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Increased HLA-DR expression and cortical demyelination in MS links with HLA-DR15
Lukas Simon Enz1, Thomas Zeis1, Daniela Schmid1
1From 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.
High expression of HLA-DRB1 and HLA-DRB5 in multiple sclerosis (MS) normal-appearing gray matter is linked to the MS-associated HLA-DR15 haplotype and increased cortical lesion size.
Area of Science:
- Neuroimmunology
- Genetics
- Molecular Biology
Background:
- Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system.
- Understanding molecular changes in normal-appearing gray matter (NAGM) is crucial for elucidating MS pathogenesis.
- The role of specific genetic factors, like the HLA complex, in MS is an active area of research.
Purpose of the Study:
- To investigate molecular alterations in normal-appearing cortical gray matter (NAGM) in multiple sclerosis (MS).
- To explore the association between gene expression, specific genetic haplotypes, and neuropathological features in MS brain tissue.
Main Methods:
- Whole-genome gene expression microarray analysis of 64 MS NAGM samples and 42 control gray matter samples.
- HLA genotyping and immunohistochemical/immunofluorescent analysis of human brain autopsy tissues.
- Quantitative analysis of gene and protein expression, and correlation with cortical lesion size.
Main Results:
- HLA-DRB1 demonstrated the highest expression in MS NAGM, with a bimodal distribution.
- Cases with the MS-associated HLA-DR15 haplotype exhibited high HLA-DRB1 and HLA-DRB5 expression.
- Increased HLA-DRB1 expression correlated with a significant increase in cortical lesion size.
Conclusions:
- Elevated expression of HLA-DRB1 and HLA-DRB5 in the MS brain may be a key mechanism by which the HLA-DR15 haplotype influences MS pathology.
- These findings highlight the potential role of specific genetic and molecular factors in the target organ of MS.
