ATlr7translocation accelerates systemic autoimmunity in murine lupus

• DOI: 10.1073/pnas.0603912103
• Publication Date: 2006-06-15T20:57:12Z
• Authors: Srividya Subramanian; Katalin Tus; Quan-Zhen Li; Andrew Wang; Xiang-Hong Tian; Jinchun Zhou; Chaoying Liang; Guy Bartov; Lisa D. McDaniel; Xin J. Zhou; Roger A. Schultz; Edward K. Wakeland
• Keywords: CD4-Positive T-Lymphocytes; Male; Transcriptional Activation; 0301 basic medicine; B-Lymphocytes; Gene Expression Profiling; Autoimmunity; Immunity, Innate; Mice, Mutant Strains; Translocation, Genetic; 3. Good health; Mice; 03 medical and health sciences; 0302 clinical medicine; Toll-Like Receptor 7; Animals; Lupus Erythematosus, Systemic

The y-linked autoimmune accelerating (yaa) locus is a potent autoimmune disease allele. Transcription profiling ofyaa-bearing B cells revealed the overexpression of a cluster of X-linked genes that includedTlr7. FISH analysis demonstrated the translocation of this segment onto theyaachromosome. The resulting overexpression ofTlr7increasedin vitroresponses to Toll-like receptor (TLR) 7 signaling in allyaa-bearing males. B6.yaamice are not overtly autoimmune, but the addition ofSle1, which contains the autoimmune-predisposingSlam/Cd2haplotype, causes the development of fatal lupus with numerous immunological aberrations. B6.Sle1yaaCD4 T cells develop the molecular signature for TFHcells and also show expression changes in numerous cytokines and chemokines. Disease development and all component autoimmune phenotypes were inhibited bySles1, a potent suppressor locus.Sles1had no effect onyaa-enhanced TLR7 signalingin vitro, and these data placeSles1downstream from the lesion in innate immune responses mediated by TLR7, suggesting thatSles1modulates the activation of adaptive immunity in response to innate immune signaling.