HIERARCHICAL SELF-TOLERANCE TO T-CELL DETERMINANTS WITHIN THE UBIQUITOUS NUCLEAR SELF-ANTIGEN LA (SS-B) PERMITS INDUCTION OF SYSTEMIC AUTOIMMUNITY IN NORMAL MICE

Systemic autoimmune diseases are frequently associated with clustering of high titer autoantibody responses towards nuclear self-antigens. L ittle is known, however, about the extent of immune tolerance to the t arget nuclear antigens or the events leading to the complex autoantibo dy responses that are characteristic of systemic autoimmunity. To addr ess these issues, we have examined the mouse immune response to La aut oantigen (mLa) and the homologous human La antigen (hLa), which are co mponents of the La(SS-B)/Ro(SS-A) ribonucleoprotein (RNP) complex targ eted in systemic lupus erythematosus and primary Sjogren's syndrome. T he findings reveal the presence of hierarchical T cell tolerance invol ving multiple autodeterminants within the La autoantigen expressed by normal H-2(k) and H-2(a) mice. At one end of this spectrum, there was no detectable T or B cell autoimmunity observed in mice that were immu nized with the immunodominant mLa(287-301) determinant, which differed by a single residue in its core sequence from the homologous but high ly immunogenic human La-288-302 determinant. Interestingly, the mLa(28 7-301) peptide acted as an altered peptide ligand that specifically an tagonized the activation of an hLa(288-302)-specific T cell hybridoma. In contrast to the tolerogenic mLa(287-301) determinant, a range of a utoimmune potential was identified among poorly tolerizing, subdominan t self-peptides present within mouse La autoantigen. Notably, immuniza tion of normal mice with the autologous subdominant La-25-44 and La-10 6-129 determinants resulted in limited or no detectable autoantibody r esponse. In contrast,immunization with the subdominant mouse La-13-30 determinant induced a proliferative T cell response associated with th e appearance of specific autoantibodies recognizing multiple intrastru ctural (La) and intermolecular components (Ro) of the murine La/Ro RNP . The findings suggest how diversified autoimmunity might follow initi ation of immunity to simple peptide mimics of poorly tolerogenic deter minants that are present within ubiquitous self-antigens.