Induction of autoimmunity by multivalent immunodominant and subdominant T cell determinants of La (SS-B)

We investigated the consequences of altering the form and valence of define d autodeterminants on the initiation and spreading of experimentally induce d La/Ro autoimmunity. Anti-La and Ro (SS-A) Ab responses were monitored fol lowing immunization of healthy mice with defined immunodominant and subdomi nant T cell determinants of the La (SS-B) autoantigen synthesized as either monomeric or multiple antigenic (MAP) peptides, Abs to mouse La (mLa) deve loped faster and were of higher titer in mice immunized with the subdominan t mLa(25-44) MAP compared with mice immunized with the 25-44 monomer, Rapid intermolecular spreading of the autoimmune response to 60-kDa Ro was obser ved in AKR/J mice immunized with mLa(25-44) MAP, but not in mice immunized repeatedly with monomeric peptide. A/J mice immunized and boosted with the known tolerogenic mLa(287-301) determinant delivered as monomeric peptide f ailed to develop Abs to either intact mLa or mLa(287-301) peptide. However, immunization with the multivalent mLa(287-301) peptide led to the rapid pr oduction of high titer mLa autoantibodies associated with a proliferative T cell response to the mLa(287-301) peptide. The data suggested that the enh anced immunogenicity of MAPs was not due to augmented Ag presentation or T cell stimulation. However, MAP-, but not monomer peptide-, containing immun e complexes were potent substrates for Ab-dependent fixation of complement. These results demonstrate that the form of Ag responsible for inducing aut oimmunity can profoundly influence the nature and magnitude of the immune r esponse. Thus, molecular mimicry of tolerogenic and nontolerogenic self det erminants might trigger autoimmunity under conditions of altered valence.