Prevalence and evolutionary origins of autoimmune susceptibility alleles in natural mouse populations

Limaye, Nisha; Belobrajdic, K A; Wandstrat, Amy E.; Bonhomme, François; Edwards, Scott V.; Wakeland, Edward K.

doi:10.1038/sj.gene.6364446

Cited by 22 publications

(14 citation statements)

References 43 publications

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“…Given previous reports implicating Slam genes in NKT development (33, 34), as well as reports demonstrating numerous polymorphisms at Slam family loci (36, 37), we evaluated the differential expression of members of this gene family on macrophages and NKT cells between the parental C57BL/6J and B6.129c1 congenic mice. We used a panel of mAbs to compare the expression of SLAMF1 (CD150), SLAMF2 (CD48), SLAMF3 (CD229), SLAMF5 (CD84), and SLAMF6 (Ly108) between C57BL/6J and B6.129c1 CD11b + Gr1 hi and CD11b + Gr1 lo monocyte/macrophages.…”

Section: Resultsmentioning

confidence: 99%

“…This is consistent with reports demonstrating that targeted deletion of members of the signaling lymphocytic activation molecule (SLAM) receptor family (34), as well as the intracellular signaling molecule SLAM-associated protein (SAP) (35), results in impaired NKT cell development. Interestingly, extensive polymorphism at the Slam locus distinguishes two major Slam haplotypes in commonly used inbred strains of mice (36, 37). Whereas Slam haplotype-2 is present in NOD, 129X1/SvJ, 129S1/SvImJ, BALB/cJ, and SM/J, Slam haplotype -1 is present in C57BL/6, C57BR/cdJ, and C57L/J among others (36).…”

Section: Introductionmentioning

confidence: 99%

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Slam Haplotypes Modulate the Response to Lipopolysaccharide In Vivo through Control of NKT Cell Number and Function

Aktan

Chant

Borg

et al. 2010

The Journal of Immunology

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CD1d-restricted NKT cells make up an innate-like T cell subset that plays a role in amplifying the response of innate immune leukocytes to TLR ligands. The Slam locus contains genes that have been implicated in innate and adaptive immune responses. In this study, we demonstrate that divergent Slam locus haplotypes modulate the response of macrophages to the TLR4 ligand LPS through their control of NKT cell number and function. In response to LPS challenge in vivo, macrophage TNF production in Slam haplotype-2+ 129S1/SvImJ and 129X1/SvJ mice was significantly impaired in comparison with macrophage TNF production in Slam haplotype-1+ C57BL/6J mice. Although no cell-intrinsic differences in macrophage responses to LPS were observed between strains, 129 mice were found to be deficient in liver NKT cell number, in NKT cell cytokine production in response to the CD1d ligand α-galactosylceramide, and in NKT cell IFN-γ production after LPS challenge in vivo. Using B6.129c1 congenic mice and adoptive transfer, we found that divergent Slam haplotypes controlled the response to LPS in vivo, as well as the diminished NKT cell number and function, and that these phenotypes were associated with differential expression of signaling lymphocytic activation molecule family receptors on NKT cells. These data suggest that the polymorphisms that distinguish two Slam haplotypes significantly modulate the innate immune response in vivo through their effect on NKT cells.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Slam Haplotypes Modulate the Response to Lipopolysaccharide In Vivo through Control of NKT Cell Number and Function

Aktan

Chant

Borg

et al. 2010

The Journal of Immunology

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“…Nevertheless, other polymorphic genes within the sst1 region may also contribute to the observed differences between the sst1 susceptible and sst1 resistant animals. Indeed, clustering of functionally related genes in mammalian genomes, as well as multiple functional polymorphisms within candidate chromosomal loci, has been documented in other forward genetic analyses of inflammatory diseases [53].…”

Section: Discussionmentioning

confidence: 99%

The sst1 Resistance Locus Regulates Evasion of Type I Interferon Signaling by Chlamydia pneumoniae as a Disease Tolerance Mechanism

Berland

Mekasha

et al. 2013

PLoS Pathog

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The sst1, “supersusceptibility to tuberculosis,” locus has previously been shown to be a genetic determinant of host resistance to infection with the intracellular pathogen, Mycobacterium tuberculosis. Chlamydia pneumoniae is an obligate intracellular bacterium associated with community acquired pneumonia, and chronic infection with C. pneumoniae has been linked to asthma and atherosclerosis. C. pneumoniae is a highly adapted pathogen that can productively infect macrophages and inhibit host cell apoptosis. Here we examined the role of sst1 in regulating the host response to infection with C. pneumoniae. Although mice carrying the sst1 susceptible (sst1S) locus were not impaired in their ability to clear the acute infection, they were dramatically less tolerant of the induced immune response, displaying higher clinical scores, more severe lung inflammation, exaggerated macrophage and neutrophil influx, and the development of fibrosis compared to wild type mice. This correlated with increased activated caspase-3 in the lungs of infected sst1S mice. Infection of sst1S macrophages with C. pneumoniae resulted in a shift in the secreted cytokine profile towards enhanced production of interferon-β and interleukin-10, and induced apoptotic cell death, which was dependent on secretion of interferon-β. Intriguingly macrophages from the sst1S mice failed to support normal chlamydial growth, resulting in arrested development and failure of the organism to complete its infectious cycle. We conclude that the sst1 locus regulates a shared macrophage-mediated innate defense mechanism against diverse intracellular bacterial pathogens. Its susceptibility allele leads to upregulation of type I interferon pathway, which, in the context of C. pneumoniae, results in decreased tolerance, but not resistance, to the infection. Further dissection of the relationship between type I interferons and host tolerance during infection with intracellular pathogens may provide identification of biomarkers and novel therapeutic targets.

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“…Homozygosity disequilibrium in the MHC region, which has been shown to contain the important functional genes related to RA and other autoimmune diseases [64], [65], [73],[74], results in a loss of genetic diversities and thereby influences quantitative and/or qualitative alternations of expression profiles. Some studies have found that autoimmunity susceptibility genes are positively selected in RA [75], [76], [77], [78]. Selected alleles accumulate in the gene pool over time and consequently increase the probability of generating an ROH.…”

Section: Discussionmentioning

confidence: 99%

A Genome-Wide Homozygosity Association Study Identifies Runs of Homozygosity Associated with Rheumatoid Arthritis in the Human Major Histocompatibility Complex

et al. 2012

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Rheumatoid arthritis (RA) is a chronic inflammatory disorder with a polygenic mode of inheritance. This study examined the hypothesis that runs of homozygosity (ROHs) play a recessive-acting role in the underlying RA genetic mechanism and identified RA-associated ROHs. Ours is the first genome-wide homozygosity association study for RA and characterized the ROH patterns associated with RA in the genomes of 2,000 RA patients and 3,000 normal controls of the Wellcome Trust Case Control Consortium. Genome scans consistently pinpointed two regions within the human major histocompatibility complex region containing RA-associated ROHs. The first region is from 32,451,664 bp to 32,846,093 bp (−log10(p)>22.6591). RA-susceptibility genes, such as HLA-DRB1, are contained in this region. The second region ranges from 32,933,485 bp to 33,585,118 bp (−log10(p)>8.3644) and contains other HLA-DPA1 and HLA-DPB1 genes. These two regions are physically close but are located in different blocks of linkage disequilibrium, and ∼40% of the RA patients' genomes carry these ROHs in the two regions. By analyzing homozygote intensities, an ROH that is anchored by the single nucleotide polymorphism rs2027852 and flanked by HLA-DRB6 and HLA-DRB1 was found associated with increased risk for RA. The presence of this risky ROH provides a 62% accuracy to predict RA disease status. An independent genomic dataset from 868 RA patients and 1,194 control subjects of the North American Rheumatoid Arthritis Consortium successfully validated the results obtained using the Wellcome Trust Case Control Consortium data. In conclusion, this genome-wide homozygosity association study provides an alternative to allelic association mapping for the identification of recessive variants responsible for RA. The identified RA-associated ROHs uncover recessive components and missing heritability associated with RA and other autoimmune diseases.

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Prevalence and evolutionary origins of autoimmune susceptibility alleles in natural mouse populations

Cited by 22 publications

References 43 publications

Slam Haplotypes Modulate the Response to Lipopolysaccharide In Vivo through Control of NKT Cell Number and Function

Slam Haplotypes Modulate the Response to Lipopolysaccharide In Vivo through Control of NKT Cell Number and Function

The sst1 Resistance Locus Regulates Evasion of Type I Interferon Signaling by Chlamydia pneumoniae as a Disease Tolerance Mechanism

A Genome-Wide Homozygosity Association Study Identifies Runs of Homozygosity Associated with Rheumatoid Arthritis in the Human Major Histocompatibility Complex

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