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

Abstract

SummaryAntinudear 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 routine 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.

Self antigens and epitope spreading in systemic autoimmunity

“…Identical mechanisms may account for the demonstration that spreading of autoantibodies to the self antigen p53 occurs after immunization with complexes of this protein and viral (simian virus 40 [SV40] T antigen) proteins (foreign-self complexes) (83); in this model, APC may process the SV40 T antigen-p53 complex differently than the latter protein alone, with resulting generation of p53 cryptic self peptides that can now serve to activate autoreactive T cells. To trigger autoantibody diversification, presentation of self peptides would necessarily develop in the setting of appropriate costimulatory molecules necessary for APC (and B cell)-T cell collaboration.…”

Autoantibodies that stabilize the molecular interaction of Ku antigen with DNA-dependent protein kinase catalytic subunit

“…By acting as a hindering structure that limits accessibility to proteases [29], autoantibodies that stabilize the quaternary structure of an antigen might enhance the presentation of abnormally processed peptides by antigenpresenting cells. In this way, an autoantibody could serve a role analogous to that of SV40 large T antigen in abrogating immune tolerance to the p53 tumour suppressor protein [30]. Alternatively, stabilizing antibodies might increase the effective concentration of a self antigen by preventing its dissociation.…”

p53 is required for spontaneous autoantibody production in B6/lpr lupus mice

“…In this regard, immunization with complexes of p53 and SV40 T antigen induces high titers of anti-p53 antibodies in mice [44], demonstrating a lack of tolerance to p53. It is known that p53 levels are elevated in inflammatory cells [10], and p53 levels increase upon exposure to sunlight [45,46].…”