Novel Quantitative Trait Loci Controlling Development of Experimental Autoimmune Encephalomyelitis and Proportion of Lymphocyte Subpopulations

Karlsson, Jenny; Zhao, Xiangshan; Lonskaya, Irina; Neptin, Malin; Holmdahl, Rikard; Andersson, Åsa

doi:10.4049/jimmunol.170.2.1019

Cited by 38 publications

(54 citation statements)

References 47 publications

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“…Interestingly, the same locus as Agnm3 have been identified in linkage studies on the susceptibility for experimental Lyme arthritis [19] and experimental encephalomyelitis [20]. This chromosomal region contains polymorphic OPN gene.…”

Section: Discussionmentioning

confidence: 84%

Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice

Miyazaki

Ono

et al. 2005

Eur J Immunol

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Potentially, autoimmune diseases develop from a combination of multiple genes with allelic polymorphisms. An MRL/Mp-Fas lpr/lpr (MRL/lpr) strain of mice develops autoimmune diseases, including lupus nephritis, but another lpr strain, C3H/HeJFas lpr/lpr (C3H/lpr) does not. This indicates that MRL polymorphic genes are involved in the development of the diseases. By quantitative trait loci (QTL) analysis using 527 of the (MRL/lpr Â C3H/lpr)F 2 mice, we identified a novel locus for susceptibility to lupus nephritis at map position D5Mit115 on chromosome 5, the same alias of the osteopontin (Opn) gene (LOD score =4.0), susceptible in the MRL allele. In functional analyses of the MRL and C3H Opn alleles using synthetic osteopontin (OPN) made with a new method "cell-free system" with wheat germ ribosomes, the MRL-OPN induced higher expression and production of immunoglobulins as well as cytokines including TNF-a, IL-1b and IFN-c in splenocytes and/or macrophages than that of the C3H allele. These findings suggest that allelic polymorphism of OPN causes the functional differences in antibody production and macrophage activation between MRL and C3H strains, possibly involved in the development of lupus nephritis.

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Section: Discussionmentioning

confidence: 84%

Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice

Miyazaki

Ono

et al. 2005

Eur J Immunol

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“…To date, gene mapping in rodent inflammatory diseases has relied on whole genome scans in backcross or F 2 populations followed by fine-mapping in congenic strains. Although ϳ35 quantitative trait loci (QTLs) regulating rodent EAE have been identified with this approach (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31), there are certain limitations. Confidence intervals in F 2 crosses are typically ϳ20 cM and contain, on average, as many as 500 genes.…”

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

An Advanced Intercross Line ResolvesEae18into Two Narrow Quantitative Trait Loci Syntenic to Multiple Sclerosis Candidate Loci

Jagodic

Bečanović

Sheng

et al. 2004

The Journal of Immunology

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Identification of polymorphic genes regulating inflammatory diseases may unravel crucial pathogenic mechanisms. Initial steps to map such genes using linkage analysis in F2 intercross or backcross populations, however, result in broad quantitative trait loci (QTLs) containing hundreds of genes. In this study, an advanced intercross line in combination with congenic strains, was used to fine-map Eae18 on rat chromosome 10 in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE). Myelin oligodendrocyte glycoprotein-induced EAE is a chronic relapsing disease that closely mimics key features of multiple sclerosis. Congenic DA.ACI rat strains localized Eae18 to an ∼30-Mb large region. Fine-mapping was then performed in an advanced intercross line consisting of a (DA × PVG.1AV1)F7 intercross, resulting in two adjacent EAE-regulating QTLs designated Eae18a and Eae18b. The two QTLs span 5.5 and 3 Mb, respectively, and the 3-Mb Eae18b contains as few as 10 genes, including a cluster of chemokine genes (CCL1, CCL2, CCL7, and CCL11). Eae18a and Eae18b are syntenic to human chromosome 17p13 and 17q11, respectively, which both display linkage to multiple sclerosis. Thus, Eae18 consists of at least two EAE-regulating genes, providing additional evidence that clustering of disease-regulating genes in QTLs is an important phenomenon. The overlap between Eae18a and Eae18b with previously identified QTLs in humans and mice further supports the notion that susceptibility alleles in inflammatory disease are evolutionary conserved between species.

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“…1). The first linkage analysis in an F2 intercross was in the mouse [51] and several others have been presented since then [52][53][54][55][56][57][58][59]. The first two linkage analyses in the rat were performed on EAE induced with whole spinal cord homogenate [60,61].…”

Section: Mapping Of Non-mhc Qtls Regulating Eaementioning

confidence: 99%

Current Gene‐Mapping Strategies in Experimental Models of Multiple Sclerosis

et al. 2004

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Both family-based linkage analyses and population-based association studies have failed to identify disease-regulatory non-human leucocyte antigen genes of importance in multiple sclerosis (MS). Instead, investigators have employed experimental models, which offer major advantages in genetic studies. We summarize the current main methodologies used and the status of both the human and experimental approaches. Why is it important to find genes regulating MS? There is an immense number of cellular and molecular interactions defined in the immunological field and it is very difficult to unravel those that are critical to an inflammatory disease, such as MS, by classical hypothesisdriven research. Unbiased genetics defines evolutionary conserved gene polymorphisms and pathways regulated by these genes, which are central in the pathogenesis. These, in turn, are of interest as therapeutic targets and pharmacogenetic markers. Genetic epidemiology of multiple sclerosisMultiple sclerosis (MS) is a chronic inflammatory disease, which affects the central nervous system (CNS) and causes neurological deficits. The prevalence of MS in high-risk areas, such as northern and central Europe, Italy, the middle part of Northern America, southeastern Australia and New Zealand, is more than 30 per 100,000. Both genetic and environmental factors contribute to the development of MS. The first evidence for a genetic contribution to MS, the association with certain human leucocyte antigen (HLA) haplotypes, was reported about 30 years ago [1,2]. Observations in twin studies and familial aggregation studies, however, reflect the relevance of non-HLA genes and polygeneity in MS [3,4]. Despite this, it remains unresolved whether specific genes are crucial for the development of MS and if so, how many. The current hypothesis describing the influence of genetics on multifactorial diseases suggests an interaction of multiple genes. There are, however, still no unequivocal demonstrations of discrete genes regulating the susceptibility or the disease course of MS. Therefore, it is unclear how many genes that might be of relevance, the strength of their impact (relative risk or odds ratio) and their potential differential distribution among different ethnic groups and/or families. In contrast to monogenic diseases, gene-environment interactions are also suggested to play a crucial role, as well as stochastic events for passing the level for the induction of disease [5]. Genomewide scans and candidate gene approaches in MSAttempts to identify non-HLA susceptibility genes in MS have been based on genomewide linkage analysis and candidate gene approaches. The first four family-based genomewide analyses in MS were published in 1996 and in 1997: Canada [6], France and the US [7], the UK [8] and Finland [9]. There were no significant linkages detected in any of these studies. Nonetheless, some regions showed maximum logarithm of odds (LOD) score >0.5 and were identified in more than one genomewide scan. The highest LOD scores were obtained for ...

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Novel Quantitative Trait Loci Controlling Development of Experimental Autoimmune Encephalomyelitis and Proportion of Lymphocyte Subpopulations

Cited by 38 publications

References 47 publications

Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice

Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice

An Advanced Intercross Line ResolvesEae18into Two Narrow Quantitative Trait Loci Syntenic to Multiple Sclerosis Candidate Loci

Current Gene‐Mapping Strategies in Experimental Models of Multiple Sclerosis

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