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Chronic cerebrospinal vascular insufficiency is not associated with HLA DRB1*1501 status in multiple sclerosis patients.

ABSTRACT: BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) was described as a vascular condition characterized by anomalies of veins outside the skull was reported to be associated with multiple sclerosis (MS). The objective was to assess the associations between HLA DRB1*1501 status and the occurrence of CCSVI in MS patients. METHODOLOGY/PRINCIPAL FINDINGS: This study included 423 of 499 subjects enrolled in the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study. The HLA DRB1*1501 status was obtained in 268 MS patients and 155 controls by genotyping rs3135005, a SNP associated with DRB1*1501 status. All subjects underwent a clinical examination and Doppler scan of the head and neck. The frequency of CCSVI was higher (OR?=?4.52, p<0.001) in the MS group 56.0% vs. 21.9% in the controls group and also higher in the progressive MS group 69.8% vs. 49.5% in the non-progressive MS group. The 51.9% frequency of HLA DRB1*1501 positivity (HLA(+)) in MS was higher compared (OR?=?2.33, p<0.001) to 31.6% to controls. The HLA(+) frequency in the non-progressive (51.6%) and progressive MS groups (52.3%) was similar. The frequency of HLA(+) CCSVI(+) was 40.7% in progressive MS, 27.5% in non-progressive MS and 8.4% in controls. The presence of CCSVI was independent of HLA DRB1*1501 status in MS patients. CONCLUSIONS/SIGNIFICANCE: The lack of strong associations of CCSVI with HLA DRB1*1501 suggests that the role of the underlying associations of CCSVI in MS should be interpreted with caution. Further longitudinal studies should determine whether interactions between these factors can contribute to disease progression in MS.

SUBMITTER: Weinstock-Guttman B

PROVIDER: S-EPMC3038867 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Chronic cerebrospinal vascular insufficiency is not associated with HLA DRB1*1501 status in multiple sclerosis patients.

Weinstock-Guttman Bianca B Zivadinov Robert R Cutter Gary G Tamaño-Blanco Miriam M Marr Karen K Badgett Darlene D Carl Ellen E Elfadil Makki M Kennedy Cheryl C Benedict Ralph H B RH Ramanathan Murali M

PloS one 20110214 2

<h4>Background</h4>Chronic cerebrospinal venous insufficiency (CCSVI) was described as a vascular condition characterized by anomalies of veins outside the skull was reported to be associated with multiple sclerosis (MS). The objective was to assess the associations between HLA DRB1*1501 status and the occurrence of CCSVI in MS patients.<h4>Methodology/principal findings</h4>This study included 423 of 499 subjects enrolled in the Combined Transcranial and Extracranial Venous Doppler Evaluation ( ...[more]

PMID: 21340025

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Project description:BackgroundIt has been proposed by Zamboni and colleagues that multiple sclerosis is caused by chronic cerebrospinal venous insufficiency, a term used to describe ultrasound-detectable abnormalities in the anatomy and flow of intra- and extracerebral veins. We conducted a meta-analysis of studies that reported the frequency of chronic cerebrospinal venous insufficiency among patients with and those without multiple sclerosis.MethodsWe searched MEDLINE and EMBASE as well as bibliographies of relevant articles for eligible studies. We included studies if they used ultrasound to diagnose chronic cerebrospinal venous insufficiency and compared the frequency of the venous abnormalities among patients with and those without multiple sclerosis.ResultsWe identified eight eligible studies: all included healthy controls, and four of them also included a control group of patients with neurologic diseases other than multiple sclerosis. Chronic cerebrospinal venous insufficiency was more frequent among patients with multiple sclerosis than among the healthy controls (odds ratio [OR] 13.5, 95% confidence interval [CI] 2.6-71.4), but there was extensive unexplained heterogeneity among the studies. The association remained significant in the most conservative sensitivity analysis (OR 3.7, 95% CI 1.2-11.0), in which we removed the initial study by Zamboni and colleagues and added a study that did not find chronic cerebrospinal venous insufficiency in any patient. Although chronic cerebrospinal venous insufficiency was also more frequent among patients with multiple sclerosis than among controls with other neurologic diseases (OR 32.5, 95% CI 0.6-1775.7), the association was not statistically significant, the 95% CI was wide, and the OR was less extreme after removal of the study by Zamboni and colleagues (OR 3.5, 95% 0.8-15.8).InterpretationOur findings showed a positive association between chronic cerebrospinal venous insufficiency and multiple sclerosis. However, poor reporting of the success of blinding and marked heterogeneity among the studies included in our review precluded definitive conclusions.

Project description:A more effective vaccine against Mycobacterium tuberculosis is needed, and a number of M. tuberculosis vaccine candidates are currently in preclinical or clinical phase I and II studies. One of the strategies to select M. tuberculosis (protein) targets to elicit a CD8(+) or CD4(+) T-cell response is to gauge the binding of candidate peptides to major histocompatibility complex (MHC) class I or class II molecules, a prerequisite for successful peptide presentation and to expand antigen-specific T cells. We scanned 61 proteins from the M. tuberculosis proteome for potential MHC class II-presented epitopes that could serve as targets for CD4(+) T-cell responses. We constructed a peptide microarray consisting of 7,466 unique peptides derived from 61 M. tuberculosis proteins. The peptides were 15-mers overlapping by 12 amino acids. Soluble recombinant DRB1*0101 (DR1), DRB1*1501 (DR2), and DRB1*0401 (DR4) monomers were used to gauge binding to individual peptide species. Out of 7,466 peptides, 1,282, 674, and 1,854 peptides formed stable complexes with HLA-DR1, -DR2, and -DR4, respectively. Five hundred forty-four peptides bound to all three MHC class II molecules, 609 bound to only two, and 756 bound to only a single MHC class II molecule. This allowed us to rank M. tuberculosis proteins by epitope density. M. tuberculosis proteins contained "hot spots," i.e., regions with enriched MHC class II binding epitopes. Two hundred twenty-two peptides that formed MHC class II-peptide complexes had previously been described as exclusively recognized by IgG in sera from patients with active pulmonary tuberculosis, but not in sera from healthy individuals, suggesting that these peptides serve as B-cell and CD4(+) T-cell epitopes. This work helps to identify not only M. tuberculosis peptides with immunogenic potential, but also the most immunogenic proteins. This information is useful for vaccine design and the development of future tools to explore immune responses to M. tuberculosis.

Project description:Multiple sclerosis (MS), a common central nervous system inflammatory disease, has a major heritable component. Susceptibility is associated with the MHC class II region, especially HLA-DRB5*0101-HLA-DRB1*1501-HLA-DQA1*0102-HLA-DQB1*0602 haplotypes(hereafter DR2), which dominate genetic contribution to MS risk. Marked linkage disequilibrium (LD) among these loci makes identification of a specific locus difficult. The once-leading candidate, HLA-DRB1*15, localizes to risk, neutral, and protective haplotypes. HLA-DRB1*15 and HLA-DQB1*0602, nearly always located together on a small ancestral chromosome segment, are strongly MS-associated. One intervening allele on this haplotype, viz. HLA-DQA1*0102, shows no primary MS association. Two Canadian cohorts (n = 830 and n = 438 trios) genotyped for HLA-DRB1, HLA-DQA1 and HLA-DQB1 alleles were tested for association using TDT. To evaluate epistasis involving HLA-DRB1*15, transmissions from HLA-DRB1*15-negative parents were stratified by the presence/absence of HLA-DRB1*15 in affected offspring. All 3 alleles contribute to MS susceptibility through novel epistatic interactions. HLA-DQA1*0102 increased disease risk when combined with HLA-DRB1*1501 in trans, thereby unambiguously implicating HLA-DQ in MS susceptibility. Three-locus haplotypes demonstrated that HLA-DRB1*1501 and HLA-DQB1*0602 each influence risk. Transmissions of rare morcellated DR2 haplotypes showed no interaction with HLA-DQA1*0102. Incomplete haplotypes bearing only HLA-DRB1*1501 or HLA-DQB1*0602 did not predispose to MS. Balanced reciprocal transmission distortion can mask epistatic allelic association. These findings implicate epistasis among HLA class II alleles in human immune responses generally, provide partial explanation for intense linkage disequilibrium in the MHC, have relevance to animal models, and demonstrate key roles for DR2-specific interactions in MS susceptibility. MHC disease associations may be more generally haplotypic or diplotypic.

Dataset Information

Chronic cerebrospinal vascular insufficiency is not associated with HLA DRB1*1501 status in multiple sclerosis patients.

Publications

Chronic cerebrospinal vascular insufficiency is not associated with HLA DRB1*1501 status in multiple sclerosis patients.

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