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. 1985 Apr 1;161(4):805–815. doi: 10.1084/jem.161.4.805

Genetic elements used for a murine lupus anti-DNA autoantibody are closely related to those for antibodies to exogenous antigens

PMCID: PMC2189057  PMID: 3920343

Abstract

The mRNAs encoding heavy and light chains of a hybridoma-derived monoclonal IgM kappa anti-DNA autoantibody from lupus-prone MRL/Mp- lpr/lpr mice (Ighj) have been transcribed into cDNA copies and molecularly cloned, and their complete nucleotide sequences have been determined. The mRNA for the heavy chain variable region, including leader peptide and 5' untranslated region, is transcribed from a heavy chain variable region (VH) gene closely related (and possibly allelic) to VH genes of the C57BL/6 (Ighb) nitrophenyl antibody family. The deduced amino acid sequence corresponding to the light chain variable region of this autoantibody shows extensive similarities with non- autoantibody molecules of the V kappa 1 group, suggesting a common variable gene origin. The joining segments, constant regions, and 3' untranslated regions of both the heavy and light chain mRNAs are nearly identical to corresponding sequences of non-autoantibodies from normal mice. Our findings suggest that this anti-DNA autoantibody originated from the same germline repertoire as antibodies to exogenous antigens.

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Selected References

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

  1. Altenburger W., Neumaier P. S., Steinmetz M., Zachau H. G. DNA sequence of the constant gene region of the mouse immunoglobulin kappa chain. Nucleic Acids Res. 1981 Feb 25;9(4):971–981. doi: 10.1093/nar/9.4.971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Andrews B. S., Eisenberg R. A., Theofilopoulos A. N., Izui S., Wilson C. B., McConahey P. J., Murphy E. D., Roths J. B., Dixon F. J. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med. 1978 Nov 1;148(5):1198–1215. doi: 10.1084/jem.148.5.1198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Aviv H., Leder P. Purification of biologically active globin messenger RNA by chromatography on oligothymidylic acid-cellulose. Proc Natl Acad Sci U S A. 1972 Jun;69(6):1408–1412. doi: 10.1073/pnas.69.6.1408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Birnboim H. C. A rapid alkaline extraction method for the isolation of plasmid DNA. Methods Enzymol. 1983;100:243–255. doi: 10.1016/0076-6879(83)00059-2. [DOI] [PubMed] [Google Scholar]
  5. Bothwell A. L., Paskind M., Reth M., Imanishi-Kari T., Rajewsky K., Baltimore D. Heavy chain variable region contribution to the NPb family of antibodies: somatic mutation evident in a gamma 2a variable region. Cell. 1981 Jun;24(3):625–637. doi: 10.1016/0092-8674(81)90089-1. [DOI] [PubMed] [Google Scholar]
  6. Cairns E., Block J., Bell D. A. Anti-DNA autoantibody-producing hybridomas of normal human lymphoid cell origin. J Clin Invest. 1984 Sep;74(3):880–887. doi: 10.1172/JCI111505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chen B. L., Poljak R. J. Amino acid sequence of the (lambda) light chain of a human myeloma immunoglobulin (IgG New). Biochemistry. 1974 Mar 12;13(6):1295–1302. doi: 10.1021/bi00703a037. [DOI] [PubMed] [Google Scholar]
  8. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  9. Clarke S. H., Claflin J. L., Potter M., Rudikoff S. Polymorphism in anti-phosphocholine antibodies reflecting evolution of immunoglobulin families. J Exp Med. 1983 Jan 1;157(1):98–113. doi: 10.1084/jem.157.1.98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cohen S. N., Chang A. C., Hsu L. Nonchromosomal antibiotic resistance in bacteria: genetic transformation of Escherichia coli by R-factor DNA. Proc Natl Acad Sci U S A. 1972 Aug;69(8):2110–2114. doi: 10.1073/pnas.69.8.2110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Datta S. K., Stollar B. D., Schwartz R. S. Normal mice express idiotypes related to autoantibody idiotypes of lupus mice. Proc Natl Acad Sci U S A. 1983 May;80(9):2723–2727. doi: 10.1073/pnas.80.9.2723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dayhoff M. O., Barker W. C., Hunt L. T. Establishing homologies in protein sequences. Methods Enzymol. 1983;91:524–545. doi: 10.1016/s0076-6879(83)91049-2. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Dighiero G., Lymberi P., Mazié J. C., Rouyre S., Butler-Browne G. S., Whalen R. G., Avrameas S. Murine hybridomas secreting natural monoclonal antibodies reacting with self antigens. J Immunol. 1983 Nov;131(5):2267–2272. [PubMed] [Google Scholar]
  15. Doolittle R. F., Armentrout R. W. Pyrrolidonyl peptidase. An enzyme for selective removal of pyrrolidonecarboxylic acid residues from polypeptides. Biochemistry. 1968 Feb;7(2):516–521. doi: 10.1021/bi00842a005. [DOI] [PubMed] [Google Scholar]
  16. Early P., Rogers J., Davis M., Calame K., Bond M., Wall R., Hood L. Two mRNAs can be produced from a single immunoglobulin mu gene by alternative RNA processing pathways. Cell. 1980 Jun;20(2):313–319. doi: 10.1016/0092-8674(80)90617-0. [DOI] [PubMed] [Google Scholar]
  17. Eilat D., Hochberg M., Pumphrey J., Rudikoff S. Monoclonal antibodies to DNA and RNA from NZB/NZW F1 mice: antigenic specificities and NH2 terminal amino acid sequences. J Immunol. 1984 Jul;133(1):489–494. [PubMed] [Google Scholar]
  18. Gibson D. M., MacLean S. J. Ef2: a new LY-3-linked light-chain marker expressed in normal mouse serum immunoglobulin. J Exp Med. 1979 Jun 1;149(6):1477–1486. doi: 10.1084/jem.149.6.1477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Goldberg G. I., Vanin E. F., Zrolka A. M., Blattner F. R. Sequence of the gene for the constant region of the mu chain of Balb/c mouse immunoglobulin. Gene. 1981 Oct;15(1):33–42. doi: 10.1016/0378-1119(81)90102-5. [DOI] [PubMed] [Google Scholar]
  20. Hang L., Slack J. H., Amundson C., Izui S., Theofilopoulos A. N., Dixon F. J. Induction of murine autoimmune disease by chronic polyclonal B cell activation. J Exp Med. 1983 Mar 1;157(3):874–883. doi: 10.1084/jem.157.3.874. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hunkapiller M. W., Hood L. E. Direct microsequence analysis of polypeptides using an improved sequenator, a nonprotein carrier (polybrene), and high pressure liquid chromatography. Biochemistry. 1978 May 30;17(11):2124–2133. doi: 10.1021/bi00604a016. [DOI] [PubMed] [Google Scholar]
  22. Imanishi T., Mäkelä O. Strain differences in the fine specificity of mouse anti-hapten antibodies. Eur J Immunol. 1973 Jun;3(6):323–330. doi: 10.1002/eji.1830030602. [DOI] [PubMed] [Google Scholar]
  23. Lazure C., Hum W. T., Gibson D. M. Sequence diversity within a subgroup of mouse immunoglobulin kappa chains controlled by the IgK-Ef2 locus. J Exp Med. 1981 Jul 1;154(1):146–155. doi: 10.1084/jem.154.1.146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Loh D. Y., Bothwell A. L., White-Scharf M. E., Imanishi-Kari T., Baltimore D. Molecular basis of a mouse strain-specific anti-hapten response. Cell. 1983 May;33(1):85–93. doi: 10.1016/0092-8674(83)90337-9. [DOI] [PubMed] [Google Scholar]
  25. Marion T. N., Lawton A. R., 3rd, Kearney J. F., Briles D. E. Anti-DNA autoantibodies in (NZB X NZW)F1 mice are clonally heterogeneous, but the majority share a common idiotype. J Immunol. 1982 Feb;128(2):668–674. [PubMed] [Google Scholar]
  26. Maxam A. M., Gilbert W. A new method for sequencing DNA. Proc Natl Acad Sci U S A. 1977 Feb;74(2):560–564. doi: 10.1073/pnas.74.2.560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Near R. I., Juszczak E. C., Huang S. Y., Sicari S. A., Margolies M. N., Gefter M. L. Expression and rearrangement of homologous immunoglobulin VH genes in two mouse strains. Proc Natl Acad Sci U S A. 1984 Apr;81(7):2167–2171. doi: 10.1073/pnas.81.7.2167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Novotnỳ J., Margolies M. N. Amino acid sequence of the light chain variable region from a mouse anti-digoxin hybridoma antibody. Biochemistry. 1983 Mar 1;22(5):1153–1158. doi: 10.1021/bi00274a025. [DOI] [PubMed] [Google Scholar]
  29. Okayama H., Berg P. A cDNA cloning vector that permits expression of cDNA inserts in mammalian cells. Mol Cell Biol. 1983 Feb;3(2):280–289. doi: 10.1128/mcb.3.2.280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Onodera T., Toniolo A., Ray U. R., Jenson A. B., Knazek R. A., Notkins A. L. Virus-induced diabetes mellitus. XX. Polyendocrinopathy and autoimmunity. J Exp Med. 1981 Jun 1;153(6):1457–1473. doi: 10.1084/jem.153.6.1457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Perlmutter R. M., Crews S. T., Douglas R., Sorensen G., Johnson N., Nivera N., Gearhart P. J., Hood L. The generation of diversity in phosphorylcholine-binding antibodies. Adv Immunol. 1984;35:1–37. doi: 10.1016/s0065-2776(08)60572-6. [DOI] [PubMed] [Google Scholar]
  32. Perlmutter R. M., Klotz J. L., Bond M. W., Nahm M., Davie J. M., Hood L. Multiple VH gene segments encode murine antistreptococcal antibodies. J Exp Med. 1984 Jan 1;159(1):179–192. doi: 10.1084/jem.159.1.179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Pisetsky D. S., Caster S. A., Roths J. B., Murphy E. D. Ipr gene control of the anti-DNA antibody response. J Immunol. 1982 May;128(5):2322–2325. [PubMed] [Google Scholar]
  34. Rauch J., Murphy E., Roths J. B., Stollar B. D., Schwartz R. S. A high frequency idiotypic marker of anti-DNA autoantibodies in MRL-Ipr/Ipr mice. J Immunol. 1982 Jul;129(1):236–241. [PubMed] [Google Scholar]
  35. Rauch J., Tannenbaum H., Stollar B. D., Schwartz R. S. Monoclonal anti-cardiolipin antibodies bind to DNA. Eur J Immunol. 1984 Jun;14(6):529–534. doi: 10.1002/eji.1830140609. [DOI] [PubMed] [Google Scholar]
  36. Schiff C., Corbet S., Milili M., Fougereau M. Interstrain conservation of the murine GAT-specific antibody V kappa repertoire as analyzed at the germline gene level. EMBO J. 1983;2(10):1771–1776. doi: 10.1002/j.1460-2075.1983.tb01656.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Seidman J. G., Edgell M. H., Leder P. Immunoglobulin light-chain structural gene sequences cloned in a bacterial plasmid. Nature. 1978 Feb 9;271(5645):582–585. doi: 10.1038/271582a0. [DOI] [PubMed] [Google Scholar]
  38. Theofilopoulos A. N., Balderas R. S., Hang L., Dixon F. J. Monoclonal IgM rheumatoid factors derived from arthritic MRL/Mp-lpr/lpr mice. J Exp Med. 1983 Sep 1;158(3):901–919. doi: 10.1084/jem.158.3.901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Tonegawa S. Somatic generation of antibody diversity. Nature. 1983 Apr 14;302(5909):575–581. doi: 10.1038/302575a0. [DOI] [PubMed] [Google Scholar]
  40. Tron F., Jacob L., Bach J. F. Murine monoclonal anti-DNA antibodies with an absolute specificity for DNA have a large amount of idiotypic diversity. Proc Natl Acad Sci U S A. 1983 Oct;80(19):6024–6027. doi: 10.1073/pnas.80.19.6024. [DOI] [PMC free article] [PubMed] [Google Scholar]

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