RESUMEN
In developing B lymphocytes, a successful V(D)J heavy chain (HC) immunoglobulin (Ig) rearrangement establishes HC allelic exclusion and signals pro-B cells to advance in development to the pre-B stage. A subsequent functional light chain (LC) rearrangement then results in the surface expression of IgM at the immature B cell stage. Here we show that interruption of basal IgM signaling in immature B cells, either by the inducible deletion of surface Ig via Cre-mediated excision or by incubating cells with the tyrosine kinase inhibitor herbimycin A or the phosphatidylinositol 3-kinase inhibitor wortmannin, led to a striking "back-differentiation" of cells to an earlier stage in B cell development, characterized by the expression of pro-B cell genes. Cells undergoing this reversal in development also showed evidence of new LC gene rearrangements, suggesting an important role for basal Ig signaling in the maintenance of LC allelic exclusion. These studies identify a previously unappreciated level of plasticity in the B cell developmental program, and have important implications for our understanding of central tolerance mechanisms.
Asunto(s)
Linfocitos B/inmunología , Inmunoglobulinas/fisiología , Transducción de Señal/inmunología , Androstadienos/farmacología , Animales , Linfocitos B/efectos de los fármacos , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Células Cultivadas , Reordenamiento Génico , Reordenamiento Génico de Linfocito B , Proteínas Fluorescentes Verdes/genética , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Ligeras de Inmunoglobulina/genética , Inmunoglobulina M/inmunología , Ratones , Ratones Noqueados , Ratones Transgénicos , WortmaninaRESUMEN
The presence of systemic lupus erythematosus (SLE) susceptibility genes on chromosome 20 is suggested by the observation of genetic linkage in several independent SLE family collections. To further localize the genetic effects, we typed 59 microsatellites in the two best regions, as defined by genome screens. Genotypes were analyzed for statistical linkage and/or association with SLE, by use of a combination of nonparametric linkage methods, family-based tests of association (transmission/disequilibrium and pedigree disequilibrium tests), and haplotype-sharing statistics (haplotype runs test), in a set of 230 SLE pedigrees. Maximal evidence for linkage to SLE was to 20p12 (LOD = 2.84) and 20q13.1 (LOD = 1.64) in the white pedigrees. Subsetting families on the basis of evidence for linkage to 16q12 significantly improved the LOD scores at both chromosome 20 locations (20p12 LOD = 5.06 and 20q13 LOD = 3.65), consistent with epistasis. We then typed 162 single-nucleotide polymorphism markers across a 1.3-Mb candidate region on 20q13.1 and identified several SNPs that demonstrated significant evidence for association. These data provide additional support for linkage and association to 20p12 and 20q13.1 in SLE and further refine the intervals of interest. These data further suggest the possibility of epistatic relationships among loci within the 20q12, 20q13, and 16q12 regions in SLE families.
Asunto(s)
Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 20/genética , Epistasis Genética , Lupus Eritematoso Sistémico/genética , Estudios de Cohortes , Salud de la Familia , Femenino , Ligamiento Genético , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Haplotipos , Humanos , Escala de Lod , Masculino , Repeticiones de Microsatélite , Linaje , Mapeo Físico de Cromosoma , Polimorfismo de Nucleótido Simple , HermanosRESUMEN
Human leukocyte antigen (HLA) class I and class II alleles are implicated as genetic risk factors for many autoimmune diseases. However, the role of the HLA loci in human systemic lupus erythematosus (SLE) remains unclear. Using a dense map of polymorphic microsatellites across the HLA region in a large collection of families with SLE, we identified three distinct haplotypes that encompassed the class II region and exhibited transmission distortion. DRB1 and DQB1 typing of founders showed that the three haplotypes contained DRB1*1501/ DQB1*0602, DRB1*0801/ DQB1*0402, and DRB1*0301/DQB1*0201 alleles, respectively. By visualizing ancestral recombinants, we narrowed the disease-associated haplotypes containing DRB1*1501 and DRB1*0801 to an approximately 500-kb region. We conclude that HLA class II haplotypes containing DRB1 and DQB1 alleles are strong risk factors for human SLE.