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Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (29 December 2022) | Viewed by 20054

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Prof. Dr. Serge Nataf

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1. Bank of Tissues and Cells, Hospices Civils de Lyon, Hôpital Edouard Herriot, Place d’Arsonval, F-69003 Lyon, France
2. Stem-Cell and Brain Research Institute, 18 Avenue de Doyen Lépine, F-69500 Bron, France
3. Lyon-Est School of Medicine, University Claude Bernard Lyon 1, 43 Bd du 11 Novembre 1918, F-69100 Villeurbanne, France
Interests: multiple sclerosis pathophysiology; CNS-targeted autoimmunity; neuroinflammation; computational data mining; systems biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

There is increasing evidence that slowly evolving disability in multiple sclerosis (MS) patients is, at least in part, disconnected from relapses. Recent findings indicate that in addition to the well-recognized progressive forms of MS, a steady aggravation of neurological deficits may also occur in patients suffering from relapsing–remitting MS. Such a clinical progression is silent (i.e., independent from both clinical relapses and brain radiological activity) and was found to be closely associated with the rate of cervical spinal cord atrophy. While neurodegeneration in MS is usually thought to result from decades-long neuroinflammatory processes, these observations indicate that autoimmunity and neurodegeneration may actually develop concurrently. This Special Issue aims to provide an updated overview of our knowledge on the links between autoimmunity and neurodegeneration in MS. All papers relating to the general topic of this Special Issue will be considered. However, we specifically encourage submission of articles addressing one or several of the following issues in the context of MS or related disorders:

Neuronal target antigens in MS and/or its animal model (experimental autoimmune encephalomyelitis);
Mechanisms favoring the intrathecal persistence of autoreactive lymphocytes;
Pro-degenerative vs. pro-regenerative impact of molecules involved in the resolution of CNS acute inflammation;
Insights into the mechanisms of inflammation-associated axonal loss and/or synaptic pruning.

Prof. Dr. Serge Nataf
Guest Editor

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Keywords

neurodegeneration
multiple sclerosis
autoimmunity
T lymphocytes
B lymphocytes
demyelination
axonal loss
synaptic pruning
microglia
astrocytes

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

4 pages, 200 KiB

Open AccessEditorial

Myelinodegeneration vs. Neurodegeneration in MS Progressive Forms

by Serge Nataf

Int. J. Mol. Sci. 2023, 24(2), 1596; https://doi.org/10.3390/ijms24021596 - 13 Jan 2023

Viewed by 927

Abstract

In MS patients with a progressive form of the disease, the slow deterioration of neurological functions is thought to result from a combination of neuronal cell death, axonal damages and synaptic dysfunctions [...] Full article

(This article belongs to the Special Issue Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration)

Research

Jump to: Editorial, Review

14 pages, 2794 KiB

Open AccessArticle

Myelin Basic Protein Fragmentation by Engineered Human Proteasomes with Different Catalytic Phenotypes Revealed Direct Peptide Ligands of MS-Associated and Protective HLA Class I Molecules

by George A. Saratov, Vasiliy I. Vladimirov, Alexey L. Novoselov, Rustam H. Ziganshin, Guo Chen, Timur N. Baymukhametov, Andrey L. Konevega, Alexey A. Belogurov, Jr. and Anna A. Kudriaeva

Int. J. Mol. Sci. 2023, 24(3), 2091; https://doi.org/10.3390/ijms24032091 - 20 Jan 2023

Viewed by 2063

Abstract

Proteasomes exist in mammalian cells in multiple combinatorial variants due to the diverse regulatory particles and exchange of catalytic subunits. Here, using biotin carboxyl carrier domain of transcarboxylase from Propionibacterium shermanii fused with different proteasome subunits of catalytic and regulatory particles, we report comprehensive characterization of highly homogenous one-step purified human constitutive and immune 20S and 26S/30S proteasomes. Hydrolysis of a multiple sclerosis (MS) autoantigen, myelin basic protein (MBP), by engineered human proteasomes with different catalytic phenotypes, revealed that peptides which may be directly loaded on the HLA class I molecules are produced mainly by immunoproteasomes. We detected at least five MBP immunodominant core regions, namely, LPRHRDTGIL, SLPQKSHGR, QDENPVVHFF, KGRGLSLSRF and GYGGRASDY. All peptides, except QDENPVVHFF, which originates from the encephalitogenic MBP part, were associated with HLA I alleles considered to increase MS risk. Prediction of the affinity of HLA class I to this peptide demonstrated that MS-protective HLA-A*44 and -B*35 molecules are high-affinity binders, whereas MS-associated HLA-A*23, -A*24, -A*26 and -B*51 molecules tend to have moderate to low affinity. The HLA-A*44 molecules may bind QDENPVVHFF and its deamidated form in several registers with unprecedently high affinity, probably linking its distinct protective phenotype with thymic depletion of the repertoire of autoreactive cytotoxic T cells or induction of CD8+ regulatory T cells, specific to the encephalitogenic MBP peptide. Full article

(This article belongs to the Special Issue Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration)

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19 pages, 10751 KiB

Open AccessArticle

High Dose Pharmaceutical Grade Biotin (MD1003) Accelerates Differentiation of Murine and Grafted Human Oligodendrocyte Progenitor Cells In Vivo

by Marion J. F. Levy, Beatriz Garcia-Diaz, Frédéric Sedel, Anne Baron-Van Evercooren and Sabah Mozafari

Int. J. Mol. Sci. 2022, 23(24), 15733; https://doi.org/10.3390/ijms232415733 - 12 Dec 2022

Viewed by 1803

Abstract

Accumulating evidences suggest a strong correlation between metabolic changes and neurodegeneration in CNS demyelinating diseases such as multiple sclerosis (MS). Biotin, an essential cofactor for five carboxylases, is expressed by oligodendrocytes and involved in fatty acid synthesis and energy production. The metabolic effect of biotin or high-dose-biotin (MD1003) has been reported on rodent oligodendrocytes in vitro, and in neurodegenerative or demyelinating animal models. However, clinical studies, showed mild or no beneficial effect of MD1003 in amyotrophic lateral sclerosis (ALS) or MS. Here, we took advantage of a mouse model of myelin deficiency to study the effects of MD1003 on the behavior of murine and grafted human oligodendrocytes in vivo. We show that MD1003 increases the number and the differentiation potential of endogenous murine oligodendroglia over time. Moreover, the levels of MD1003 are increased in the plasma and brain of pups born to treated mothers, indicating that MD1003 can pass through the mother’s milk. The histological analysis of the grafted animals shows that MD1003 increased proliferation and accelerates differentiation of human oligodendroglia, but without enhancing their myelination potential. These findings provide important insights into the role of MD1003 on murine and human oligodendrocyte maturation/myelination that may explain the mitigated outcome of ALS/MS clinical trials. Full article

(This article belongs to the Special Issue Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration)

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14 pages, 1750 KiB

Open AccessArticle

Irrespective of Plaque Activity, Multiple Sclerosis Brain Periplaques Exhibit Alterations of Myelin Genes and a TGF-Beta Signature

by Serge Nataf, Marine Guillen and Laurent Pays

Int. J. Mol. Sci. 2022, 23(23), 14993; https://doi.org/10.3390/ijms232314993 - 30 Nov 2022

Cited by 2 | Viewed by 1397

Abstract

In a substantial share of patients suffering from multiple sclerosis (MS), neurological functions slowly deteriorate despite a lack of radiological activity. Such a silent progression, observed in either relapsing-remitting or progressive forms of MS, is driven by mechanisms that appear to be independent from plaque activity. In this context, we previously reported that, in the spinal cord of MS patients, periplaques cover large surfaces of partial demyelination characterized notably by a transforming growth factor beta (TGF-beta) molecular signature and a decreased expression of the oligodendrocyte gene NDRG1 (N-Myc downstream regulated 1). In the present work, we re-assessed a previously published RNA expression dataset in which brain periplaques were originally used as internal controls. When comparing the mRNA profiles obtained from brain periplaques with those derived from control normal white matter samples, we found that, irrespective of plaque activity, brain periplaques exhibited a TGF-beta molecular signature, an increased expression of TGFB2 (transforming growth factor beta 2) and a decreased expression of the oligodendrocyte genes NDRG1 (N-Myc downstream regulated 1) and MAG (myelin-associated glycoprotein). From these data obtained at the mRNA level, a survey of the human proteome allowed predicting a protein–protein interaction network linking TGFB2 to the down-regulation of both NDRG1 and MAG in brain periplaques. To further elucidate the role of NDRG1 in periplaque-associated partial demyelination, we then extracted the interaction network linking NDRG1 to proteins detected in human central myelin sheaths. We observed that such a network was highly significantly enriched in RNA-binding proteins that notably included several HNRNPs (heterogeneous nuclear ribonucleoproteins) involved in the post-transcriptional regulation of MAG. We conclude that both brain and spinal cord periplaques host a chronic process of tissue remodeling, during which oligodendrocyte myelinating functions are altered. Our findings further suggest that TGFB2 may fuel such a process. Overall, the present work provides additional evidence that periplaque-associated partial demyelination may drive the silent progression observed in a subset of MS patients. Full article

(This article belongs to the Special Issue Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration)

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16 pages, 3694 KiB

Open AccessArticle

Toward a Combination of Biomarkers for Molecular Characterization of Multiple Sclerosis

by Dafni Birmpili, Imane Charmarke Askar, Lucas Dinh Pham-Van, Thomas Kuntzel, Caroline Spenlé, Aurélien Riou and Dominique Bagnard

Int. J. Mol. Sci. 2022, 23(22), 14000; https://doi.org/10.3390/ijms232214000 - 13 Nov 2022

Viewed by 1363

Abstract

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system associated with chronic inflammation, demyelination, and axonal damage. MS is a highly heterogeneous disease that leads to discrepancies regarding the clinical appearance, progression, and therapy response of patients. Therefore, there is a strong unmet need for clinically relevant biomarkers capable of recapitulating the features of the disease. Experimental autoimmune encephalomyelitis (EAE) is a valuable model for studying the pathophysiology of MS as it recapitulates the main hallmarks of the disease: inflammation, blood-brain barrier (BBB) disruption, gliosis, myelin damage, and repair mechanisms. In this study, we used the EAE-PLP animal model and established a molecular RNA signature for each phase of the disease (onset, peak, remission). We compared variances of expression of known biomarkers by RT-qPCR in the brain and spinal cord of sham and EAE animals monitoring each of the five hallmarks of the disease. Using magnetic cell isolation technology, we isolated microglia and oligodendrocytes of mice of each category, and we compared the RNA expression variations. We identify genes deregulated during a restricted time frame, and we provide insight into the timing and interrelationships of pathological disease processes at the organ and cell levels. Full article

(This article belongs to the Special Issue Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration)

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13 pages, 2096 KiB

Open AccessArticle

Serum Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Biomarkers in Primary Progressive Multiple Sclerosis and Hereditary Spastic Paraplegia Type 4

by Christoph Kessler, Christoph Ruschil, Ahmed Abdelhak, Carlo Wilke, Aleksandra Maleska, Jens Kuhle, Markus Krumbholz, Markus C. Kowarik and Rebecca Schüle

Int. J. Mol. Sci. 2022, 23(21), 13466; https://doi.org/10.3390/ijms232113466 - 03 Nov 2022

Cited by 1 | Viewed by 1633

Abstract

In patients with slowly progressive spastic paraparesis, the differential diagnosis of primary progressive multiple sclerosis (PPMS) and hereditary spastic paraplegia (HSP) can be challenging. Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising fluid biomarkers to support the diagnostic workup. Serum NfL is a marker of neuroaxonal decay sensitive to temporal changes, while elevated sGFAP levels may reflect astrocytal involvement in PPMS. We assessed sNfL and sGFAP levels in 25 patients with PPMS, 25 patients with SPG4 (the most common type of HSP) and 60 controls, using the highly sensitive single-molecule array (Simoa) platform. Patients were matched in age, sex, age at onset, disease duration and disease severity. Serum NfL levels were significantly increased in PPMS compared to SPG4 (p = 0.041, partial η² = 0.088), and there was a trend toward relatively higher sGFAP levels in PPMS (p = 0.097). However, due to overlapping biomarker values in both groups, we did not find sNfL and sGFAP to be useful as differential biomarkers in our cohort. The temporal dynamics indicate sNfL and sGFAP levels are most markedly elevated in PPMS in earlier disease stages, supporting their investigation in this group most in need of a diagnostic biomarker. Full article

(This article belongs to the Special Issue Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration)

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14 pages, 1503 KiB

Open AccessArticle

CNS Pericytes Modulate Local T Cell Infiltration in EAE

by Kathrin Koch, Maren Lindner, Ann-Katrin Fleck, Marie Liebmann, Melanie Eschborn, Lisa Zondler, Rodrigo Diéguez-Hurtado, Ralf H. Adams, Gerd Meyer zu Hörste, Alexander Zarbock, Tanja Kuhlmann, Heinz Wiendl and Luisa Klotz

Int. J. Mol. Sci. 2022, 23(21), 13081; https://doi.org/10.3390/ijms232113081 - 28 Oct 2022

Cited by 4 | Viewed by 2078

Abstract

Pericytes at the blood–brain barrier (BBB) are located between the tight endothelial cell layer of the blood vessels and astrocytic endfeet. They contribute to central nervous system (CNS) homeostasis by regulating BBB development and maintenance. Loss of pericytes results in increased numbers of infiltrating immune cells in the CNS in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis (MS). However, little is known about their competence to modulate immune cell activation or function in CNS autoimmunity. To evaluate the capacity of pericytes to directly interact with T cells in an antigen-specific fashion and potentially (re)shape their function, we depleted major histocompatibility complex (MHC) class II from pericytes in a cell type-specific fashion and performed T cell-pericyte cocultures and EAE experiments. We found that pericytes present antigen in vitro to induce T cell activation and proliferation. In an adoptive transfer EAE experiment, pericyte-specific MHC II KO resulted in locally enhanced T cell infiltration in the CNS; even though, overall disease course of mice was not affected. Thus, pericytes may serve as non-professional antigen-presenting cells affecting states of T cell activation, thereby locally shaping lesion formation in CNS inflammation but without modulating disease severity. Full article

(This article belongs to the Special Issue Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration)

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15 pages, 970 KiB

Open AccessArticle

Sphingolipid Catabolism and Glycerophospholipid Levels Are Altered in Erythrocytes and Plasma from Multiple Sclerosis Patients

by Albena Momchilova, Roumen Pankov, Alexander Alexandrov, Tania Markovska, Stefan Pankov, Plamen Krastev, Galya Staneva, Evgenia Vassileva, Nikolai Krastev and Adriana Pinkas

Int. J. Mol. Sci. 2022, 23(14), 7592; https://doi.org/10.3390/ijms23147592 - 08 Jul 2022

Cited by 5 | Viewed by 1630

Abstract

Multiple sclerosis (MS) is an autoimmune, inflammatory, degenerative disease of the central nervous system. Changes in lipid metabolism have been suggested to play important roles in MS pathophysiology and progression. In this work we analyzed the lipid composition and sphingolipid-catabolizing enzymes in erythrocytes and plasma from MS patients and healthy controls. We observed reduction of sphingomyelin (SM) and elevation of its products—ceramide (CER) and shingosine (SPH). These changes were supported by the detected up-regulation of the activity of acid sphingomyelinase (ASM) in MS plasma and alkaline ceramidase (ALCER) in erythrocytes from MS patients. In addition, Western blot analysis showed elevated expression of ASM, but not of ALCER. We also compared the ratios between saturated (SAT), unsaturated (UNSAT) and polyunsaturated fatty acids and suggest, based on the significant differences observed for this ratio, that the UNSAT/SAT values could serve as a marker distinguishing erythrocytes and plasma of MS from controls. In conclusion, the application of lipid analysis in the medical practice would contribute to definition of more precise diagnosis, analysis of disease progression, and evaluation of therapeutic strategies. Based on the molecular changes of blood lipids in neurodegenerative pathologies, including MS, clinical lipidomic analytical approaches could become a promising contemporary tool for personalized medicine. Full article

(This article belongs to the Special Issue Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration)

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Review

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19 pages, 1202 KiB

Open AccessReview

Single-Cell Analysis to Better Understand the Mechanisms Involved in MS

by Emilie Dugast, Sita Shah and David-Axel Laplaud

Int. J. Mol. Sci. 2022, 23(20), 12142; https://doi.org/10.3390/ijms232012142 - 12 Oct 2022

Cited by 2 | Viewed by 1800

Abstract

Multiple sclerosis is a chronic and inflammatory disease of the central nervous system. Although this disease is widely studied, many of the precise mechanisms involved are still not well known. Numerous studies currently focusing on multiple sclerosis highlight the involvement of many major immune cell subsets, such as CD4+ T cells, CD8+ T cells and more recently B cells. However, our vision of its pathology has remained too broad to allow the proper use of targeted therapeutics. This past decade, new technologies have emerged, enabling deeper research into the different cell subsets at the single-cell level both in the periphery and in the central nervous system. These technologies could allow us to identify new cell populations involved in the disease process and new therapeutic targets. In this review, we briefly introduce the major single-cell technologies currently used in studies before diving into the major findings from the multiple sclerosis research from the past 5 years. We focus on results that were obtained using single-cell technologies to study immune cells and cells from the central nervous system. Full article

(This article belongs to the Special Issue Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration)

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20 pages, 2592 KiB

Open AccessReview

The Translatability of Multiple Sclerosis Animal Models for Biomarkers Discovery and Their Clinical Use

by Dafni Birmpili, Imane Charmarke Askar, Kévin Bigaut and Dominique Bagnard

Int. J. Mol. Sci. 2022, 23(19), 11532; https://doi.org/10.3390/ijms231911532 - 29 Sep 2022

Cited by 10 | Viewed by 2205

Abstract

Multiple Sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system which is characterized by demyelinating lesions and axonal damage. MS is a complex disease characterized by important pathophysiological heterogeneity affecting the clinical appearance, progression and therapeutic response for each patient. Therefore, there is a strong unmet need to define specific biomarkers that will reflect the different features of the disease. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental model for the study of MS, as it resembles the pathological features of human MS in many aspects and has allowed for the elucidation of pathogenesis pathways and the validation of certain targets for MS therapies. In this review, we discuss clinically relevant MS molecular biomarkers, divided into five groups based on the key pathological hallmarks of MS: inflammation, blood–brain barrier disruption, myelin and axonal damage, gliosis and, ultimately, repair mechanisms. To address the feasibility of translation between the animal model and human disease, we present an overview of several molecular biomarkers of each category and compare their respective deregulation patterns. We conclude that, like any disease animal model, EAE models can sometimes fail to mimic the entire spectrum of human disease, but they can nonetheless recapitulate the disease’s primary hallmarks. We show that the EAE model is a valuable tool for understanding MS physiopathological mechanisms and for identifying biomarkers fundamental for drug development. Full article

(This article belongs to the Special Issue Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration)

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12 pages, 680 KiB

Open AccessReview

The Possible Role of Neural Cell Apoptosis in Multiple Sclerosis

by Peter G. E. Kennedy, Woro George and Xiaoli Yu

Int. J. Mol. Sci. 2022, 23(14), 7584; https://doi.org/10.3390/ijms23147584 - 08 Jul 2022

Cited by 15 | Viewed by 2434

Abstract

The etiology of multiple sclerosis (MS), a demyelinating disease affecting the central nervous system (CNS), remains obscure. Although apoptosis of oligodendrocytes and neurons has been observed in MS lesions, the contribution of this cell death process to disease pathogenesis remains controversial. It is usually considered that MS-associated demyelination and axonal degeneration result from neuroinflammation and an autoimmune process targeting myelin proteins. However, experimental data indicate that oligodendrocyte and/or neuronal cell death may indeed precede the development of inflammation and autoimmunity. These findings raise the question as to whether neural cell apoptosis is the key event initiating and/or driving the pathological cascade, leading to clinical functional deficits in MS. Similarly, regarding axonal damage, a key pathological feature of MS lesions, the roles of inflammation-independent and cell autonomous neuronal processes need to be further explored. While oligodendrocyte and neuronal loss in MS may not necessarily be mutually exclusive, particular attention should be given to the role of neuronal apoptosis in the development of axonal loss. If proven, MS could be viewed primarily as a neurodegenerative disease accompanied by a secondary neuroinflammatory and autoimmune process. Full article

(This article belongs to the Special Issue Multiple Sclerosis at the Crossroads of Autoimmunity and Neurodegeneration)

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