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A Tlr7 translocation accelerates systemic autoimmunity in murine lupus.
Srividya Subramanian1, Katalin Tus, Quan-Zhen Li
1Center for Immunology and Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Summary
The y-linked autoimmune accelerating (yaa) locus causes Toll-like receptor 7 (TLR7) overexpression, increasing autoimmune responses. A suppressor locus, Sles1, inhibits disease by modulating adaptive immunity downstream of TLR7 signaling.
Area of Science:
- Immunology
- Genetics
Background:
- The y-linked autoimmune accelerating (yaa) locus is a significant autoimmune disease allele.
- Overexpression of X-linked genes, including Toll-like receptor 7 (TLR7), is observed in B cells with the yaa locus.
Purpose of the Study:
- To investigate the role of the yaa locus in autoimmune disease development.
- To understand the mechanism by which Sles1 suppresses autoimmune phenotypes.
Main Methods:
- Transcription profiling of B cells from yaa-bearing mice.
- Fluorescence in situ hybridization (FISH) analysis to detect gene translocations.
- In vitro studies of Toll-like receptor (TLR) 7 signaling.
- Analysis of CD4 T cell molecular signatures and cytokine/chemokine expression in B6.Sle1yaa mice.
Main Results:
- Overexpression of TLR7 due to translocation onto the yaa chromosome increases TLR7 signaling responses.
- B6.Sle1yaa mice develop fatal lupus with immunological aberrations.
- Sles1, a suppressor locus, inhibits disease development and autoimmune phenotypes without affecting yaa-enhanced TLR7 signaling.
Conclusions:
- The yaa locus potentiates autoimmune responses through TLR7 overexpression.
- Sles1 acts downstream of TLR7-mediated innate immune responses, modulating adaptive immunity activation.
- These findings provide insights into the genetic regulation of autoimmune diseases and potential therapeutic targets.