Ro60 peptides induce antibodies to similar epitopes shared among lupus-related autoantigens

The coexistence of autoantibodies to ribonucleoproteins (RNP) in sera of pa tients with systemic lupus erythematosus has been attributed to intermolecu lar determinant spreading among physically associated proteins. Recently, w e showed that murine Ab responses to rRo60 or Ro60 peptides were diversifie d unexpectedly to small nuclear RNP, In this investigation, the mechanisms for this autoantibody diversification were examined. Intramolecular determi nant spreading was demonstrated in mice immunized with human or mouse Ro60( 316-335). Immune sera depleted of anti-peptide Ab immunoprecipitated Ro60-a ssociated mY1 and mY3 RNA and remained reactive to a determinant on Ro60(12 8-285). Absorption with the immunogen depleted the immune sera completely o f anti-Golgi complex Ab (inducible only with human Ro60(316-335)) and anti- La Ab, and reduced substantially Ab to SmD and 70-kDa U1RNP, Mouse rRo60 co mpletely inhibited the immune sera reactivity to La, SmD, and 70-kDa U1RNP, However, La, SmD, and 70-kDa U1RNP preferentially inhibited the antiserum reactivities to these Ags, respectively. Affinity-purified anti-La Ab were reactive with Ro60, La, SmD, and 70-kDa U1RNP, These results provide eviden ce that a population of the induced autoantibodies recognized determinants shared by these autoantigens. Lack of sequence homology between Ro60(316-33 5) and La, SmD, or 70-kDa U1RNP suggests that these determinants are confor mational, Interestingly, similar cross-reactive autoantibodies were found i n NZB/NZW F-1 sera. Thus, a single molecular mimic may generate Ab to multi ple RNP Ags, Furthermore, crossreactive determinants shared between antigen ic systems that are not associated physically (Ro/La RNP and small nuclear RNP) may be important in the generation of autoantibody diversity in system ic lupus erythematosus.