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Evidence for genes in addition to Tlr7 in the Yaa translocation linked with acceleration of systemic lupus erythematosus

Borel, Paula
Uematsu, Satoshi
Akira, Shizuo
Kotzin, Brian L.
Published in The Journal of immunology. 2008, vol. 181, no. 2, p. 1556-1562
Abstract The accelerated development of systemic lupus erythematosus (SLE) in male BXSB mice is associated with the genetic abnormality in its Y chromosome, designated Yaa (Y-linked autoimmune acceleration). Recently, the Yaa mutation was identified to be a translocation from the telomeric end of the X chromosome (containing the gene encoding TLR7) onto the Y chromosome. In the present study, we determined whether the Tlr7 gene duplication is indeed responsible for the Yaa-mediated acceleration of SLE. Analysis of C57BL/6 mice congenic for the Nba2 (NZB autoimmunity 2) locus (B6.Nba2) bearing the Yaa mutation revealed that introduction of the Tlr7 null mutation on the X chromosome significantly reduced serum levels of IgG autoantibodies against DNA and ribonucleoproteins, as well as the incidence of lupus nephritis. However, the protection was not complete, because these mice still developed high titers of anti-chromatin autoantibodies and retroviral gp70-anti-gp70 immune complexes, and severe lupus nephritis, which was not the case in male B6.Nba2 mice lacking the Yaa mutation. Moreover, we found that the Tlr7 gene duplication contributed to the development of monocytosis, but not to the reduction of marginal zone B cells, which both are cellular abnormalities causally linked to the Yaa mutation. Our results indicate that the Yaa-mediated acceleration of SLE as well as various Yaa-linked cellular traits cannot be explained by the Tlr7 gene duplication alone, and suggest additional contributions from other duplicated genes in the translocated X chromosome.
Keywords AnimalsAntibodies, Antinuclear/biosynthesis/immunologyAutoantibodies/biosynthesis/immunologyB-Lymphocytes/immunologyGene DuplicationGenes, Y-LinkedGenotypeLupus Erythematosus, Systemic/genetics/immunologyMaleMembrane Glycoproteins/genetics/immunology/metabolismMiceMice, CongenicMice, Inbred C57BLMice, Mutant StrainsMutationRibonucleoproteins/immunologyToll-Like Receptor 7/genetics/immunology/metabolismTranslocation, GeneticX Chromosome/genetics
PMID: 18606711
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Other version: http://www.jimmunol.org/cgi/content/full/181/2/1556
Research groups Groupe Santiago-Raber Marie-Laure (pathologie et immunologie) (915)
Lupus érythémateux systémique, de l'anémie hémolytique et de la glomérulonéphrite (168)
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SANTIAGO-RABER, Marie-Laure et al. Evidence for genes in addition to Tlr7 in the Yaa translocation linked with acceleration of systemic lupus erythematosus. In: The Journal of immunology, 2008, vol. 181, n° 2, p. 1556-1562. doi: 10.4049/jimmunol.181.2.1556 https://archive-ouverte.unige.ch/unige:1080

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Deposited on : 2009-03-05

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