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

The Journal of Immunology : Official Journal of the American Association of Immunologists
Robyn E MillsMichelle L Hermiston

Abstract

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 TLR9(B6) signals, but not weaker TLR9(BALB/c) signals, negatively regulate CD45E613R B cell development during competitive reconstitution at the central tolerance checkpoint. Our results ident...Continue Reading

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Citations

Jun 13, 2015·International Journal of Molecular Sciences·Kongyang MaLiwei Lu
Apr 11, 2017·Nature Reviews. Immunology·David J RawlingsShaun W Jackson
Dec 20, 2015·Immunological Reviews·Robert M ClancyJill P Buyon
Jun 30, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Lukas BossallerAnn Marshak-Rothstein

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