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J Exp Med. Apr 1, 1994; 179(4): 1243–1252.
PMCID: PMC2191430

Initiation of autoimmunity to the p53 tumor suppressor protein by complexes of p53 and SV40 large T antigen

Abstract

Antinuclear antibodies (ANAs) reactive with a limited spectrum of nuclear antigens are characteristic of systemic lupus erythematosus (SLE) and other collagen vascular diseases, and are also associated with certain viral infections. The factors that initiate ANA production and determine ANA specificity are not well understood. In this study, high titer ANAs specific for the p53 tumor suppressor protein were induced in mice immunized with purified complexes of murine p53 and the Simian virus 40 large T antigen (SVT), but not in mice immunized with either protein separately. The autoantibodies to p53 in these mice were primarily of the IgG1 isotype, were not cross-reactive with SVT, and were produced at titers up to 1:25,000, without the appearance of other autoantibodies. The high levels of autoantibodies to p53 in mice immunized with p53/SVT complexes were transient, but low levels of the autoantibodies persisted. The latter may have been maintained by self antigen, since the anti-p53, but not the SVT, response in these mice could be boosted by immunizing with murine p53. Thus, once autoimmunity to p53 was established by immunizing with p53/SVT complexes, it could be maintained without a requirement for SVT. These data may be explained in at least two ways. First, altered antigen processing resulting from the formation of p53/SVT complexes might activate autoreactive T helper cells specific for cryptic epitopes of murine p53, driving anti-p53 autoantibody production. Alternatively, SVT- responsive T cells may provide intermolecular-intrastructural help to B cells specific for murine p53. In a second stage, these activated B cells might themselves process self p53, generating p53-responsive autoreactive T cells. The induction of autoantibodies during the course of an immune response directed against this naturally occurring complex of self and nonself antigens may be relevant to the generation of specific autoantibodies in viral infections, and may also have implications for understanding the pathogenesis of ANAs in SLE. In particular, our results imply that autoimmunity can be initiated by a "hit and run" mechanism in which the binding of a viral antigen to a self protein triggers an immune response that subsequently can be perpetuated by self antigen.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Tan EM. Autoantibodies to nuclear antigens (ANA): their immunobiology and medicine. Adv Immunol. 1982;33:167–240. [PubMed]
  • Hardin JA. The lupus autoantigens and the pathogenesis of systemic lupus erythematosus. Arthritis Rheum. 1986 Apr;29(4):457–460. [PubMed]
  • Rajewsky K, Rottländer E, Peltre G, Müller B. The immune response to a hybrid protein molecule; specificity of secondary stimulation and of tolerance induction. J Exp Med. 1967 Oct 1;126(4):581–606. [PMC free article] [PubMed]
  • Allison AC, Denman AM, Barnes RD. Cooperating and controlling functions of thymus-derived lymphocytes in relation to autoimmunity. Lancet. 1971 Jul 17;2(7716):135–140. [PubMed]
  • Russell SM, Liew FY. T cells primed by influenza virion internal components can cooperate in the antibody response to haemagglutinin. Nature. 1979 Jul 12;280(5718):147–148. [PubMed]
  • Russell SM, Liew FY. Cell cooperation in antibody responses to influenza virus. I. priming of helper t cells by internal components of virion. Eur J Immunol. 1980 Oct;10(10):791–796. [PubMed]
  • Scherle PA, Gerhard W. Functional analysis of influenza-specific helper T cell clones in vivo. T cells specific for internal viral proteins provide cognate help for B cell responses to hemagglutinin. J Exp Med. 1986 Oct 1;164(4):1114–1128. [PMC free article] [PubMed]
  • Milich DR, McLachlan A, Thornton GB, Hughes JL. Antibody production to the nucleocapsid and envelope of the hepatitis B virus primed by a single synthetic T cell site. Nature. 1987 Oct 8;329(6139):547–549. [PubMed]
  • Gammon G, Sercarz E. How some T cells escape tolerance induction. Nature. 1989 Nov 9;342(6246):183–185. [PubMed]
  • Oki A, Sercarz E. T cell tolerance studied at the level of antigenic determinants. I. Latent reactivity to lysozyme peptides that lack suppressogenic epitopes can be revealed in lysozyme-tolerant mice. J Exp Med. 1985 May 1;161(5):897–911. [PMC free article] [PubMed]
  • Lehmann PV, Forsthuber T, Miller A, Sercarz EE. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature. 1992 Jul 9;358(6382):155–157. [PubMed]
  • Atassi MZ, Yoshioka M, Bixler GS., Jr T cells specific for alpha-beta interface regions of hemoglobin recognize the isolated subunit but not the tetramer and indicate presentation without processing. Proc Natl Acad Sci U S A. 1989 Sep;86(17):6729–6733. [PMC free article] [PubMed]
  • Rouas N, Christophe S, Housseau F, Bellet D, Guillet JG, Bidart JM. Influence of protein-quaternary structure on antigen processing. J Immunol. 1993 Feb 1;150(3):782–792. [PubMed]
  • O'Reilly DR, Miller LK. Expression and complex formation of simian virus 40 large T antigen and mouse p53 in insect cells. J Virol. 1988 Sep;62(9):3109–3119. [PMC free article] [PubMed]
  • Gurney EG, Tamowski S, Deppert W. Antigenic binding sites of monoclonal antibodies specific for simian virus 40 large T antigen. J Virol. 1986 Mar;57(3):1168–1172. [PMC free article] [PubMed]
  • Gurney EG, Harrison RO, Fenno J. Monoclonal antibodies against simian virus 40 T antigens: evidence for distinct sublcasses of large T antigen and for similarities among nonviral T antigens. J Virol. 1980 Jun;34(3):752–763. [PMC free article] [PubMed]
  • Reeves WH. Use of monoclonal antibodies for the characterization of novel DNA-binding proteins recognized by human autoimmune sera. J Exp Med. 1985 Jan 1;161(1):18–39. [PMC free article] [PubMed]
  • Smith DE, Fisher PA. Identification, developmental regulation, and response to heat shock of two antigenically related forms of a major nuclear envelope protein in Drosophila embryos: application of an improved method for affinity purification of antibodies using polypeptides immobilized on nitrocellulose blots. J Cell Biol. 1984 Jul;99(1 Pt 1):20–28. [PMC free article] [PubMed]
  • Levine AJ. Tumor suppressor genes. Bioessays. 1990 Feb;12(2):60–66. [PubMed]
  • Kaplan ME, Tan EM. Antinuclear antibodies in infectious mononucleosis. Lancet. 1968 Mar 16;1(7542):561–563. [PubMed]
  • Lindenmann J. Viruses as immunological adjuvants in cancer. Biochim Biophys Acta. 1974 Apr 29;355(1):49–75. [PubMed]
  • Onodera T, Toniolo A, Ray UR, Jenson AB, Knazek RA, Notkins AL. Virus-induced diabetes mellitus. XX. Polyendocrinopathy and autoimmunity. J Exp Med. 1981 Jun 1;153(6):1457–1473. [PMC free article] [PubMed]
  • Rhodes G, Rumpold H, Kurki P, Patrick KM, Carson DA, Vaughan JH. Autoantibodies in infectious mononucleosis have specificity for the glycine-alanine repeating region of the Epstein-Barr virus nuclear antigen. J Exp Med. 1987 Apr 1;165(4):1026–1040. [PMC free article] [PubMed]
  • Wolfgram LJ, Beisel KW, Rose NR. Heart-specific autoantibodies following murine coxsackievirus B3 myocarditis. J Exp Med. 1985 May 1;161(5):1112–1121. [PMC free article] [PubMed]
  • Imai H, Ochs RL, Kiyosawa K, Furuta S, Nakamura RM, Tan EM. Nucleolar antigens and autoantibodies in hepatocellular carcinoma and other malignancies. Am J Pathol. 1992 Apr;140(4):859–870. [PMC free article] [PubMed]
  • Lane DP, Crawford LV. T antigen is bound to a host protein in SV40-transformed cells. Nature. 1979 Mar 15;278(5701):261–263. [PubMed]
  • Linzer DI, Levine AJ. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell. 1979 May;17(1):43–52. [PubMed]
  • Crawford LV, Pim DC, Bulbrook RD. Detection of antibodies against the cellular protein p53 in sera from patients with breast cancer. Int J Cancer. 1982 Oct 15;30(4):403–408. [PubMed]
  • DeLeo AB, Jay G, Appella E, Dubois GC, Law LW, Old LJ. Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse. Proc Natl Acad Sci U S A. 1979 May;76(5):2420–2424. [PMC free article] [PubMed]
  • Levine AJ, Momand J, Finlay CA. The p53 tumour suppressor gene. Nature. 1991 Jun 6;351(6326):453–456. [PubMed]
  • Davidoff AM, Iglehart JD, Marks JR. Immune response to p53 is dependent upon p53/HSP70 complexes in breast cancers. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3439–3442. [PMC free article] [PubMed]
  • Winter SF, Minna JD, Johnson BE, Takahashi T, Gazdar AF, Carbone DP. Development of antibodies against p53 in lung cancer patients appears to be dependent on the type of p53 mutation. Cancer Res. 1992 Aug 1;52(15):4168–4174. [PubMed]
  • Lin RH, Mamula MJ, Hardin JA, Janeway CA., Jr Induction of autoreactive B cells allows priming of autoreactive T cells. J Exp Med. 1991 Jun 1;173(6):1433–1439. [PMC free article] [PubMed]
  • Mamula MJ, Lin RH, Janeway CA, Jr, Hardin JA. Breaking T cell tolerance with foreign and self co-immunogens. A study of autoimmune B and T cell epitopes of cytochrome c. J Immunol. 1992 Aug 1;149(3):789–795. [PubMed]
  • Puccetti A, Koizumi T, Migliorini P, André-Schwartz J, Barrett KJ, Schwartz RS. An immunoglobulin light chain from a lupus-prone mouse induces autoantibodies in normal mice. J Exp Med. 1990 Jun 1;171(6):1919–1930. [PMC free article] [PubMed]
  • Finnegan A, Smith MA, Smith JA, Berzofsky J, Sachs DH, Hodes RJ. The T cell repertoire for recognition of a phylogenetically distant protein antigen. Peptide specificity and MHC restriction of staphylococcal nuclease-specific T cell clones. J Exp Med. 1986 Sep 1;164(3):897–910. [PMC free article] [PubMed]
  • Buus S, Sette A, Colon SM, Miles C, Grey HM. The relation between major histocompatibility complex (MHC) restriction and the capacity of Ia to bind immunogenic peptides. Science. 1987 Mar 13;235(4794):1353–1358. [PubMed]
  • Shivakumar S, Sercarz EE, Krzych U. The molecular context of determinants within the priming antigen establishes a hierarchy of T cell induction: T cell specificities induced by peptides of beta-galactosidase vs. the whole antigen. Eur J Immunol. 1989 Apr;19(4):681–687. [PubMed]
  • Glimcher LH, Schroer JA, Chan C, Shevach EM. Fine specificity of cloned insulin-specific T cell hybridomas: evidence supporting a role for tertiary conformation. J Immunol. 1983 Dec;131(6):2868–2874. [PubMed]
  • Mamula MJ. The inability to process a self-peptide allows autoreactive T cells to escape tolerance. J Exp Med. 1993 Feb 1;177(2):567–571. [PMC free article] [PubMed]
  • Labrecque S, Naor N, Thomson D, Matlashewski G. Analysis of the anti-p53 antibody response in cancer patients. Cancer Res. 1993 Aug 1;53(15):3468–3471. [PubMed]
  • Hall CL, Colvin RB, Carey K, McCluskey RT. Passive transfer of autoimmune disease with isologous IgG1 and IgG2 antibodies to the tubular basement membrane in strain XIII guinea pigs: loss of self-tolerance induced by autoantibodies. J Exp Med. 1977 Nov 1;146(5):1246–1260. [PMC free article] [PubMed]
  • Stocks MR, Williams DG, Maini RN. Analysis of a positive feedback mechanism in the anti-Sm autoantibody response of MRL/MPJ-lpr/lpr mice. Eur J Immunol. 1991 Feb;21(2):267–272. [PubMed]
  • Arthur RR, Shah KV. Occurrence and significance of papovaviruses BK and JC in the urine. Prog Med Virol. 1989;36:42–61. [PubMed]
  • Stoner GL, Ryschkewitsch CF, Walker DL, Webster HD. JC papovavirus large tumor (T)-antigen expression in brain tissue of acquired immune deficiency syndrome (AIDS) and non-AIDS patients with progressive multifocal leukoencephalopathy. Proc Natl Acad Sci U S A. 1986 Apr;83(7):2271–2275. [PMC free article] [PubMed]
  • Flaegstad T, Fredriksen K, Dahl B, Traavik T, Rekvig OP. Inoculation with BK virus may break immunological tolerance to histone and DNA antigens. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8171–8175. [PMC free article] [PubMed]
  • Newton P, Aldridge RD, Lessells AM, Best PV. Progressive multifocal leukoencephalopathy complicating systemic lupus erythematosus. Arthritis Rheum. 1986 Mar;29(3):337–343. [PubMed]

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