RESUMEN
To determine the regulation of B cells specific for the ribonucleoprotein Sm, a target of the immune system in human and mouse lupus, we have generated mice carrying an anti-Sm H chain transgene (2-12H). Anti-Sm B cells in nonautoimmune 2-12H-transgenic (Tg) mice are functional, but, in the absence of immunization, circulating anti-Sm Ab levels are not different from those of non-Tg mice. In this report, we compare the regulation of anti-Sm B cells in nonautoimmune and autoimmune MRL/Mp-lpr/lpr (MRL/lpr) and bcl-2-22-Tg mice. Activation markers are elevated on splenic and peritoneal anti-Sm B cells of both nonautoimmune and autoimmune genetic backgrounds indicating Ag encounter. Although tolerance to Sm is maintained in 2-12H/bcl-2-22-Tg mice, it is lost in 2-12H-Tg MRL/lpr mice, as the transgene accelerates and increases the prevalence of the anti-Sm response. The 2-12H-Tg MRL/lpr mice have transitional anti-Sm B cells in the spleen similar to nonautoimmune mice. However, in contrast to nonautoimmune mice, there are few if any peritoneal anti-Sm B-1 cells. These data suggest that a defect in B-1 differentiation may be a factor in the loss of tolerance to Sm and provide insight into the low prevalence of the anti-Sm response in lupus.
Asunto(s)
Autoantígenos/inmunología , Subgrupos de Linfocitos B/citología , Subgrupos de Linfocitos B/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Activación de Linfocitos/genética , Ribonucleoproteínas Nucleares Pequeñas/inmunología , Envejecimiento/genética , Envejecimiento/inmunología , Animales , Antígenos de Diferenciación de Linfocitos B/biosíntesis , Autoanticuerpos/biosíntesis , Enfermedades Autoinmunes/genética , Subgrupos de Linfocitos B/metabolismo , Biomarcadores , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Relación Dosis-Respuesta Inmunológica , Regulación de la Expresión Génica/inmunología , Genes bcl-2/inmunología , Inmunofenotipificación , Ratones , Ratones Endogámicos MRL lpr , Ratones Transgénicos , Peritoneo/citología , Peritoneo/inmunología , Peritoneo/metabolismo , Bazo/citología , Bazo/inmunología , Bazo/metabolismo , Transgenes/inmunología , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología , Proteínas Nucleares snRNPRESUMEN
Autoantibodies directed at a diverse group of proteins of the U1/Sm ribonucleoprotein (snRNP) are characteristic of systemic lupus erythematosus and are found in the MRL murine model of this disease. This study examines the role of transgenic B lymphocytes in the regulation of autoreactive T cells to the snRNP autoantigen. Transgenic mice were developed bearing an Ig heavy chain gene specific for the D protein component of murine snRNP. B lymphocytes in these mice are neither deleted nor anergic and are of an immature (heat-stable Aghigh) phenotype. T lymphocytes from anti-snRNP transgenic mice were examined using a recombinant form of the D protein of the murine snRNP complex. Our results revealed that transgenic anti-snRNP B cell APCs stimulated CD4 T cells from wild-type C57BL/6 and MRL lpr/lpr mice, while nonspecific APCs failed to stimulate CD4 T cells. This study demonstrates that autoreactive T cells are not deleted from wild-type mice, although their activation is facilitated by autoantigen-specific APCs. The snRNP-reactive T cells in C57BL/6 transgenic mice are tolerized, in contrast to those T cells from MRL lpr/lpr transgenic mice. These studies implicate a role for autoreactive B lymphocytes in the in vivo activation and/or diversification of autoreactive T cells.
Asunto(s)
Genes de Inmunoglobulinas/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Linfocitos T/inmunología , Animales , Presentación de Antígeno , Autoantígenos/inmunología , Autoantígenos/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Citometría de Flujo , Antígenos de Histocompatibilidad Clase II/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos MRL lpr , Ratones Transgénicos , Péptidos/inmunología , Péptidos/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Ribonucleoproteínas Nucleares Pequeñas/inmunología , Linfocitos T/metabolismoRESUMEN
Anti-Sm and anti-ssDNA transgenic (Tg) mice were generated using the VH-D-JH rearrangement of an anti-Sm hybridoma of MRL/Mp-lpr/lpr origin. B cells of each specificity account for 15%-35% of the splenic repertoire, but no circulating anti-Sm or anti-ssDNA antibodies are detected. Most autoreactive cells exhibit an immature B cell phenotype and have short half-lives equivalent to those of non-Tg immature B cells. However, at least some anti-Sm B cells are functional, because immunization with murine snRNPs induces anti-Sm secretion. We propose that anti-Sm and anti-ssDNA are eliminated during the transition to mature B cells and that this late stage of tolerance induction is consequential to their spontaneous activation in murine lupus.