1. Unbiased modifier screen reveals that signal strength determines the regulatory role murine TLR9 plays in autoantibody production.
- Author
-
Mills, Robyn E, Lam, Viola C, Tan, Allison, Cresalia, Nicole, Oksenberg, Nir, Zikherman, Julie, Anderson, Mark, Weiss, Arthur, and Hermiston, Michelle L
- Subjects
B-Lymphocytes ,Chromosomes ,Mammalian ,Animals ,Mice ,Inbred BALB C ,Mice ,Knockout ,Mice ,Lupus Erythematosus ,Systemic ,Antibodies ,Antinuclear ,Amino Acid Substitution ,Signal Transduction ,Antibody Formation ,Immune Tolerance ,Mutation ,Missense ,Polymorphism ,Genetic ,Toll-Like Receptor 9 ,Genome-Wide Association Study ,Genetic Loci ,Leukocyte Common Antigens ,Chromosomes ,Mammalian ,Inbred BALB C ,Knockout ,Lupus Erythematosus ,Systemic ,Antibodies ,Antinuclear ,Mutation ,Missense ,Polymorphism ,Genetic ,Antigens ,CD45 ,Autoimmune Disease ,Biotechnology ,Human Genome ,Genetics ,Lupus ,2.1 Biological and endogenous factors ,Immunology - 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 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 disease-associated polymorphisms at a discrete step of systemic lupus erythematosus pathogenesis.
- Published
- 2015