scholarly journals Peculiarities of the Presentation of the Encephalitogenic MBP Peptide by HLA-DR Complexes Providing Protection and Predisposition to Multiple Sclerosis

Acta Naturae ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 127-133
Author(s):  
Azad E. Mamedov ◽  
Ioanna N. Filimonova ◽  
Ivan V. Smirnov ◽  
Alexey A. Belogurov
Keyword(s):  
Multiple Sclerosis ◽  
Basic Protein ◽  
Terminal Part ◽  
High Affinity ◽  
Viral Peptide ◽  
Hla Dr ◽  
Allele Group ◽  
Order Of Magnitude ◽  
The Central Nervous System ◽  
Chronic Autoimmune Disease

Predisposition to multiple sclerosis (MS), a chronic autoimmune disease of the central nervous system, is due to various factors. The genetic component is considered one of the most important factors. HLA class II genes contribute the most to the development of MS. The HLA-DRB1*15 allele group is considered one of the main genetic risk factors predisposing to MS. The group of HLA-DRB1*01 alleles was shown to have a protective effect against this disease in the Russian population. In this work, we compared the binding of the encephalitogenic fragment of the myelin basic protein (MBP) to two HLA-DR complexes that provide protection against and predisposition to MS: HLA-DR1 (HLA-DRB1*0101) and HLA-DR15 (HLA-DRB1*1501), respectively. We found that the myelin peptide MBP88-100 binds to HLA-DR1 at a rate almost an order of magnitude lower than the viral peptide of hemagglutinin (HA). The same was true for the binding of MBP85-97 to HLA-DR15 in comparison with viral pp65. The structure of the C-terminal part of the peptide plays a key role in the binding to HLA-DR1 for equally high-affinity N-terminal regions of the peptides. The IC50 of the myelin peptide MBP88-100 competing with viral HA for binding to HLA-DR1 is almost an order of magnitude higher than that of HA. As for HA, the same was also true for the binding of MBP85-97 to HLA-DR15 in comparison with viral pp65. Thus, autoantigenic MBP cannot compete with the viral peptide for binding to protective HLA-DR1. However, it is more competitive than viral peptide for HLA-DR15.

Oligoclonal IgGs against DNA, Histones, and Myelin Basic Protein in the Cerebrospinal Fluid of Patients with Multiple Sclerosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Kostrikina IA ◽  
◽  
Granieri E ◽  
Nevinsky GA ◽  
◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Myelin Basic Protein ◽  
Basic Protein ◽  
Main Role ◽  
Barr Virus ◽  
The Central Nervous System ◽  
Epstein Barr ◽  
Ms Pathogenesis ◽  
Myelin Proteolipid

Multiple Sclerosis (MS) is known as a chronic demyelinating pathology of the central nervous system. The most accepted MS pathogenesis theory assigns the main role to demyelination of myelin-proteolipid shells due to inflammationrelated with autoimmune reactions. One of the features of MS patients is the enhanced synthesis of oligoclonal IgGs in the bone marrow Cerebrospinal Fluid (CSF). By antigen-specific immunoblotting after isoelectrofocusing of IgGs, oligoclonal IgGs in CSF of MS patients were revealed only against the components of Epstein-Barr virus and Chlamydia. However, there was still unknown to which human auto-antigens in MS patients oligoclonal IgGs may be produced. Here it was first shown that in the CSF of a narrow percentage of MS patients, oligoclonal IgGs are produced against their own antigens: DNA (24% patients), histones (20%), and myelin basic protein (12%). At the same time, the CSF of MS patients contains a very large amount of auto-IgGs-abzymes that hydrolyze DNA, histones, and myelin basic protein, which during isofocusing, are distributed throughout the gel from pH 3 to 10. It is concluded that these multiple IgGs-abzymes, which are dangerous to humans since stimulate development of MS, in the main are non-oligoclonal antibodies.

scholarly journals Disrupted microglial iron homeostasis in progressive multiple sclerosis

2021 ◽  
Author(s):  
Dimitry Ofengeim ◽  
Jonathan D Proto ◽  
Mindy Zhang ◽  
Sean Ryan ◽  
Xinting Yao ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Iron Homeostasis ◽  
Clinical Symptoms ◽  
Cell Types ◽  
Progressive Multiple Sclerosis ◽  
Post Mortem Brain ◽  
The Central Nervous System ◽  
Single Nucleus ◽  
Multiple Cell ◽  
Chronic Autoimmune Disease

Multiple Sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS). Despite therapies that reduce relapses, many patients eventually develop secondary progressive MS (SPMS), characterized by ongoing and irreversible neurodegeneration and worsening clinical symptoms. Microglia are the resident innate immune cells of the CNS. While the cellular and molecular determinants of disability progression in MS remain incompletely understood, they are thought to include non resolving microglial activation and chronic oxidative injury. In this study, our aim was to better characterize microglia in SPMS tissues to identify disease-related changes at the single cell level. We performed single nucleus RNA-seq (snRNA-seq) on cryopreserved post-mortem brain cortex and identified disease associated changes in multiple cell types and in particular distinct SPMS enriched microglia subsets. When compared to the cluster most enriched in healthy controls (i.e. homeostatic microglia), we found a number of SPMS-enriched clusters with transcriptional profiles reflecting increased oxidative stress and perturbed iron homeostasis. Using histology and RNA-scope, we confirmed the presence of iron accumulating, ferritin-light chain (FTL)-expressing microglia in situ. Among disease-enriched clusters, we found evidence for divergent responses to iron accumulation and identified the antioxidant enzyme GPX as a key fate determinant. These data help elucidate processes that occur in progressive MS brains, and highlight novel nodes for therapeutic intervention.

scholarly journals Multiple Sclerosis

2020 ◽  
Author(s):  
Amirhossein Azari Jafari ◽  
Seyyedmohammadsadeq Mirmoeeni
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Optic Nerve ◽  
Autoimmune Disease ◽  
The Central Nervous System ◽  
Genetic And Environmental Factors ◽  
Chronic Autoimmune Disease ◽  
The Brain

Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS), caused by genetic and environmental factors. It is characterized by intermittent and recurrent episodes of inflammation that result in the demyelination and subsequent damage of the underlying axons present in the brain, optic nerve and spinal cord [1][2][3].

scholarly journals Role of Immune Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

2020 ◽  
Author(s):  
Sarah Dhaiban ◽  
Mena Al-Ani ◽  
Noha Mousaad Elemam ◽  
Mahmood H Al-Aawad ◽  
Zeinab Al-Rawi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cells ◽  
T Regulatory Cells ◽  
Cell Types ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Chronic Autoimmune Disease ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system (CNS) characterized by varying degrees of demyelination of uncertain etiology, and is associated with specific environmental and genetic factors. Upon recognition of CNS antigens, the immune cells initiate an inflammatory process which leads to destruction and deterioration of the neurons. Innate immune cells such as macrophages, dendritic cells and natural killer cells are known to play critical roles in the pathogenesis of MS. Also, the activation of peripheral CD4+ T cells by CNS antigens leads to their extravasation into the CNS causing damages that exacerbates the disease. This could be accompanied by dysregulation of T regulatory cells and other cell types functions. Experimental autoimmune encephalomyelitis (EAE) is a mouse model used to study the pathophysiology of MS disease. In this review, we highlight the roles of innate and adaptive immune players in the pathogenesis of MS and EAE.

scholarly journals Fatigue and Affective Manifestations in Multiple Sclerosis—A Cluster Approach

2019 ◽  
Vol 10 (1) ◽  
pp. 10 ◽  
Author(s):  
Samar S. Ayache ◽  
Moussa A. Chalah
Keyword(s):  
Quality Of Life ◽  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Economic Cost ◽  
Cluster Approach ◽  
High Prevalence ◽  
The Central Nervous System ◽  
Chronic Autoimmune Disease

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, characterized by a high prevalence in young people, a drastic impact on the quality of life, and an important economic cost to society [...]

RNA-Seq profiling of leukocytes reveals a sex-dependent global circular RNA upregulation in multiple sclerosis and 6 candidate biomarkers

2020 ◽  
Vol 29 (20) ◽  
pp. 3361-3372
Author(s):  
Leire Iparraguirre ◽  
Ainhoa Alberro ◽  
Lucía Sepúlveda ◽  
Iñaki Osorio-Querejeta ◽  
Laura Moles ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Differential Expression Analysis ◽  
Area Under The Curve ◽  
Circular Rna ◽  
Circular Rnas ◽  
Rna Seq ◽  
Paired Samples ◽  
The Central Nervous System ◽  
Chronic Autoimmune Disease ◽  
Diagnosis Classification

Abstract Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, with higher prevalence in women, that leads to neurological disability. The disease course and clinical phenotype are highly variable, and therefore, biomarkers for the diagnosis, classification, monitoring of the disease and treatment assessment are needed. Studies have shown a dysregulation in the coding and non-coding RNAs and proposed some as biomarkers. However, still none of them have reached the clinical practice. Recently, circular RNAs (circRNAs) have emerged as new players in the transcriptome that hold a great potential as biomarkers in several diseases. Leukocytes from 30 MS patients and 20 healthy controls (HCs) were RNA-sequenced to study the linear and circular transcriptome. Differential expression analysis was performed by DESeq, and circRNA candidates were studied in a second cohort (70 MS and 46 HC) by RT-qPCR and in paired samples drawn during the relapse and remission phases (20 patients). Among the differentially expressed circRNAs, 96.1% are upregulated in patients compared with controls, but similar circRNA profiles are found between MS types. The same upregulation trend was observed in females but not in males or in the linear transcriptome. The upregulation of 6 circRNAs was validated, and a change in their expression was found between relapse and remission. The 6 circRNAs showed a good performance to discriminate patients from HC with a combined area under the curve of 0.852. There is global, specific and sex-dependent increase of circRNA expression in MS, and 6 circRNAs are proposed as potential biomarkers.

Loading rate of exogenous and autoantigenic determinants on major histocompatibility complex class ii mediates resistance to multiple sclerosis

2019 ◽  
Vol 485 (2) ◽  
pp. 238-241
Author(s):  
A. E. Mamedov ◽  
M. Y. Zakharova ◽  
O. O. Favorova ◽  
O. G. Kulakova ◽  
A. N. Boyko ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Major Histocompatibility Complex ◽  
Genetic Analysis ◽  
Major Histocompatibility Complex Class ◽  
Basic Protein ◽  
Loading Rate ◽  
Complex Class ◽  
Protective Properties ◽  
High Affinity ◽  
Histocompatibility Complex

Genetic analysis of thousands of patients with multiple sclerosis (MS) and healthy Russian donors showed that the carriage of groups of HLA-DRB1*15 and HLA-DRB1*03 alleles is associated with the risk of MS, whereas the carriage of groups of HLA-DRB1*01 and HLA-DRB1*11 alleles is protective. Recombinant HLA-DRB1*01:01 with a high affinity can recognize the fragments of myelin basic protein (MBP), one of the autoantigens in MS. However, the comparison of the kinetic parameters of the load of MBP and viral HA peptides on HLA-DRB1*01:01, which is catalyzed by HLA-DM, showed a significantly lower rate of exchange of CLIP for MBP peptides. We assume that the observed protective properties of the group of HLA-DRB1*01 alleles may be directly associated with the ability of HLA-DRB1*01:01 to kinetically distinguish peptides of exogenous and endogenous nature.

The role of Toll-like receptors in multiple sclerosis and possible targeting for therapeutic purposes

2014 ◽  
Vol 0 (0) ◽  
Author(s):  
Maziar Gooshe ◽  
Amir Hossein Abdolghaffari ◽  
Maria Elsa Gambuzza ◽  
Nima Rezaei
Keyword(s):  
Multiple Sclerosis ◽  
Host Defense ◽  
Toll Like Receptors ◽  
Autoimmune Encephalomyelitis ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Chronic Autoimmune Disease ◽  
Ms Therapy ◽  
Experimental Autoimmune

AbstractThe interaction between the immune and nervous systems suggests invaluable mechanisms for several pathological conditions, especially neurodegenerative disorders. Multiple sclerosis (MS) is a potentially disabling chronic autoimmune disease, characterized by chronic inflammation and neurodegenerative pathology of the central nervous system. Toll-like receptors (TLRs) are an important family of receptors involved in host defense and in recognition of invading pathogens. The role of TLRs in the pathogenesis of autoimmune disorders such as MS is only starting to be uncovered. Recent studies suggest an ameliorative role of TLR3 and a detrimental role of other TLRs in the onset and progression of MS and experimental autoimmune encephalomyelitis, a murine model of MS. Thus, modulating TLRs can represent an innovative immunotherapeutic approach in MS therapy. This article outlines the role of these TLRs in MS, also discussing TLR-targeted agonist or antagonists that could be used in the different stages of the disease.

scholarly journals Strategies for the identification of loci responsible for the pathogenesis of multiple sclerosis

2008 ◽  
Vol 13 (4) ◽  
Author(s):  
Joel Stern ◽  
Derin Keskin
Keyword(s):  
Multiple Sclerosis ◽  
Genetic Factors ◽  
Basic Protein ◽  
Accurate Determination ◽  
Proteolipid Protein ◽  
Disease Epidemiology ◽  
Sibling Pairs ◽  
Recent Developments ◽  
The Central Nervous System

AbstractMultiple sclerosis (MS) is a chronic, debilitating disease, which manifests itself by de-myelination of the central nervous system (CNS). MS is predominantly found in Caucasians of European decent and is more prominent in females than males. MS is one of the most prevalent causes of disability of young adults in the world. The exact cause of MS is not known, however genetic susceptibility to MS is linked to the major histocompability complex (MHC). Self reactive CD4+ T cells, specific for CNS antigens, such as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and proteolipid protein (PLP), are detectable in MS patients along with pathogenic autoantibodies specific to these CNS antigens produced by B cells. These observations suggest that MS is an autoimmune disease. Epidemiology of MS along with the analysis of sibling pairs and twins suggest that the multiple genetic factors and their interaction with environment contribute to disease susceptibility. Recent developments and advancements in genetic analysis may aid in accurate determination of genetic risk factors for the development of MS. We review these developments, advances in technology and discuss recent results in this article.

scholarly journals A myelin basic protein peptide is recognized by cytotoxic T cells in the context of four HLA-DR types associated with multiple sclerosis.

1991 ◽  
Vol 173 (1) ◽  
pp. 19-24 ◽  
Author(s):  
R Martin ◽  
M D Howell ◽  
D Jaraquemada ◽  
M Flerlage ◽  
J Richert ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Amino Acids ◽  
T Cell ◽  
Myelin Basic Protein ◽  
Basic Protein ◽  
Cytotoxic T Cells ◽  
Cell Receptor ◽  
T Cell Response ◽  
Hla Dr ◽  
T Cell Lines

We have examined previously the peptide specificity of the T cell response to myelin basic protein (MBP) in patients with multiple sclerosis (MS) and healthy controls, and demonstrated that an epitope spanning amino acids 87-106 was frequently recognized. Because this region is encephalitogenic in some experimental animals, it has been postulated that the response to the epitope may have relevance to MS. In this study, the fine specificity of this response is studied using four well-characterized, monospecific T cell lines from three MS patients and an identical twin of a patient. Each of the lines recognized a peptide with the same core sequence, amino acids 89-99, although the responses were affected to various degrees by truncations at the COOH- or NH2 terminal ends of the 87-106 epitope. Importantly, the epitope was recognized in conjunction with four different HLA-DR molecules. Also, the T cell receptor beta chain usage was heterogeneous, and each line expressed a different VDJ sequence. The four HLA-DR molecules restricting the response to this epitope have been shown to be overrepresented in MS populations in various geographic areas, suggesting that the response to this region of the MBP molecule may be relevant to the pathogenesis of MS. These findings may have important implications in designing therapeutic strategies for the disease.

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