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. 1996 Jun 1;97(11):2619–2626. doi: 10.1172/JCI118711

Distinctive immune response patterns of human and murine autoimmune sera to U1 small nuclear ribonucleoprotein C protein.

M Satoh 1, J J Langdon 1, K J Hamilton 1, H B Richards 1, D Panka 1, R A Eisenberg 1, W H Reeves 1
PMCID: PMC507349  PMID: 8647956

Abstract

The Ul small nuclear ribonucleoprotein (snRNP), a complex of nine proteins with Ul RNA, is a frequent target of autoantibodies in human and murine systemic lupus erythematosus (SLE). Anti-Sm antibodies recognizing the B'/B, D, E, F, and G proteins of Ul snRNPs are highly specific for SLE, and are nearly always accompanied by anti-nRNP antibodies recognizing the Ul snRNP-specific 70K, A, and/or C proteins. Previous studies suggest that human anti-nRNP antibodies recognize primarily the U1-70K and Ul-A proteins, whereas recognition of Ul-C is less frequent. We report here that autoantibodies to U1-C are more common in human autoimmune sera than believed previously. Using a novel immunoprecipitation technique to detect autoantibodies to native Ul-C, 75/78 human sera with anti-nRNP/ Sm antibodies were anti-Ul-C (+). In striking contrast, only 1/65 anti-nRNP/Sm (+) MRL mouse sera of various Igh allotypes was positive. Two of ten anti-nRNP/Sm (+) sera from BALB/c mice with a lupus-like syndrome induced by pristane recognized Ul-C. Thus, lupus in MRL mice was characterized by a markedly lower frequency of anti-U1-C antibodies than seen in human SLE or pristane-induced lupus. The results may indicate different pathways of intermolecular-intrastructural diversification of autoantibody responses to the components of Ul snRNPs in human and murine lupus, possibly mediated by alterations in antigen processing induced by the autoantibodies themselves.

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Selected References

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  1. Billings P. B., Allen R. W., Jensen F. C., Hoch S. O. Anti-RNP monoclonal antibodies derived from a mouse strain with lupus-like autoimmunity. J Immunol. 1982 Mar;128(3):1176–1180. [PubMed] [Google Scholar]
  2. Bloom D. D., Davignon J. L., Retter M. W., Shlomchik M. J., Pisetsky D. S., Cohen P. L., Eisenberg R. A., Clarke S. H. V region gene analysis of anti-Sm hybridomas from MRL/Mp-lpr/lpr mice. J Immunol. 1993 Feb 15;150(4):1591–1610. [PubMed] [Google Scholar]
  3. Bohan A., Peter J. B. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975 Feb 13;292(7):344–347. doi: 10.1056/NEJM197502132920706. [DOI] [PubMed] [Google Scholar]
  4. Combe B., Rucheton M., Graafland H., Lussiez V., Brunel C., Sany J. Clinical significance of anti-RNP and anti-Sm autoantibodies as determined by immunoblotting and immunoprecipitation in sera from patients with connective tissue diseases. Clin Exp Immunol. 1989 Jan;75(1):18–24. [PMC free article] [PubMed] [Google Scholar]
  5. Craft J. Antibodies to snRNPs in systemic lupus erythematosus. Rheum Dis Clin North Am. 1992 May;18(2):311–335. [PubMed] [Google Scholar]
  6. Eisenberg R. A., Tan E. M., Dixon F. J. Presence of anti-Sm reactivity in autoimmune mouse strains. J Exp Med. 1978 Feb 1;147(2):582–587. doi: 10.1084/jem.147.2.582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fatenejad S., Brooks W., Schwartz A., Craft J. Pattern of anti-small nuclear ribonucleoprotein antibodies in MRL/Mp-lpr/lpr mice suggests that the intact U1 snRNP particle is their autoimmunogenic target. J Immunol. 1994 Jun 1;152(11):5523–5531. [PubMed] [Google Scholar]
  8. Fatenejad S., Mamula M. J., Craft J. Role of intermolecular/intrastructural B- and T-cell determinants in the diversification of autoantibodies to ribonucleoprotein particles. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):12010–12014. doi: 10.1073/pnas.90.24.12010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fisher D. E., Conner G. E., Reeves W. H., Wisniewolski R., Blobel G. Small nuclear ribonucleoprotein particle assembly in vivo: demonstration of a 6S RNA-free core precursor and posttranslational modification. Cell. 1985 Oct;42(3):751–758. doi: 10.1016/0092-8674(85)90271-5. [DOI] [PubMed] [Google Scholar]
  10. Fisher D. E., Reeves W. H., Conner G. E., Blobel G., Kunkel H. G. Pulse labeling of small nuclear ribonucleoproteins in vivo reveals distinct patterns of antigen recognition by human autoimmune antibodies. Proc Natl Acad Sci U S A. 1984 May;81(10):3185–3189. doi: 10.1073/pnas.81.10.3185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Francoeur A. M. Anti-SM and anti-U1-RNP lupus antibody fine specificities. J Clin Immunol. 1989 May;9(3):256–263. doi: 10.1007/BF00916822. [DOI] [PubMed] [Google Scholar]
  12. Habets W. J., Hoet M. H., De Jong B. A., Van der Kemp A., Van Venrooij W. J. Mapping of B cell epitopes on small nuclear ribonucleoproteins that react with human autoantibodies as well as with experimentally-induced mouse monoclonal antibodies. J Immunol. 1989 Oct 15;143(8):2560–2566. [PubMed] [Google Scholar]
  13. Habets W. J., Hoet M. H., van Venrooij W. J. Epitope patterns of anti-RNP antibodies in rheumatic diseases. Evidence for an antigen-driven autoimmune response. Arthritis Rheum. 1990 Jun;33(6):834–841. doi: 10.1002/art.1780330610. [DOI] [PubMed] [Google Scholar]
  14. Habets W. J., Sillekens P. T., Hoet M. H., McAllister G., Lerner M. R., van Venrooij W. J. Small nuclear RNA-associated proteins are immunologically related as revealed by mapping of autoimmune reactive B-cell epitopes. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4674–4678. doi: 10.1073/pnas.86.12.4674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Habets W., Hoet M., Bringmann P., Lührmann R., van Venrooij W. Autoantibodies to ribonucleoprotein particles containing U2 small nuclear RNA. EMBO J. 1985 Jun;4(6):1545–1550. doi: 10.1002/j.1460-2075.1985.tb03815.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Halpern M. D., Craven S. Y., Cohen P. L., Eisenberg R. A. Regulation of anti-Sm autoantibodies by the immunoglobulin heavy chain locus. J Immunol. 1993 Dec 15;151(12):7268–7272. [PubMed] [Google Scholar]
  17. Halpern M. D., Fisher C. L., Cohen P. L., Eisenberg R. A. Influence of the Ig H chain locus on autoantibody production in autoimmune mice. J Immunol. 1992 Dec 1;149(11):3735–3740. [PubMed] [Google Scholar]
  18. Homma M., Tojo T., Akizuki M., Yamagata H. Criteria for Sjögren's syndrome in Japan. Scand J Rheumatol Suppl. 1986;61:26–27. [PubMed] [Google Scholar]
  19. Hultman P., Eneström S., Pollard K. M., Tan E. M. Anti-fibrillarin autoantibodies in mercury-treated mice. Clin Exp Immunol. 1989 Dec;78(3):470–477. [PMC free article] [PubMed] [Google Scholar]
  20. James J. A., Gross T., Scofield R. H., Harley J. B. Immunoglobulin epitope spreading and autoimmune disease after peptide immunization: Sm B/B'-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity. J Exp Med. 1995 Feb 1;181(2):453–461. doi: 10.1084/jem.181.2.453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lerner E. A., Lerner M. R., Janeway C. A., Jr, Steitz J. A. Monoclonal antibodies to nucleic acid-containing cellular constituents: probes for molecular biology and autoimmune disease. Proc Natl Acad Sci U S A. 1981 May;78(5):2737–2741. doi: 10.1073/pnas.78.5.2737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lerner M. R., Steitz J. A. Antibodies to small nuclear RNAs complexed with proteins are produced by patients with systemic lupus erythematosus. Proc Natl Acad Sci U S A. 1979 Nov;76(11):5495–5499. doi: 10.1073/pnas.76.11.5495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lundberg I., Nyman U., Pettersson I., Hedfors E. Clinical manifestations and anti-(U1)snRNP antibodies: a prospective study of 29 anti-RNP antibody positive patients. Br J Rheumatol. 1992 Dec;31(12):811–817. doi: 10.1093/rheumatology/31.12.811. [DOI] [PubMed] [Google Scholar]
  24. Mattioli M., Reichlin M. Physical association of two nuclear antigens and mutual occurrence of their antibodies: the relationship of the SM and RNAprotein (MO) systems in SLE sera. J Immunol. 1973 May;110(5):1318–1324. [PubMed] [Google Scholar]
  25. McAllister G., Amara S. G., Lerner M. R. Tissue-specific expression and cDNA cloning of small nuclear ribonucleoprotein-associated polypeptide N. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5296–5300. doi: 10.1073/pnas.85.14.5296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nelissen R. L., Heinrichs V., Habets W. J., Simons F., Lührmann R., van Venrooij W. J. Zinc finger-like structure in U1-specific protein C is essential for specific binding to U1 snRNP. Nucleic Acids Res. 1991 Feb 11;19(3):449–454. doi: 10.1093/nar/19.3.449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nelissen R. L., Will C. L., van Venrooij W. J., Lührmann R. The association of the U1-specific 70K and C proteins with U1 snRNPs is mediated in part by common U snRNP proteins. EMBO J. 1994 Sep 1;13(17):4113–4125. doi: 10.1002/j.1460-2075.1994.tb06729.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ohosone Y., Mimori T., Fujii T., Akizuki M., Matsuoka Y., Irimajiri S., Hardin J. A., Craft J., Homma M. Autoantigenic epitopes of the B polypeptide of Sm small nuclear RNP particles. Identification of regions accessible only within the U1 small nuclear RNP. Arthritis Rheum. 1992 Aug;35(8):960–966. doi: 10.1002/art.1780350818. [DOI] [PubMed] [Google Scholar]
  29. Pettersson I., Hinterberger M., Mimori T., Gottlieb E., Steitz J. A. The structure of mammalian small nuclear ribonucleoproteins. Identification of multiple protein components reactive with anti-(U1)ribonucleoprotein and anti-Sm autoantibodies. J Biol Chem. 1984 May 10;259(9):5907–5914. [PubMed] [Google Scholar]
  30. Pettersson I., Wang G., Smith E. I., Wigzell H., Hedfors E., Horn J., Sharp G. C. The use of immunoblotting and immunoprecipitation of (U) small nuclear ribonucleoproteins in the analysis of sera of patients with mixed connective tissue disease and systemic lupus erythematosus. A cross-sectional, longitudinal study. Arthritis Rheum. 1986 Aug;29(8):986–996. doi: 10.1002/art.1780290807. [DOI] [PubMed] [Google Scholar]
  31. Pisetsky D. S., Hoch S. O., Klatt C. L., O'Donnell M. A., Keene J. D. Specificity and idiotypic analysis of a monoclonal anti-Sm antibody with anti-DNA activity. J Immunol. 1985 Dec;135(6):4080–4085. [PubMed] [Google Scholar]
  32. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum. 1980 May;23(5):581–590. doi: 10.1002/art.1780230510. [DOI] [PubMed] [Google Scholar]
  33. Reeves W. H., Fisher D. E., Lahita R. G., Kunkel H. G. Autoimmune sera reactive with Sm antigen contain high levels of RNP-like antibodies. J Clin Invest. 1985 Feb;75(2):580–587. doi: 10.1172/JCI111734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Reuter R., Tessars G., Vohr H. W., Gleichmann E., Lührmann R. Mercuric chloride induces autoantibodies against U3 small nuclear ribonucleoprotein in susceptible mice. Proc Natl Acad Sci U S A. 1989 Jan;86(1):237–241. doi: 10.1073/pnas.86.1.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Satoh M., Reeves W. H. Induction of lupus-associated autoantibodies in BALB/c mice by intraperitoneal injection of pristane. J Exp Med. 1994 Dec 1;180(6):2341–2346. doi: 10.1084/jem.180.6.2341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Satoh M., Yamagata H., Watanabe F., Matsushita Y., Sakamoto K., Yoshida K., Nakayama S., Akizuki M. A case of long-standing classical rheumatoid arthritis complicated by serological and clinical characteristics of SLE. Scand J Rheumatol. 1993;22(3):138–140. doi: 10.3109/03009749309099259. [DOI] [PubMed] [Google Scholar]
  37. Schneider C., Newman R. A., Sutherland D. R., Asser U., Greaves M. F. A one-step purification of membrane proteins using a high efficiency immunomatrix. J Biol Chem. 1982 Sep 25;257(18):10766–10769. [PubMed] [Google Scholar]
  38. Sharp G. C., Irvin W. S., Tan E. M., Gould R. G., Holman H. R. Mixed connective tissue disease--an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. 1972 Feb;52(2):148–159. doi: 10.1016/0002-9343(72)90064-2. [DOI] [PubMed] [Google Scholar]
  39. Sillekens P. T., Beijer R. P., Habets W. J., van Venrooij W. J. Human U1 snRNP-specific C protein: complete cDNA and protein sequence and identification of a multigene family in mammals. Nucleic Acids Res. 1988 Sep 12;16(17):8307–8321. doi: 10.1093/nar/16.17.8307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. 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]
  41. Tan E. M., Kunkel H. G. Characteristics of a soluble nuclear antigen precipitating with sera of patients with systemic lupus erythematosus. J Immunol. 1966 Mar;96(3):464–471. [PubMed] [Google Scholar]
  42. Topfer F., Gordon T., McCluskey J. Intra- and intermolecular spreading of autoimmunity involving the nuclear self-antigens La (SS-B) and Ro (SS-A). Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):875–879. doi: 10.1073/pnas.92.3.875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wang J., Satoh M., Pierani A., Schmitt J., Chou C. H., Stunnenberg H. G., Roeder R. G., Reeves W. H. Assembly and DNA binding of recombinant Ku (p70/p80) autoantigen defined by a novel monoclonal antibody specific for p70/p80 heterodimers. J Cell Sci. 1994 Nov;107(Pt 11):3223–3233. doi: 10.1242/jcs.107.11.3223. [DOI] [PubMed] [Google Scholar]
  44. Watts C., Lanzavecchia A. Suppressive effect of antibody on processing of T cell epitopes. J Exp Med. 1993 Oct 1;178(4):1459–1463. doi: 10.1084/jem.178.4.1459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Yamamoto K., Miura H., Moroi Y., Yoshinoya S., Goto M., Nishioka K., Miyamoto T. Isolation and characterization of a complementary DNA expressing human U1 small nuclear ribonucleoprotein C polypeptide. J Immunol. 1988 Jan 1;140(1):311–317. [PubMed] [Google Scholar]

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