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. 1992 Dec 1;89(23):11179–11183. doi: 10.1073/pnas.89.23.11179

Identification of a pathogenic epitope involved in initiation of Heymann nephritis.

D Kerjaschki 1, R Ullrich 1, K Diem 1, S Pietromonaco 1, R A Orlando 1, M G Farquhar 1
PMCID: PMC50513  PMID: 1280820

Abstract

Heymann nephritis is an experimental autoimmune disease model for human membranous nephropathy. We have recently identified a pathogenic epitope, clone 14 (C14), responsible for formation and deposition of glomerular immune complexes that is contained within the small subunit of the Heymann nephritis antigenic complex (HNAC). HNAC is a heterodimer composed of a large subunit designated gp330 and a smaller (44 kDa) subunit, which is immunologically identical to the receptor-associated protein. In this study, we prepared antibodies to fusion proteins with C-terminal deletions in the C14 sequence and assessed their ability to promote formation of immune deposits (IDs). When IgG specific for the shortest truncated fusion protein (C14/delta 3; 86 amino acids) was injected into rats, small IDs developed. In contrast, when IgG raised against the full-length C14 sequence was depleted of its reactivity toward the C14/delta 3 fusion protein (C14/delta 3-fp), no IDs could be detected. These data indicate that at least one pathogenic epitope is contained within the N-terminal 86 amino acids of C14. Since the IDs induced with the C14/delta 3-fp-specific IgG are smaller than those induced with the poly-epitope-specific anti-gp330 antibodies, it is likely that other epitopes in addition to those expressed by the C14/delta 3-fp are required for formation and growth of immune complexes.

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Selected References

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

  1. Amit A. G., Mariuzza R. A., Phillips S. E., Poljak R. J. Three-dimensional structure of an antigen-antibody complex at 2.8 A resolution. Science. 1986 Aug 15;233(4765):747–753. doi: 10.1126/science.2426778. [DOI] [PubMed] [Google Scholar]
  2. Furukawa T., Ozawa M., Huang R. P., Muramatsu T. A heparin binding protein whose expression increases during differentiation of embryonal carcinoma cells to parietal endoderm cells: cDNA cloning and sequence analysis. J Biochem. 1990 Aug;108(2):297–302. doi: 10.1093/oxfordjournals.jbchem.a123197. [DOI] [PubMed] [Google Scholar]
  3. Hashim G. A., Day E. D. Role of antibodies in T cell-mediated experimental allergic encephalomyelitis. J Neurosci Res. 1988 Sep;21(1):1–5. doi: 10.1002/jnr.490210102. [DOI] [PubMed] [Google Scholar]
  4. Henikoff S. Unidirectional digestion with exonuclease III in DNA sequence analysis. Methods Enzymol. 1987;155:156–165. doi: 10.1016/0076-6879(87)55014-5. [DOI] [PubMed] [Google Scholar]
  5. Kerjaschki D., Farquhar M. G. Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats. J Exp Med. 1983 Feb 1;157(2):667–686. doi: 10.1084/jem.157.2.667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Kerjaschki D., Farquhar M. G. The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. Proc Natl Acad Sci U S A. 1982 Sep;79(18):5557–5561. doi: 10.1073/pnas.79.18.5557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Kerjaschki D., Miettinen A., Farquhar M. G. Initial events in the formation of immune deposits in passive Heymann nephritis. gp330-anti-gp330 immune complexes form in epithelial coated pits and rapidly become attached to the glomerular basement membrane. J Exp Med. 1987 Jul 1;166(1):109–128. doi: 10.1084/jem.166.1.109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kounnas M. Z., Morris R. E., Thompson M. R., FitzGerald D. J., Strickland D. K., Saelinger C. B. The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A. J Biol Chem. 1992 Jun 25;267(18):12420–12423. [PubMed] [Google Scholar]
  9. Kristensen T., Moestrup S. K., Gliemann J., Bendtsen L., Sand O., Sottrup-Jensen L. Evidence that the newly cloned low-density-lipoprotein receptor related protein (LRP) is the alpha 2-macroglobulin receptor. FEBS Lett. 1990 Dec 10;276(1-2):151–155. doi: 10.1016/0014-5793(90)80530-v. [DOI] [PubMed] [Google Scholar]
  10. Kumar V., Urban J. L., Horvath S. J., Hood L. Amino acid variations at a single residue in an autoimmune peptide profoundly affect its properties: T-cell activation, major histocompatibility complex binding, and ability to block experimental allergic encephalomyelitis. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1337–1341. doi: 10.1073/pnas.87.4.1337. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  11. Orlando R. A., Kerjaschki D., Kurihara H., Biemesderfer D., Farquhar M. G. gp330 associates with a 44-kDa protein in the rat kidney to form the Heymann nephritis antigenic complex. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6698–6702. doi: 10.1073/pnas.89.15.6698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Padlan E. A., Silverton E. W., Sheriff S., Cohen G. H., Smith-Gill S. J., Davies D. R. Structure of an antibody-antigen complex: crystal structure of the HyHEL-10 Fab-lysozyme complex. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5938–5942. doi: 10.1073/pnas.86.15.5938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Pietromonaco S., Kerjaschki D., Binder S., Ullrich R., Farquhar M. G. Molecular cloning of a cDNA encoding a major pathogenic domain of the Heymann nephritis antigen gp330. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1811–1815. doi: 10.1073/pnas.87.5.1811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Raychowdhury R., Niles J. L., McCluskey R. T., Smith J. A. Autoimmune target in Heymann nephritis is a glycoprotein with homology to the LDL receptor. Science. 1989 Jun 9;244(4909):1163–1165. doi: 10.1126/science.2786251. [DOI] [PubMed] [Google Scholar]
  15. Roberge F. G., Lorberboum-Galski H., Le Hoang P., de Smet M., Chan C. C., Fitzgerald D., Pastan I. Selective immunosuppression of activated T cells with the chimeric toxin IL-2-PE40. Inhibition of experimental autoimmune uveoretinitis. J Immunol. 1989 Dec 1;143(11):3498–3502. [PubMed] [Google Scholar]
  16. Sheriff S., Silverton E. W., Padlan E. A., Cohen G. H., Smith-Gill S. J., Finzel B. C., Davies D. R. Three-dimensional structure of an antibody-antigen complex. Proc Natl Acad Sci U S A. 1987 Nov;84(22):8075–8079. doi: 10.1073/pnas.84.22.8075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Smilek D. E., Lock C. B., McDevitt H. O. Antigen recognition and peptide-mediated immunotherapy in autoimmune disease. Immunol Rev. 1990 Dec;118:37–71. doi: 10.1111/j.1600-065x.1990.tb00813.x. [DOI] [PubMed] [Google Scholar]
  18. Steinman L. The development of rational strategies for selective immunotherapy against autoimmune demyelinating disease. Adv Immunol. 1991;49:357–379. doi: 10.1016/s0065-2776(08)60779-8. [DOI] [PubMed] [Google Scholar]
  19. Strickland D. K., Ashcom J. D., Williams S., Burgess W. H., Migliorini M., Argraves W. S. Sequence identity between the alpha 2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. J Biol Chem. 1990 Oct 15;265(29):17401–17404. [PubMed] [Google Scholar]
  20. Talal N. The goals of immunologic intervention in autoimmune disease. J Autoimmun. 1989 Jun;2 (Suppl):257–264. doi: 10.1016/0896-8411(89)90138-8. [DOI] [PubMed] [Google Scholar]
  21. Thurau S. R., Chan C. C., Suh E., Nussenblatt R. B. Induction of oral tolerance to S-antigen induced experimental autoimmune uveitis by a uveitogenic 20mer peptide. J Autoimmun. 1991 Jun;4(3):507–516. doi: 10.1016/0896-8411(91)90162-6. [DOI] [PubMed] [Google Scholar]
  22. Tulip W. R., Varghese J. N., Webster R. G., Air G. M., Laver W. G., Colman P. M. Crystal structures of neuraminidase-antibody complexes. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 1):257–263. doi: 10.1101/sqb.1989.054.01.032. [DOI] [PubMed] [Google Scholar]
  23. Tzartos S. J., Kokla A., Walgrave S. L., Conti-Tronconi B. M. Localization of the main immunogenic region of human muscle acetylcholine receptor to residues 67-76 of the alpha subunit. Proc Natl Acad Sci U S A. 1988 May;85(9):2899–2903. doi: 10.1073/pnas.85.9.2899. [DOI] [PMC free article] [PubMed] [Google Scholar]

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