Skip to main content
SpringerLink
Log in

Structural properties of a subset of nephritogenic anti-DNA antibodies

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Structural analysis of lupus autoantibodies is beginning to provide clues to the molecular basis for antigenic specificity and pathogenicity. The present analysis indicates that multiple light and heavy chains contain residues which can facilitate DNA binding, reaffirming the notion that there are multiple ways that different amino acids combine to form an antigen-binding pocket with affinity for dsDNA and ssDNA. Furthermore, this analysis suggests that these conformations and contact residues are intrinsic to germline sequences, although amino acid changes at critical locations (somatically introduced) modulate antigen binding, and appear to influence the capacity of individual immunoglobulin to form immune deposits. Analysis of additional individual immunoglobulins with closely related V-region sequences and differing pathogenic properties will be required to resolve the contribution of specific motifs to pathogenecity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Chien NC, Roberts VA, Giusti AM, Scharff MD, Getzoff ED: Significant structural and functional change of an antigen-binding site by a distant amino acid substitution: Proposal of a structural mechanism. Proc Natl Acad Sci USA 1989;86: 5532–5536.

    Article  PubMed  CAS  Google Scholar 

  2. Chothia C, Lesk AM, Gherardi E, Tomlinson IM, Walter G, Marks JD, Llewelyn MB, Winter G: Structural repertoire of the human VH segments. J Mol Biol 1992;227:799–817.

    Article  PubMed  CAS  Google Scholar 

  3. Kabat EA, Wu TT: Identical V region amino acid sequences and segments of sequences in antibodies of different specificities. Relative contributions of VH and VL genes, minigenes, and complementarity-determining regions to binding of antibody-combining sites. J Immunol 1991;147:1709–1719.

    PubMed  CAS  Google Scholar 

  4. Radic MZ, Mascelli MA, Erikson J, Shan H, Weigert M: IgH and L chain contributions to autoimmune specificities. J Immunol 1991;146: 176–182.

    PubMed  CAS  Google Scholar 

  5. Paul E, Manheimer LA, Livneh A, Solomon A, Aranow C, Ghossein C, Shefner R, Offen D, Pillinger M, Diamond B: Pathogenic anti-DNA antibodies in SLE: Idiotypic families and genetic origins. Int Rev Immunol 1990;5:295–313.

    Article  PubMed  CAS  Google Scholar 

  6. Radic MZ, Mackle J, Erikson J, Mol C, Anderson WF, Weigert M: Residues that mediate DNA binding of autoimmune antibodies. J Immunol 1993;150:4966.

    PubMed  CAS  Google Scholar 

  7. Davidson A, Smith A, Katz J, Preud'Homme JL, Solomon A, Diamond B: A cross-reactive idiotype on anti-DNA antibodies defines a H chain determinant present almost exclusively on IgG antibodies. J Immunol 1989;143:174–180.

    PubMed  CAS  Google Scholar 

  8. Gaither KK, Harley JB: A shared idiotype among human anti-Ro/SSA autoantibodies. J Exp Med 1989; 169:1583–1588.

    Article  PubMed  CAS  Google Scholar 

  9. Gavalchin J, Seder RA, Datta SK: The NZBxSWR model of lupus nephritis. I. Cross-reactive idiotypes of monoclonal anti-DNA antibodies in relation to antigenic specificity, charge, and allotype. Identification of interconnected idiotype families inherited from the normal SWR and the autoimmune NZB parents. J Immunol 1987;138:128–137.

    PubMed  CAS  Google Scholar 

  10. Monestier M, Manheimer-Lory A, Bellon B, Painter C, Dang H, Talal N, Zanetti M, Schwartz RS, Pisetsky D, Kuppers R, Rose N, Brochier J, Klareskog L, Holmdahl R, Erlanger B, Alt F, Bona C: Shared idiotopes and restricted immunoglobulin variable region heavy chain genes characterize murine autoantibodies of various specificities. J Clin Invest 1986;78:753–759.

    Article  PubMed  CAS  Google Scholar 

  11. Schwartz R, Stollar B: Origins of anti-DNA antibodies. J Clin Invest 1985;75:321–327.

    Article  PubMed  CAS  Google Scholar 

  12. Couser WG: Mediation of immune glomerular injury. J Am Soc Nephrol 1990;1:13–29.

    PubMed  CAS  Google Scholar 

  13. van Es JH, Gmelig-Meyling FH, van de Akker WR, Aanstoot H, Derksen RH, 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;173:461–470.

    Article  PubMed  Google Scholar 

  14. Foster MH, Cizman B, Madaio MP: Biology of disease. Nephritogenic autoantibodies in systemic lupus erythematosus: Immunochemical properties, mechanisms of immune deposition and genetic origins. Lab Invest 1993;69:494–503.

    PubMed  CAS  Google Scholar 

  15. Vlahakos DV, Foster MH, Ucci AA, Barrett KJ, Datta SK, Madaio MP: Murine monoclonal anti-DNA antibodies penetrate cells, bind to nuclei and induce glomerular proliferation and proteinuria in vivo. J Am Soc Nephrol 1992;2:1345–1354.

    PubMed  CAS  Google Scholar 

  16. Katz MS, Foster MH, Madaio MP: Independently derived murine glomerular immune deposit forming anti-DNA antibodies are encoded by near identical VH gene sequences. J Clin Invest 1993;91:402–408.

    Article  PubMed  CAS  Google Scholar 

  17. Herron JN, He XM, Ballard DW, Blier EJ, Pace PE, Rothwell AL, Voss EJ, Edmunson AB: An autoantibody to single-stranded DNA: Comparison of the three-dimensional structures of the unliganded Fab and a deoxynucleotide-Fab complex. Proteins 1991;11:159–175.

    Article  PubMed  CAS  Google Scholar 

  18. Bernstein FC, Koetzle TF, Williams GJB, Meyer EF Jr, Brice MD, Rodgers JR, Kennard O, Shimanouchi T, Tasumi M: The protein data-bank: A computer-based archival file for macromolecular structure. J Mol Biol 1977;112:535–542.

    Article  PubMed  CAS  Google Scholar 

  19. Kieber-Emmons T, Getzof E, Kohler H: Perspectives on idiotypes and antigenicity. Int Rev Immunol 1987;2:339–356.

    Article  PubMed  CAS  Google Scholar 

  20. Kieber-Emmons T, Williams WV, Greene MI: Antireceptor antibody structure and peptide design; in Epenetos AA (ed): Monoclonal Antibodies: Applications in Clinical Oncology. New York, Chapman & Hall, 1992, pp 53–63.

    Google Scholar 

  21. Williams W, Guy H, Rubin D, Robey F, Myers J, Kieber-Emmons T, Weiner D, Greene M: Sequences of the cell-attachment sites of reovirus type 3 and its anti-idiotypic/antireceptor antibody: Modelling of their three-dimensional structures. Proc Natl Acad Sci USA 1988;85:6488–6492.

    Article  PubMed  CAS  Google Scholar 

  22. Williams W, Moss D, Kieber-Emmons T, Cohen J, Myers J, Weiner D, Greene M: Development of biologically active peptides based on antibody structure. Proc Natl Acad Sci USA 1989;86:5537–5541.

    Article  PubMed  CAS  Google Scholar 

  23. Williams W, Kieber-Emmons T, Weiner D, Rubin D, Greene M: Contact residues and predicted structure of the reovirus type 3-receptor interaction. J Biol Chem 1991;266:9241–9250.

    PubMed  CAS  Google Scholar 

  24. Williams W, Kieber-Emmons T, VonFeldt J, Weiner D: Cyclic bioactive peptides derived from antibody hypervariable loop structures. J Biol Chem 1991;266:5182–5190.

    PubMed  CAS  Google Scholar 

  25. Tomiyama Y, Brojer E, Ruggeri ZM, Shattil SJ, Smiltneck J, Gorski J, Kumar A, Kieber-Emmons T, Kunicki TJ: A molecular model of RGD ligands. Antibody D gene segments that direct specificity for the integrin alpha IIb beta 3. J Biol Chem 1992;267:18085–18095.

    PubMed  CAS  Google Scholar 

  26. Karp SL, Kieber-Emmons T, Sun MJ, Wolf G, Neilson EG: Molecular structure of a cross-reactive idiotype on autoantibodies recognizing parenchymal self. J Immunol 1993; 150:867–879.

    PubMed  CAS  Google Scholar 

  27. Jones TA, Thirup S: Using known substructures in protein model building and crystallography. EMBO J 1986;5:819–822.

    PubMed  CAS  Google Scholar 

  28. Eilat D, Webster DM, Rees AR: V region sequences of anti-DNA and anti-RNA autoantibodies from NZB/NZW F1 mice. J Immunol 1988;141:1745–1753.

    PubMed  CAS  Google Scholar 

  29. Tsao BP, Ebling FM, Roman C, Panosian SN, Calame K, Hahn BH: Structural characteristics of the variable regions of immunoglobulin genes encoding a pathogenic autoantibody in murine lupus. J Clin Invest 1990;85:530–540.

    Article  PubMed  CAS  Google Scholar 

  30. Foster MH, Kieber-Emmons T, Madaio MP: Basic pentapeptides in the primary structure of anti-DNA antibodies: A potential mechanism of nuclear localization. Immunol Res 13:186–206.

  31. Gangemi RMR, Singh AK, Barrett KJ: Independently derived IgG anti-DNA autoantibodies from two lupus-prone mouse strains express a VH gene that is not present in most murine strains. J Immunol 1993; 151:4660–4671.

    PubMed  CAS  Google Scholar 

  32. Kieber-Emmons T, Kohler H: Towards a unified theory of immunoglobulin structure-function relations. Immunol Rev 1986;90:29–48.

    Article  PubMed  CAS  Google Scholar 

  33. Foster M, Madaio M, Barrett K: Variable region sequence analysis of anti-DNA antibodies: Evidence for a family of closely related germ-line VH genes encoding lupus autoantibodies. DNA Cell Biol 1992;11:92.

    Google Scholar 

  34. Trepicchio W Jr, Maruya A, Barrett KJ: The heavy chain genes of a lupus anti-DNA autoantibody are encoded in the germ line of a nonautoimmune strain of mouse and conserved in strains of mice polymorphic for this gene locus. J. Immunol 1987;139:3139–3145.

    PubMed  CAS  Google Scholar 

  35. Chothia C, Lesk AM, Tramontano A, Levitt M, Smith-Gill SJ, Air G, Sheriff S, Padlan EA, Davies D, Tulip WR, et al: Conformations of immunoglobulin hypervariable regions (see comments). Nature 1989;342: 877–883.

    Article  PubMed  CAS  Google Scholar 

  36. Lohman KL, Kieber-Emmons T, Kennedy RC: Molecular characterization and structural modeling of immunoglobulin variable regions from murine monoclonal antibodies specific for hepatitis B virus surface antigens. Mol Immunol 1993;30: 1295–1306.

    Article  PubMed  CAS  Google Scholar 

  37. Kieber-Emmons T, Von Feldt JM, Godillot PA, McCallus D, Weiner DB, Williams WV: Isolated VH4 heavy chain variable regions bind DNA. Characterization of a recombinant antibody heavy chain library derived from patient(s) with active SLE. Lupus 1994;3:379–392.

    Article  PubMed  CAS  Google Scholar 

  38. Kabat EA, Wu TT, Perry HM, Gottesman KS, Foeller C: Sequences of proteins of immunological interest. Bethesda, US Department of Health and Human Services, 1991, p. 2597.

    Google Scholar 

  39. O'Keefe TL, Datta SK, Imanishi KT: Cationic residues in pathogenic anti-DNA autoantibodies arise by mutations of a germ-line gene that belongs to a large VH gene subfamily. Eur J Immunol 1992;22:619–624.

    Article  PubMed  Google Scholar 

  40. Diamond B, Scharff MD: Somatic mutation of the T15 heavy chain gives rise to an antibody with autoantibody specificity. Proc Natl Acad Sci USA 1984;81:5841–5844.

    Article  PubMed  CAS  Google Scholar 

  41. Manheimer LA, Katz JB, Pillinger M, Ghossein C, Smith A, Diamond B: Molecular characteristics of antibodies bearing an anti-DNA-associated idiotype. J Exp Med 1991;174: 1639–1652. Published erratum appears in J Exp Med 1992;176:309.

    Article  Google Scholar 

  42. Smith-Gill SJ, Mainhart CR, Lavoie TB, Rudikoff S, Potter M: VL-VH expression by monoclonal antibodies recognizing avian lysozyme. J Immunol 1984;132:963–967.

    PubMed  CAS  Google Scholar 

  43. Schiff C, Milili M, Fougereau M: Functional and pseudogenes are similarly organized and may equally contribute to the extensive antibody diversity of the IgVHII family. EMBO J 1985;4:1225–1230.

    PubMed  CAS  Google Scholar 

  44. Kofler R, Strohal R, Balderas RS, Johnson ME, Noonan DJ, Duchosal MA, Dixon FJ, Theofilopoulos AN: Immunoglobulin κ light chain variable region gene complex organization and immunoglobulin genes encoding anti-DNA autoantibodies in lupus mice. J Clin Invest 1988;82: 852–860.

    Article  PubMed  CAS  Google Scholar 

  45. Singh AK, Gangemi RMR: The role of VL gene structural determinants in the fine specificity of anti-DNA antibodies. Autoimmunity 1994;16: in press.

  46. Eilat D, Hochberg M, Tron F, Jacob L, Bach JF: The VH gene sequences of anti-DNA antibodies in two different strains of lupus-prone mice are highly related. Eur J Immunol 1989;19:1241–1246.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Wistar Institute of Biology and Anatomy, University of Pennsylvania, Philadelphia, Pa., USA

    Thomas Kieber-Emmons

  2. Penn Center for Molecular Studies of Kidney Disease and Renal-Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pa., USA

    Mary H. Foster & Michael P. Madaio

  3. Department of Medicine, Rheumatology Division, University of Pennsylvania, Philadelphia, Pa., USA

    William V. Williams

  4. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 19104-6082, Philadelphia, Pa., (USA)

    Thomas Kieber-Emmons

Authors
  1. Thomas Kieber-Emmons
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mary H. Foster
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William V. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael P. Madaio
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kieber-Emmons, T., Foster, M.H., Williams, W.V. et al. Structural properties of a subset of nephritogenic anti-DNA antibodies. Immunol Res 13, 172–185 (1994). https://doi.org/10.1007/BF02918278

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02918278

Key Words

Search

Navigation