A Tlr7 Translocation Accelerates Systemic Autoimmunity in Murine Lupus

The y-linked autoimmune accelerating (yaa) locus is a potent autoimmune disease allele. Transcription profiling of yaa-bearing B cells revealed the overexpression of a cluster of X-linked genes that included T/r7. FISH analysis demonstrated the translocation of this segment onto the yaa chromosome....

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Published in:Proceedings of the National Academy of Sciences - PNAS 2006-06, Vol.103 (26), p.9970-9975
Main Authors: Subramanian, Srividya, Tus, Katalin, Li, Quan-Zhen, Wang, Andrew, Tian, Xiang-Hong, Zhou, Jinchun, Liang, Chaoying, Bartov, Guy, McDaniel, Lisa D., Zhou, Xin J., Schultz, Roger A., Wakeland, Edward K.
Format: Article
Language:English
Subjects:
Animals
Autoimmune diseases
Autoimmunity
Autoimmunity - genetics
B lymphocytes
B-Lymphocytes - immunology
Biological Sciences
CD4-Positive T-Lymphocytes - immunology
Chromosomes
Gene Expression Profiling
Gene loci
Genes
Genetic loci
Genetics
Immune system
Immunity, Innate - genetics
Lupus
Lupus Erythematosus, Systemic - genetics
Male
Medical genetics
Mice
Mice, Mutant Strains
Phenotypes
T lymphocytes
Toll-Like Receptor 7 - genetics
Transcriptional Activation
Translocation, Genetic
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Summary:The y-linked autoimmune accelerating (yaa) locus is a potent autoimmune disease allele. Transcription profiling of yaa-bearing B cells revealed the overexpression of a cluster of X-linked genes that included T/r7. FISH analysis demonstrated the translocation of this segment onto the yaa chromosome. The resulting overexpression of T/r7 increased in vitro responses to Toll-like receptor (TLR) 7 signaling in all yaa-bearing males. B6.yaa mice are not overtly autoimmune, but the addition of Slel, which contains the autoimmune-predisposing Slam/Cd2 haplotype, causes the development of fatal lupus with numerous immunological aberrations. B6.Slelyaa CD4 T cells develop the molecular signature for TFH cells and also show expression changes in numerous cytokines and chemokines. Disease development and all component autoimmune phenotypes were inhibited by Sles1, a potent suppressor locus. Slesl had no effect on yaa-enhanced TLR7 signaling in vitro, and these data place Sles1 downstream from the lesion in innate immune responses mediated by TLR7, suggesting that Sles1 modulates the activation of adaptive immunity in response to innate immune signaling.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0603912103