Systemic lupus erythematosus is characterized by high titers of autoantibodies directed at multiple proteins of the U1/Sm small nuclear ribonucleoproteins (snRNPs). The origin of this type of autoimmunity, that is, whether it is initiated by foreign molecular mimics or by the self-snRNPs, is not known. In this study using normal mice, we investigated the presence of autoreactive B and T cells to the D protein of murine snRNPs. Although neither B nor T cell responses could be detected after immunization with native self-snRNPs, two synthetic self-peptides corresponding to amino acids 26-40 and 56-70 of the snRNP D protein elicited strong autoreactive T cell proliferation as well as a limited Ab response that bound the self-protein in immunoblots. T cells elicited by these peptides did not respond to stimulation with native snRNPs, suggesting that the peptides are cryptic and are not processed from the native protein for presentation by APCs. After priming with either of these cryptic self-peptides, exposure of the immune system to native murine snRNPs resulted in a diversified response with Abs that immunoprecipitated snRNPs and that produced an antinuclear immunofluorescence pattern on murine cell substrates. These studies demonstrate that autoreactive B and T cells specific for self-snRNPs are components of the normal repertoire of mouse lymphocytes; they have been neither deleted nor irreversibly anergized. Furthermore, we show that a diverse autoimmune response to lupus autoantigens, snRNPs, can originate from self-peptides without the influence of foreign Ags or molecular mimics.