Chen P. P. Genetic analysis of self-associating immunoglobulin G rheumatoid factors from two rheumatoid synovia implicates an antigen-driven response. J Exp Med. 1992 Mar 1;175(3):831–842. doi: 10.1084/jem.175.3.831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Pascual V., Andris J., Capra J. D. Heavy chain variable region gene utilization in human antibodies. Int Rev Immunol. 1990;5(3-4):231–238. doi: 10.3109/08830189009056731. [DOI] [PubMed] [Google Scholar]
  13. Pascual V., Victor K., Lelsz D., Spellerberg M. B., Hamblin T. J., Thompson K. M., Randen I., Natvig J., Capra J. D., Stevenson F. K. 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. 1991 Jun 15;146(12):4385–4391. [PubMed] [Google Scholar]
  14. Pascual V., Victor K., Spellerberg M., Hamblin T. J., Stevenson F. K., Capra J. D. VH restriction among human cold agglutinins. The VH4-21 gene segment is required to encode anti-I and anti-i specificities. J Immunol. 1992 Oct 1;149(7):2337–2344. [PubMed] [Google Scholar]
  15. Paul E., Livneh A., Manheimer-Lory A. J., Diamond B. Characterization of the human Ig V lambda II gene family and analysis of V lambda II and C lambda polymorphism in systemic lupus erythematosus. J Immunol. 1991 Oct 15;147(8):2771–2776. [PubMed] [Google Scholar]
  16. Pruzanski W., Shumak K. H. Biologic activity of cold-reacting autoantibodies (first of two parts). N Engl J Med. 1977 Sep 8;297(10):538–542. doi: 10.1056/NEJM197709082971005. [DOI] [PubMed] [Google Scholar]
  17. Roelcke D. Cold agglutination. Transfus Med Rev. 1989 Apr;3(2):140–166. doi: 10.1016/s0887-7963(89)70075-4. [DOI] [PubMed] [Google Scholar]
  18. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. 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]
  21. Scott M. G., Crimmins D. L., McCourt D. W., Chung G., Schäble K. F., Thiebe R., Quenzel E. M., Zachau H. G., Nahm M. H. Clonal characterization of the human IgG antibody repertoire to Haemophilus influenzae type b polysaccharide. IV. The less frequently expressed VL are heterogeneous. J Immunol. 1991 Dec 1;147(11):4007–4013. [PubMed] [Google Scholar]
  22. Sharon J., Gefter M. L., Wysocki L. J., Margolies M. N. Recurrent somatic mutations in mouse antibodies to p-azophenylarsonate increase affinity for hapten. J Immunol. 1989 Jan 15;142(2):596–601. [PubMed] [Google Scholar]
  23. Shlomchik M. J., Aucoin A. H., Pisetsky D. S., Weigert M. G. Structure and function of anti-DNA autoantibodies derived from a single autoimmune mouse. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9150–9154. doi: 10.1073/pnas.84.24.9150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Silberstein L. E., Goldman J., Kant J. A., Spitalnik S. L. Comparative biochemical and genetic characterization of clonally related human B-cell lines secreting pathogenic anti-Pr2 cold agglutinins. Arch Biochem Biophys. 1988 Jul;264(1):244–252. doi: 10.1016/0003-9861(88)90591-7. [DOI] [PubMed] [Google Scholar]
  25. Silberstein L. E., Jefferies L. C., Goldman J., Friedman D., Moore J. S., Nowell P. C., Roelcke D., Pruzanski W., Roudier J., Silverman G. J. Variable region gene analysis of pathologic human autoantibodies to the related i and I red blood cell antigens. Blood. 1991 Nov 1;78(9):2372–2386. [PubMed] [Google Scholar]
  26. Silberstein L. E., Jefferies L. C., Goldman J., Spitalnik S. L. Production of carbohydrate-specific human monoclonal antibodies in vitro. Methods Enzymol. 1989;179:299–304. doi: 10.1016/0076-6879(89)79131-x. [DOI] [PubMed] [Google Scholar]
  27. Silberstein L. E., Litwin S., Carmack C. E. Relationship of variable region genes expressed by a human B cell lymphoma secreting pathologic anti-Pr2 erythrocyte autoantibodies. J Exp Med. 1989 May 1;169(5):1631–1643. doi: 10.1084/jem.169.5.1631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Silverman G. J., Carson D. A. Structural characterization of human monoclonal cold agglutinins: evidence for a distinct primary sequence-defined VH4 idiotype. Eur J Immunol. 1990 Feb;20(2):351–356. doi: 10.1002/eji.1830200218. [DOI] [PubMed] [Google Scholar]
  29. Springer G. F., Horton R. E. Blood group isoantibody stimulation in man by feeding blood group-active bacteria. J Clin Invest. 1969 Jul;48(7):1280–1291. doi: 10.1172/JCI106094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Stevenson F. K., Wrightham M., Glennie M. J., Jones D. B., Cattan A. R., Feizi T., Hamblin T. J., Stevenson G. T. Antibodies to shared idiotypes as agents for analysis and therapy for human B cell tumors. Blood. 1986 Aug;68(2):430–436. [PubMed] [Google Scholar]
  31. 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