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

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

doi:10.1212/nxi.0000000000000656

Cited by 29 publications

(18 citation statements)

References 48 publications

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“…However, while NAWM microglia have a lipid signature, NAGM microglia have increased expression of genes related to glycolysis and iron homeostasis ( SCL25A37, ABCB6 ) and a neurodegenerative profile ( CXCR4, GPNMB, OPN/SPP1 ) ( Figure 3 ). Furthermore, in HLADRB1*15:01 positive patients, HLA-DRB1 and B5 were the highest expressed genes in NAGM ( 37 ).…”

Section: Resultsmentioning

confidence: 99%

A Systematic Review of Tissue and Single Cell Transcriptome/Proteome Studies of the Brain in Multiple Sclerosis

Elkjaer

Röttger

Baumbach³

et al. 2022

Front. Immunol.

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Multiple sclerosis (MS) is an inflammatory demyelinating and degenerative disease of the central nervous system (CNS). Although inflammatory responses are efficiently treated, therapies for progression are scarce and suboptimal, and biomarkers to predict the disease course are insufficient. Cure or preventive measures for MS require knowledge of core pathological events at the site of the tissue damage. Novelties in systems biology have emerged and paved the way for a more fine-grained understanding of key pathological pathways within the CNS, but they have also raised questions still without answers. Here, we systemically review the power of tissue and single-cell/nucleus CNS omics and discuss major gaps of integration into the clinical practice. Systemic search identified 49 transcriptome and 11 proteome studies of the CNS from 1997 till October 2021. Pioneering molecular discoveries indicate that MS affects the whole brain and all resident cell types. Despite inconsistency of results, studies imply increase in transcripts/proteins of semaphorins, heat shock proteins, myelin proteins, apolipoproteins and HLAs. Different lesions are characterized by distinct astrocytic and microglial polarization, altered oligodendrogenesis, and changes in specific neuronal subtypes. In all white matter lesion types, CXCL12, SCD, CD163 are highly expressed, and STAT6- and TGFβ-signaling are increased. In the grey matter lesions, TNF-signaling seems to drive cell death, and especially CUX2-expressing neurons may be susceptible to neurodegeneration. The vast heterogeneity at both cellular and lesional levels may underlie the clinical heterogeneity of MS, and it may be more complex than the current disease phenotyping in the clinical practice. Systems biology has not solved the mystery of MS, but it has discovered multiple molecules and networks potentially contributing to the pathogenesis. However, these results are mostly descriptive; focused functional studies of the molecular changes may open up for a better interpretation. Guidelines for acceptable quality or awareness of results from low quality data, and standardized computational and biological pipelines may help to overcome limited tissue availability and the “snap shot” problem of omics. These may help in identifying core pathological events and point in directions for focus in clinical prevention.

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Section: Resultsmentioning

confidence: 99%

A Systematic Review of Tissue and Single Cell Transcriptome/Proteome Studies of the Brain in Multiple Sclerosis

Elkjaer

Röttger

Baumbach³

et al. 2022

Front. Immunol.

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“…Thus, the cooperation of DR2a and DR2b may increase the fitness to cope with viral infection but also the risk of pathogenic autoreactivity. A recent study documented that DR2a and DR2b are expressed highly in normal-appearing gray matter in MS brains ( Enz et al., 2019 ), the region where RASGRP2 is found in cortical neurons ( Jelcic et al., 2018 ).…”

Section: Discussionmentioning

confidence: 99%

HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis

Wang

Jelčić

Mühlenbruch

et al. 2020

Cell

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157

126

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Summary The HLA-DR15 haplotype is the strongest genetic risk factor for multiple sclerosis (MS), but our understanding of how it contributes to MS is limited. Because autoreactive CD4 + T cells and B cells as antigen-presenting cells are involved in MS pathogenesis, we characterized the immunopeptidomes of the two HLA-DR15 allomorphs DR2a and DR2b of human primary B cells and monocytes, thymus, and MS brain tissue. Self-peptides from HLA-DR molecules, particularly from DR2a and DR2b themselves, are abundant on B cells and thymic antigen-presenting cells. Furthermore, we identified autoreactive CD4 + T cell clones that can cross-react with HLA-DR-derived self-peptides (HLA-DR-SPs), peptides from MS-associated foreign agents (Epstein-Barr virus and Akkermansia muciniphila ), and autoantigens presented by DR2a and DR2b. Thus, both HLA-DR15 allomorphs jointly shape an autoreactive T cell repertoire by serving as antigen-presenting structures and epitope sources and by presenting the same foreign peptides and autoantigens to autoreactive CD4 + T cells in MS.

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“…DRB1*15:01 and DRB5*01:01 are the two genes with highest differential expression in normal appearing gray matter of the brains of MS patients [66].…”

Section: Trends In Geneticsmentioning

confidence: 97%

“…Furthermore, studies of DR2a and DR2b expression by different immune cells, but also in the thymus and the brain of MS patients, demonstrated that both alleles are always coexpressed, although at varied levels in different cell types [65]. A recent study of gene expression in normal-appearing cortical gray matter in MS patients surprisingly demonstrated that the most strongly upregulated genes are DR2b and DR2a, even in the absence of overt signs of inflammation or damage [66]. Most likely, microglial cells are responsible for these changes.…”

Section: Trends In Geneticsmentioning

confidence: 99%

Multiple sclerosis: doubling down on MHC

et al. 2021

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Human leukocyte antigen (HLA)-encoded surface molecules present antigenic peptides to T lymphocytes and play a key role in adaptive immune responses.Besides their physiological role of defending the host against infectious pathogens, specific alleles serve as genetic risk factors for autoimmune diseases. For multiple sclerosis (MS), an autoimmune disease that affects the brain and spinal cord, an association with the HLA-DR15 haplotype was described in the early 1970s. This short opinion piece discusses the difficulties of disentangling the details of this association and recent observations about the functional involvement of not only one, but also the second gene of the HLA-DR15 haplotype. This information is not only important for understanding the pathomechanism of MS, but also for antigen-specific therapies.

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

Cited by 29 publications

References 48 publications

A Systematic Review of Tissue and Single Cell Transcriptome/Proteome Studies of the Brain in Multiple Sclerosis

A Systematic Review of Tissue and Single Cell Transcriptome/Proteome Studies of the Brain in Multiple Sclerosis

HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis

Multiple sclerosis: doubling down on MHC

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