Modes of Action of HLA-DR Susceptibility Specificities in Multiple Sclerosis

Modin, H; Olsson, Wiveka; Hillert, Jan; Masterman, Thomas

doi:10.1086/420977

Cited by 33 publications

(30 citation statements)

References 9 publications

(6 reference statements)

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“…For example, a predominant role of HLA-DRB1*03, *04, *13 and *15 alleles in susceptibility to multiple sclerosis has been observed in various populations. [94][95][96][97][98] These alleles have promoters of different apparent strengths, indicating several haplotypes can contribute to the same autoimmune disease. If expression is important in disease etiology, it is more likely an additional layer of complexity enables tissue and/or timing-specific MHC class II gene regulation in autoimmune diseases resulting in variable levels of class II molecules.…”

Section: Hla-drb9 Dr8mentioning

confidence: 99%

“…Epistasis among HLA-DRB1, HLA-DQA1 and HLA-DQB1 loci has been shown to influence MS risk. [94][95][96][97][98]179 Narcolepsy HLA-DQB1*0602 HLA-DQB1*06011associated with protection [180][181][182] Rheumatoid arthritis Figure 1 Genes and genetic diversity in the MHC class II region. The classical MHC class I, class III and class II regions are shown together with a higher resolution plot showing the location of genes within the MHC class II region chr6:32 250 000-33 300 000 (hg18 build 36.1).…”

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confidence: 99%

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Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

et al. 2009

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Major histocompatibility complex (MHC) class II molecules are central to adaptive immune responses and maintenance of selftolerance. Since the early 1970s, the MHC class II region at chromosome 6p21 has been shown to be associated with a remarkable number of autoimmune, inflammatory and infectious diseases. Given that a full explanation for most MHC class II disease associations has not been reached through analysis of structural variation alone, in this review we examine the role of genetic variation in modulating gene expression. We describe the intricate architecture of the MHC class II regulatory system, indicating how its unique characteristics may relate to observed associations with disease. There is evidence that haplotypespecific variation involving proximal promoter sequences can alter the level of gene expression, potentially modifying the emergence and expression of key phenotypic traits. Although much emphasis has been placed on cis-regulatory elements, we also examine the role of more distant enhancer elements together with the evidence of dynamic inter-and intra-chromosomal interactions and epigenetic processes. The role of genetic variation in such mechanisms may hold profound implications for susceptibility to common disease.

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Section: Hla-drb9 Dr8mentioning

confidence: 99%

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confidence: 99%

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

et al. 2009

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“…However, HLA-DR3 may confer a low relative risk compared to HLA-DRB1*1501, and large data sets may be necessary to detect its effect. Interestingly, a dose effect for HLA-DR3 has also been proposed in MS cases and controls, 29 and confirmed in family studies (Barcellos et al, unpublished data) However, in contrast to HLA-DR2, the risk conferred by DR3 appears to be recessive, with two copies (DR3/DR3) significantly increasing risk, compared to no risk for DR3/DRX individuals.…”

Section: Rr-ms Sp-msmentioning

confidence: 68%

“…3, confirming yet again, the known association with the HLA class II DR2 haplotype (HLA-DRB1*1501-DQA1*0102-DQB1*0602). Interestingly, an effect of HLA-DR2 copy number on disease risk has also been detected; [27][28][29] this observation was to a certain degree unexpected because if HLA-DRb molecules confer susceptibility in MS by presenting an encephalitogenic peptide, then a dominant effect would be anticipated. In the animal model of MS, experimental autoimmune encephalomyelitis or EAE, a single copy of a diseaseassociated MHC haplotype, when present in the context of an appropriate genetic background, is generally sufficient for the induction of susceptibility.…”

Section: Ms Genomicsmentioning

confidence: 98%

Multiple sclerosis genetics: leaving no stone unturned

2005

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Compelling epidemiologic and molecular data indicate that genes play a primary role in determining who is at risk for developing multiple sclerosis (MS), how the disease progresses, and how someone responds to therapy. The genetic component of MS etiology is believed to result from the action of allelic variants in several genes. Their incomplete penetrance and moderate individual effect probably reflects epistatic interactions, post-transcriptional regulatory mechanisms, and significant environmental influences. Equally significant, it is also likely that locus heterogeneity exists, whereby specific genes influence susceptibility and pathogenesis in some individuals but not in others. With the aid of novel analytical algorithms, the combined study of genomic, transcriptional, proteomic, and phenotypic information in well-controlled study groups will define a useful conceptual model of pathogenesis and a framework for understanding the mechanisms of action of existing therapies for this disorder, as well as the rationale for novel curative strategies.

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“…However, significant association was seen in Sweden 1 and Denmark, indicating a possible importance of this rare haplotype (Table 3b). Table 2a), also apparent when using a multiplicative model 55,56 for HLA-DRB1*15 and chemokine gene effects (data not shown). In contrast, no SNPs were associated to MS in the HLA-DRB1*15 negative subgroup (408 cases, 885 controls).…”

Section: Resultsmentioning

confidence: 88%

Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis

et al. 2009

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Multiple sclerosis (MS) is a complex disorder of the central nervous system, causing inflammation, demyelination and axonal damage. A limited number of genetic risk factors for MS have been identified, but the etiology of the disease remains largely unknown. For the identification of genes regulating neuroinflammation we used a rat model of MS, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), and carried out a linkage analysis in an advanced intercross line (AIL). We thereby redefine the Eae18b locus to a 0.88 Mb region, including a cluster of chemokine genes. Further, we show differential expression of Ccl2, Ccl11 and Ccl11 during EAE in rat strains with opposite susceptibility to EAE, regulated by genotype in Eae18b. The human homologous genes were tested for association to MS in 3841 cases and 4046 controls from four Nordic countries. A haplotype in CCL2 and rs3136682 in CCL1 show a protective association to MS, whereas a haplotype in CCL13 is disease predisposing. In the HLA-DRB1*15 positive subgroup, we also identified an association to a risk haplotype in CCL2, suggesting an influence from the human leukocyte antigen (HLA) locus. We further identified association to rheumatoid arthritis in CCL2, CCL8 and CCL13, indicating common regulatory mechanisms for complex diseases.

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Modes of Action of HLA-DR Susceptibility Specificities in Multiple Sclerosis

Cited by 33 publications

References 9 publications

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

Multiple sclerosis genetics: leaving no stone unturned

Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis

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