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

Lukas Simon Enz; Thomas Zeis; Daniela Schmid; Florian Geier; Franziska van der Meer; Guido Steiner; Ulrich Certa; Thomas Martin Christian Binder; Christine Stadelmann; Roland Martin; Nicole Schaeren-Wiemers

doi:10.1212/NXI.0000000000000656

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

Neurol Neuroimmunol Neuroinflamm. 2019 Dec 27;7(2):e656. doi: 10.1212/NXI.0000000000000656. Print 2020 Mar.

Affiliations

¹ From the Neurobiology (L.S.E., T.Z., D.S., N.S.-W.), Department of Biomedicine, University Hospital Basel, University Basel, Zentrum für Lehre und Forschung, Switzerland; Department of Biomedicine (F.G.), Bioinformatics Core Facility, University Hospital Basel, Switzerland; SIB Swiss Institute of Bioinformatics (F.G.), Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center, Göttingen, Germany; Roche Pharma Research and Early Development (pRED) (G.S., U.C.), Roche Innovation Center Basel, Switzerland; Institute of Clinical Transfusion Medicine (T.M.C.B.), Hospital Braunschweig, Germany; and Neuroimmunology and MS Research (R.M.), Neurology Clinic, University Hospital Zurich, University Zurich, Switzerland.
² From the Neurobiology (L.S.E., T.Z., D.S., N.S.-W.), Department of Biomedicine, University Hospital Basel, University Basel, Zentrum für Lehre und Forschung, Switzerland; Department of Biomedicine (F.G.), Bioinformatics Core Facility, University Hospital Basel, Switzerland; SIB Swiss Institute of Bioinformatics (F.G.), Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center, Göttingen, Germany; Roche Pharma Research and Early Development (pRED) (G.S., U.C.), Roche Innovation Center Basel, Switzerland; Institute of Clinical Transfusion Medicine (T.M.C.B.), Hospital Braunschweig, Germany; and Neuroimmunology and MS Research (R.M.), Neurology Clinic, University Hospital Zurich, University Zurich, Switzerland. Nicole.schaeren-wiemers@unibas.ch.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Autopsy
Female
Gene Expression Profiling
Gray Matter / metabolism*
Gray Matter / pathology*
HLA-DR Serological Subtypes / genetics*
HLA-DRB1 Chains / genetics
HLA-DRB1 Chains / metabolism*
HLA-DRB5 Chains / metabolism*
Haplotypes
Humans
Immunohistochemistry
Male
Middle Aged
Multiple Sclerosis / genetics*
Multiple Sclerosis / metabolism*
Multiple Sclerosis / pathology*
Protein Array Analysis

Substances

HLA-DR Serological Subtypes
HLA-DR15 antigen
HLA-DRB1 Chains
HLA-DRB1*15:01 antigen
HLA-DRB5 Chains