Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 Feb 1;181(2):453–461. doi: 10.1084/jem.181.2.453

Immunoglobulin epitope spreading and autoimmune disease after peptide immunization: Sm B/B'-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity

PMCID: PMC2191871  PMID: 7530756

Abstract

Autoantibodies from many patients with systemic lupus erythematosus bind the Sm autoantigen B/B' polypeptide. The binding of serial serum specimens to the 233 overlapping octapeptides of Sm B/B' have shown that of the B/B'-derived octapeptides, PPPGMRPP and PPPGIRGP are early targets of the autoimmune response in some lupus patients. Rabbits immunized with PPPGMRPP and PPPGIRGP develop antibodies which not only bind these octapeptides, but also subsequently bind many other octapeptides of Sm B/B'. Eventually, the rabbits immunized with one octapeptide develop autoantibodies that bind other spliceosomal proteins including D, 70K, A, and C. Any mechanisms that operate to maintain tolerance or anergy for the spliceosome are thus overcome. Features considered typical of human systemic lupus erythematosus are also found in these peptide-immunized animals, such as antinuclear antibodies, anti-Sm precipitins, anti-double-stranded DNA, thrombocytopenia, seizures, and proteinuria. This disease model provides access to a mechanism for the development of humoral autoimmunity and may provide a basis to explain the immunopathogenesis of lupus in humans.

Full Text

The Full Text of this article is available as a PDF (1.6 MB).

Selected References

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

  1. Aarden L. A., de Groot E. R., Feltkamp T. E. Immunology of DNA. III. Crithidia luciliae, a simple substrate for the determination of anti-dsDNA with the immunofluorescence technique. Ann N Y Acad Sci. 1975 Jun 30;254:505–515. doi: 10.1111/j.1749-6632.1975.tb29197.x. [DOI] [PubMed] [Google Scholar]
  2. Axén R., Porath J., Ernback S. Chemical coupling of peptides and proteins to polysaccharides by means of cyanogen halides. Nature. 1967 Jun 24;214(5095):1302–1304. doi: 10.1038/2141302a0. [DOI] [PubMed] [Google Scholar]
  3. Bardana E. J., Jr, Malinow M. R., Houghton D. C., McNulty W. P., Wuepper K. D., Parker F., Pirofsky B. Diet-induced systemic lupus erythematosus (SLE) in primates. Am J Kidney Dis. 1982 May;1(6):345–352. doi: 10.1016/s0272-6386(82)80005-x. [DOI] [PubMed] [Google Scholar]
  4. Fisher D. E., Reeves W. H., Wisniewolski R., Lahita R. G., Chiorazzi N. Temporal shifts from Sm to ribonucleoprotein reactivity in systemic lupus erythematosus. Arthritis Rheum. 1985 Dec;28(12):1348–1355. doi: 10.1002/art.1780281206. [DOI] [PubMed] [Google Scholar]
  5. Forman M. S., Nakamura M., Mimori T., Gelpi C., Hardin J. A. Detection of antibodies to small nuclear ribonucleoproteins and small cytoplasmic ribonucleoproteins using unlabeled cell extracts. Arthritis Rheum. 1985 Dec;28(12):1356–1361. doi: 10.1002/art.1780281207. [DOI] [PubMed] [Google Scholar]
  6. Gleichmann E., Van Elven E. H., Van der Veen J. P. A systemic lupus erythematosus (SLE)-like disease in mice induced by abnormal T-B cell cooperation. Preferential formation of autoantibodies characteristic of SLE. Eur J Immunol. 1982 Feb;12(2):152–159. doi: 10.1002/eji.1830120210. [DOI] [PubMed] [Google Scholar]
  7. Gonzalez E. N., Rothfield N. F. Immunoglobulin class and pattern of nuclear fluorescence in systemic lupus erythematosus. N Engl J Med. 1966 Jun 16;274(24):1333–1338. doi: 10.1056/NEJM196606162742401. [DOI] [PubMed] [Google Scholar]
  8. Hinterberger M., Pettersson I., Steitz J. A. Isolation of small nuclear ribonucleoproteins containing U1, U2, U4, U5, and U6 RNAs. J Biol Chem. 1983 Feb 25;258(4):2604–2613. [PubMed] [Google Scholar]
  9. James J. A., Dickey W. D., Fujisaku A., O'Brien C. A., Deutscher S. L., Keene J. D., Harley J. B. Antigenicity of a recombinant Ro (SS-A) fusion protein. Arthritis Rheum. 1990 Jan;33(1):102–106. doi: 10.1002/art.1780330114. [DOI] [PubMed] [Google Scholar]
  10. James J. A., Harley J. B. Linear epitope mapping of an Sm B/B' polypeptide. J Immunol. 1992 Apr 1;148(7):2074–2079. [PubMed] [Google Scholar]
  11. James J. A., Scofield R. H., Harley J. B. Basic amino acids predominate in the sequential autoantigenic determinants of the small nuclear 70K ribonucleoprotein. Scand J Immunol. 1994 Jun;39(6):557–566. doi: 10.1111/j.1365-3083.1994.tb03413.x. [DOI] [PubMed] [Google Scholar]
  12. Lehmann P. V., Forsthuber T., Miller A., Sercarz E. E. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature. 1992 Jul 9;358(6382):155–157. doi: 10.1038/358155a0. [DOI] [PubMed] [Google Scholar]
  13. Lin R. H., Mamula M. J., Hardin J. A., Janeway C. A., Jr Induction of autoreactive B cells allows priming of autoreactive T cells. J Exp Med. 1991 Jun 1;173(6):1433–1439. doi: 10.1084/jem.173.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Maddison P. J., Reichlin M. Quantitation of precipitating antibodies to certain soluble nuclear antigens in SLE. Arthritis Rheum. 1977 Apr;20(3):819–824. doi: 10.1002/art.1780200310. [DOI] [PubMed] [Google Scholar]
  15. Malinow M. R., Bardana E. J., Jr, Pirofsky B., Craig S., McLaughlin P. Systemic lupus erythematosus-like syndrome in monkeys fed alfalfa sprouts: role of a nonprotein amino acid. Science. 1982 Apr 23;216(4544):415–417. doi: 10.1126/science.7071589. [DOI] [PubMed] [Google Scholar]
  16. Mamula M. J., Janeway C. A., Jr Do B cells drive the diversification of immune responses? Immunol Today. 1993 Apr;14(4):151–154. doi: 10.1016/0167-5699(93)90274-O. [DOI] [PubMed] [Google Scholar]
  17. Mattioli M., Reichlin M. Characterization of a soluble nuclear ribonucleoprotein antigen reactive with SLE sera. J Immunol. 1971 Nov;107(5):1281–1290. [PubMed] [Google Scholar]
  18. Oldstone M. B., Nerenberg M., Southern P., Price J., Lewicki H. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell. 1991 Apr 19;65(2):319–331. doi: 10.1016/0092-8674(91)90165-u. [DOI] [PubMed] [Google Scholar]
  19. Oldstone M. B. Overview: infectious agents as etiologic triggers of autoimmune disease. Curr Top Microbiol Immunol. 1989;145:1–3. doi: 10.1007/978-3-642-74594-2_1. [DOI] [PubMed] [Google Scholar]
  20. Scofield R. H., Harley J. B. Autoantigenicity of Ro/SSA antigen is related to a nucleocapsid protein of vesicular stomatitis virus. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3343–3347. doi: 10.1073/pnas.88.8.3343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Tam J. P. Synthetic peptide vaccine design: synthesis and properties of a high-density multiple antigenic peptide system. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5409–5413. doi: 10.1073/pnas.85.15.5409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Tan E. M., Cohen A. S., Fries J. F., Masi A. T., McShane D. J., Rothfield N. F., Schaller J. G., Talal N., Winchester R. J. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982 Nov;25(11):1271–1277. doi: 10.1002/art.1780251101. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES