A Tlr7 translocation accelerates systemic autoimmunity in murine lupus

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

Research output: Contribution to journalArticle

455 Scopus citations

Abstract

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 Tlr7. FISH analysis demonstrated the translocation of this segment onto the yaa chromosome. The resulting overexpression of Tlr7 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 Sle1, which contains the autoimmune- predisposing Slam/Cd2 haplotype, causes the development of fatal lupus with numerous immunological aberrations. B6.Sle1yaa 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. Sles1 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.

Original languageEnglish (US)
Pages (from-to)9970-9975
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number26
DOIs
StatePublished - Jun 27 2006

Keywords

  • Sle1
  • Sles1
  • Toll-like receptor 7
  • yaa

ASJC Scopus subject areas

  • General

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    Subramanian, S., Tus, K., Li, Q. Z., Wang, A., Tian, X. H., Zhou, J., Liang, C., Bartov, G., McDaniel, L. D., Zhou, X. J., Schultz, R. A., & Wakeland, E. K. (2006). A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. Proceedings of the National Academy of Sciences of the United States of America, 103(26), 9970-9975. https://doi.org/10.1073/pnas.0603912103