期刊
JOURNAL OF IMMUNOLOGY
卷 194, 期 8, 页码 3675-+出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1500026
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资金
- National Science Foundation [GRFP1144247]
- National Institutes of Health [T32AI007334, K08 AR059723, P01 AI355297, R01 AI089831]
- Rosalind Russell Medical Research Foundation Bechtel Award
- Campini Foundation
- Pepp Family Foundation
- St. Baldrick's Foundation
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.
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