Influence of antigen organization on the development of lupus autoantibodies.
OBJECTIVE
To investigate the reason for grouping of antibodies against 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 vector was constructed to induce high-level expression of the human U1 snRNP-associated A protein in murine cells. Native chimeric (mouse/human) snRNP particles were used to immunize normal mice of both H-2k and H-2b 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 development of antibodies against a set of snRNP-associated proteins, a response which was accompanied by breakdown in T cell tolerance to mouse snRNPs in mice immunized with chimeric snRNPs. We also demonstrated that the ordered production of these antibodies was due to the fact that snRNP-associated proteins are grouped together in snRNP particles, since disruption of the particles resulted in development of antibodies in a random order, distinct from antibodies seen with intact particles.


CONCLUSIONS
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 results 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 immune response to foreign immunogens.
Fatenejad
S
S
Yale University School of Medicine, New Haven, Connecticut 06520-8031, USA.
Bennett
M
M
Moslehi
J
J
Craft
J
J
D000818:Animals; D000906:Antibodies / Q000032:analysis / Q000187:drug effects / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007108:Immune Tolerance; D007114:Immunization; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000235:genetics; D017411:Ribonucleoproteins, Small Nuclear / Q000276:immunology / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured
D000906:Antibodies; D001323:Autoantibodies; D001324:Autoantigens; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D017412:Ribonucleoprotein, U1 Small Nuclear; D017411:Ribonucleoproteins, Small Nuclear; C075339:U1A protein