Role of intermolecular/intrastructural B- and T-cell determinants in the diversification of autoantibodies to ribonucleoprotein particles.
The U1 small nuclear ribonucleoprotein (sn-RNP) particle, which consists of the U1 small RNA and multiple polypeptides, is a central target of the autoimmune response in systemic lupus erythematosus. Autoantibodies to the individual proteins of the U1 snRNP typically co-occur in patients with systemic lupus erythematosus, an observation reconciled by postulating that the intact RNA-protein complex serves as the autoimmunogen and that snRNP-specific autoreactive T cells are necessary for autoantibody production. In this study, we demonstrated that normal mice did not develop antibody responses following immunization with purified self (murine) snRNPs. However, when such mice were coimmunized with self snRNPs in conjunction with the human (foreign) U1 snRNP A protein, they developed autoantibodies directed against individual proteins of the U1 snRNP, in addition to anti-A antibodies; we have previously shown that such mice develop snRNP-specific, autoreactive T cells. Intact snRNPs as a co-immunogen were a prerequisite for antibody expansion, since this response was abrogated by disruption of snRNP particles 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 possess intrastructural B-cell and helper-T-cell determinants. These results also suggest that induction of an immune response to one component of an autoantigenic snRNP complex, possibly through priming with molecular mimics, can induce the diversification of autoantibodies that is characteristic of that found in patients with systemic lupus erythematosus.
Fatenejad
S
S
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510.
Mamula
M J
MJ
Craft
J
J
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D011994:Recombinant Proteins / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000276:immunology* / Q000302:isolation & purification / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D001323:Autoantibodies; D046911:Macromolecular Substances; D011994:Recombinant Proteins; D017412:Ribonucleoprotein, U1 Small Nuclear