INFLUENCE OF ANTIGEN ORGANIZATION ON THE DEVELOPMENT OF LUPUS AUTOANTIBODIES

Objective, To investigate the reason for grouping of antibodies agains t small nuclear RNP (snRNP) particles, which are major autoantigens in systemic lupus erythematosus (SLE), Methods. Mice were immunized with biochemically purified native snRNP particles or recombinant proteins , followed by assessment of antibody and T cell responses, Since mouse (self) snRNPs are not immunogenic in mice, a eukaryotic expression ve ctor was constructed to induce high-level expression of the human U1 s nRNP-associated A protein in murine cells, Native chimeric (mouse/huma n) snRNP particles were used to immunize normal mice of both H-2(k) an d H-2(b) backgrounds, We also disrupted the native snRNPs by digestion with ribonuclease and used this mixture of proteins to immunize mice, Results, Immunization with native chimeric snRNPs resulted in the dev elopment of antibodies against a set of snRNP-associated proteins, a r esponse which was accompanied by breakdown in T cell tolerance to mous e snRNPs in mice immunized with chimeric snRNPs, We also demonstrated that the ordered production of these antibodies was due to the fact th at snRNP-associated proteins are grouped together in snRNP particles, since disruption of the particles resulted in development of antibodie s in a random order, distinct from antibodies seen with intact particl es. Conclusion. Our findings directly demonstrate that the pattern of development of antibodies to native snRNPs is similar to that which is commonly observed in SLE, and that disruption of the particles result s in disappearance of this ordered pattern, These results suggest that the autoimmune response to snRNPs, and possibly to other autoantigens , in lupus is a specific reaction similar to that seen in a typical im mune response to foreign immunogens.