The role of the CD58 locus in multiple sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system associated with demyelination and axonal loss. A whole genome association scan suggested that allelic variants in the CD58 gene region, encoding the costimulatory molecule LFA-3, are associated with risk of developing MS. We now report additional genetic evidence, as well as resequencing and fine mapping of the CD58 locus in patients with MS and control subjects. These efforts identify a CD58 variant that provides further evidence of association with MS (P ‫؍‬ 1.1 ؋ 10 ؊6 , OR 0.82) and the single protective effect within the CD58 locus is captured by the rs2300747 G allele. This protective rs2300747 G allele is associated with a dose-dependent increase in CD58 mRNA expression in lymphoblastic cell lines (P ‫؍‬ 1.1 ؋ 10 ؊10 ) and in peripheral blood mononuclear cells from MS subjects (P ‫؍‬ 0.0037). This protective effect of enhanced CD58 expression on circulating mononuclear cells in patients with MS is supported by finding that CD58 mRNA expression is higher in MS subjects during clinical remission. Functional investigations suggest a potential mechanism whereby increases in CD58 expression, mediated by the protective allele, up-regulate the expression of transcription factor FoxP3 through engagement of the CD58 receptor, CD2, leading to the enhanced function of CD4 ؉ CD25 high regulatory T cells that are defective in subjects with MS.M ultiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system associated with demyelination, axonal loss, and brain atrophy; susceptibility to this disease is affected by both genetic variation and environmental risk factors (1, 2). The initial episode of neurologic dysfunction results in a clinical diagnosis of a clinically isolated demyelinating syndrome (CIS), and a second episode leads to a diagnosis of MS (1). Increasing evidence suggests that activated, autoreactive T cells play a central role in MS pathophysiology, as evidenced by the efficacy of treatments such as Natalizumab (anti-VLA-4 monoclonal antibody) that block lymphocyte egress from the vascular compartment into the CNS (3). Furthermore, the control of activated T cells by natural regulatory CD4 ϩ T cells is impaired in subjects with MS (4). This population of regulatory CD4 ϩ T cells expresses high levels of the IL-2 receptor (CD25) and FoxP3, an important transcription factor for regulatory T cells (4). We have now begun to integrate these immunologic observations with results of our genetic studies in patients with MS.Two novel MS susceptibility loci have recently been identified using a genome-wide association scan approach, and these 2 loci, IL2RA and IL7R, have now been validated in independent subject collections (5-9). In the genome scan, several other loci, including the CD58 locus, displayed suggestive evidence of association with MS susceptibility. Since CD58 (LFA-3) costimulates and enhances T cell receptor signaling by engaging CD2 (10), the CD58 locus is an attractive target for understanding ...

Functionally Significant Differences in Expression of Disease-Associated IL-7 Receptor α Haplotypes in CD4 T Cells and Dendritic Cells

“…The net effect of differential haplotype effects on expression may need to be determined from correlations of genotype with immunophenotype. In MS there is evidence of an altered immunophenotype (7,40), but as yet no correlation with IL-7Ra genotype has been described for these aberrant cell subsets. It is also possible that immunophenotype differences are dynamic, differing at the onset of disease and as it progresses, so that genotype effect on it are masked or difficult to dissect.…”

“…This is especially so for those genes expressed predominantly in T cells and DCs, such as IL-2Ra (CD25), CD6, CD40, CD58, IFN regulatory factor 8, and CD120a, now also confirmed as associated with MS (4,40,41).…”

Gender-Associated Differences of Perforin Polymorphisms in the Susceptibility to Multiple Sclerosis

“…Although the etiology of the disease is unknown, both genetic and environmental factors are playing a role in MS etiopathogenesis (1). In addition to the wellknown association with the MHC on chromosome 6p21, in particular the HLA-DRB1 p 1501 allele that contributes by far the most to genetic susceptibility to MS (2,3), other loci outside the MHC region with modest effects on the MS genetic risk have been recently identified (4)(5)(6)(7).…”

Multiple sclerosis

“…The co-stimulatory molecule CD58/LFA-3 engages CD2 to co-stimulate T cell receptor signaling, including Treg activation (95). Increased levels of CD58 appear to be protective for MS (96), likely because the increased CD2 co-stimulation promotes FoxP3 expression and improves Treg suppressive activity (97,98). Defects in CD58 expression with reduced CD2 co-stimulation might explain the low FoxP3 expression levels observed in MS patients (99).…”