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Unbiased modifier screen reveals that signal strength determines the regulatory role murine TLR9 plays in autoantibody production

  • Author(s): Mills, RE
  • Lam, VC
  • Tan, A
  • Cresalia, N
  • Oksenberg, N
  • Zikherman, J
  • Anderson, M
  • Weiss, A
  • Hermiston, ML
  • et al.

Published Web Location

http://www.ncbi.nlm.nih.gov/pubmed/?term=PMC4503364
No data is associated with this publication.
Abstract

Copyright © 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00. The autoimmune disease systemic lupus erythematosus has a complex environmental and multifactorial genetic basis. Genome-wide association studies have recently identified numerous disease-associated polymorphisms, but it remains unclear in which cells and during which step of pathogenesis specific polymorphisms interact to cause disease. Using a mouse model in which the same activating mutation (CD45E613R) causes distinct genetic background-dependent disease phenotypes, we performed a screen for genetic modifiers of autoreactivity between anti-nuclear Ab (ANA)-resistant CD45E613R.B6 and ANA-permissive CD45E613R. BALB/c mice. Within a novel autoreactivity-associated locus on chromosome 9, we identify a putative modifier, TLR9. Validating a role for TLR9 in modifying autoreactivity in the context of the CD45E613R mutation, manipulation of TLR9 gene dosage eliminates ANA in CD45E613R.BALB/c mice, but confoundingly permits ANA in CD45E613R.B6 mice. We demonstrate that sensitivity to ANA is modulated by strength of TLR9 signal, because stronger TLR9B6 signals, but not weaker TLR9BALB/c signals, negatively regulate CD45E613R B cell development during competitive reconstitution at the central tolerance checkpoint. Our results identify a novel autoreactivity-associated locus and validate Tlr9 as a candidate gene within the locus. We further demonstrate a novel role for TLR9 signal strength in central tolerance, providing insight into the interplay of diseaseassociated polymorphisms at a discrete step of systemic lupus erythematosus pathogenesis.

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