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Increased HLA-DR expression and cortical demyelination in MS links with HLA-DR15.

ABSTRACT: OBJECTIVE:To investigate molecular changes in multiple sclerosis (MS) normal-appearing cortical gray matter (NAGM). METHODS:We performed a whole-genome gene expression microarray analysis of human brain autopsy tissues from 64 MS NAGM samples and 42 control gray matter samples. We further examined our cases by HLA genotyping and performed immunohistochemical and immunofluorescent analysis of all human brain tissues. RESULTS:HLA-DRB1 is the transcript with highest expression in MS NAGM with a bimodal distribution among the examined cases. Genotyping revealed that every case with the MS-associated HLA-DR15 haplotype also shows high HLA-DRB1 expression and also of the tightly linked HLA-DRB5 allele. Quantitative immunohistochemical analysis confirmed the higher expression of HLA-DRB1 in HLA-DRB1*15:01 cases at the protein level. Analysis of gray matter lesion size revealed a significant increase of cortical lesion size in cases with high HLA-DRB1 expression. CONCLUSIONS:Our data indicate that increased HLA-DRB1 and -DRB5 expression in the brain of patients with MS may be an important factor in how the HLA-DR15 haplotype contributes to MS pathomechanisms in the target organ.

SUBMITTER: Enz LS

PROVIDER: S-EPMC6943368 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Increased HLA-DR expression and cortical demyelination in MS links with HLA-DR15.

Enz Lukas Simon LS Zeis Thomas T Schmid Daniela D Geier Florian F van der Meer Franziska F Steiner Guido G Certa Ulrich U Binder Thomas Martin Christian TMC Stadelmann Christine C Martin Roland R Schaeren-Wiemers Nicole N

Neurology(R) neuroimmunology & neuroinflammation 20191227 2

<h4>Objective</h4>To investigate molecular changes in multiple sclerosis (MS) normal-appearing cortical gray matter (NAGM).<h4>Methods</h4>We performed a whole-genome gene expression microarray analysis of human brain autopsy tissues from 64 MS NAGM samples and 42 control gray matter samples. We further examined our cases by HLA genotyping and performed immunohistochemical and immunofluorescent analysis of all human brain tissues.<h4>Results</h4>HLA-DRB1 is the transcript with highest expression ...[more]

PMID: 31882398

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Project description:BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease under genetic control. Growing evidences support the genetic predisposition of HLA-DRB1 gene polymorphisms to SLE, yet the results are not often reproducible. The purpose of this study was to assess the association of two polymorphisms of HLA-DRB1 gene (HLA-DR3 and HLA-DR15) with the risk of SLE via a comprehensive meta-analysis.MethodsThis study complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Case-control studies on HLA-DRB1 and SLE were searched from PubMed, Elsevier Science, Springer Link, Medline, and Cochrane Library database as of June 2018. Analysis was based on the random-effects model using STATA software version 14.0.ResultsA total of 23 studies were retained for analysis, including 5261 cases and 9838 controls. Overall analysis revealed that HLA-DR3 and HLA-DR15 polymorphisms were associated with the significant risk of SLE (odds ratio [OR]: 1.60, 95% confidence interval (CI): 1.316-1.934, P = 0.129 and OR: 1.68, 95% CI: 1.334-2.112, P = 0.001, respectively). Subgroup analyses demonstrated that for both HLA-DR3 and HLA-DR15 polymorphisms, ethnicity was a possible source of heterogeneity. Specifically, HLA-DR3 polymorphism was not associated with SLE in White populations (OR: 1.60, 95% CI: 1.320-1.960, P = 0.522) and HLA-DR15 polymorphism in East Asian populations (OR: 1.65, 95% CI: 1.248-2.173, P = 0.001). In addition, source of control was another possible source for both HLA-DR3 and HLA-DR15 polymorphisms, with observable significance for HLA-DR3 in only population-based studies (OR: 1.65, 95% CI: 1.370-1.990, P = 0.244) and for HLA-DR15 in both population-based and hospital-based studies (OR: 1.38, 95% CI: 1.078-1.760, P = 0.123 and OR: 2.08, 95% CI: 1.738-2.490, P = 0.881, respectively).ConclusionsHLA-DRB1 gene may be a SLE-susceptibility gene, and it shows evident ethnic heterogeneity. Further prospective validations across multiple ethnical groups are warranted.

Dataset Information

Increased HLA-DR expression and cortical demyelination in MS links with HLA-DR15.

Publications

Increased HLA-DR expression and cortical demyelination in MS links with HLA-DR15.

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