ROLE OF INTERMOLECULAR INTRASTRUCTURAL B-CELL AND T-CELL DETERMINANTSIN THE DIVERSIFICATION OF AUTOANTIBODIES TO RIBONUCLEOPROTEIN-PARTICLES

The U1 small nuclear ribonucleoprotein (snRNP) particle, which consist s of the U1 small RNA and multiple polypeptides, is a central target o f the autoimmune response in systemic lupus erythematosus. Autoantibod ies to the individual proteins of the U1 snRNP typically co-occur in p atients with systemic lupus erythematosus, an observation reconciled b y postulating that the intact RNA-protein complex serves as the autoim munogen and that snRNP-specific autoreactive T cells are necessary for autoantibody production. In this study, we demonstrated that normal m ice did not develop antibody responses following immunization with pur ified self (murine) snRNPs. However, when such mice were coimmunized w ith self snRNPs in conjunction with the human (foreign) U1 snRNP A pro tein, they developed autoantibodies directed against individual protei ns of the U1 snRNP, in addition to anti-A antibodies; we have previous ly shown that such mice develop snRNP-specific, autoreactive T cells. Intact snRNPs as a coimmunogen were a prerequisite for antibody expans ion, since this response was abrogated by disruption of snRNP particle s with pancreatic RNase prior to immunization. These findings indicate that autoreactive helper T cells can drive autoantibody production to the individual proteins of snRNP particles and that such autoantibody responses may require the presence of intact snRNP particles that pos sess intrastructural B-cell and helper-T-cell determinants. These resu lts also suggest that induction of an immune response to one component of an autoantigenic snRNP complex, possibly through priming with mole cular mimics, can induce the diversification of autoantibodies that is characteristic of that found in patients with systemic lupus erythema tosus.