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Orian JM. A New Perspective on Mechanisms of Neurodegeneration in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis: the Early and Critical Role of Platelets in Neuro/Axonal Loss. J Neuroimmune Pharmacol 2025; 20:14. [PMID: 39904925 PMCID: PMC11794395 DOI: 10.1007/s11481-025-10182-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 01/26/2025] [Indexed: 02/06/2025]
Abstract
Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disorder, with limited treatment options. This disease is characterized by differential pathophysiology between grey matter (GM) and white matter (WM). The predominant WM hallmark is the perivascular plaque, associated with blood brain barrier (BBB) loss of function, lymphocytic infiltration, microglial reactivity, demyelination and axonal injury and is adequately addressed with immunomodulatory drugs. By contrast, mechanisms underlying GM damage remain obscure, with consequences for neuroprotective strategies. Cortical GM pathology is already significant in early MS and characterized by reduced BBB disruption and lymphocytic infiltration relative to WM, but a highly inflammatory environment, microglial reactivity, demyelination and neuro/axonal loss. There is no satisfactory explanation for the occurrence of neurodegeneration without large-scale inflammatory cell influx in cortical GM. A candidate mechanism suggests that it results from soluble factors originating from meningeal inflammatory cell aggregates, which diffuse into the underlying cortical tissue and trigger microglial activation. However, the recent literature highlights the central role of platelets in inflammation, together with the relationship between coagulation factors, particularly fibrinogen, and tissue damage in MS. Using the experimental autoimmune encephalomyelitis (EAE) model, we identified platelets as drivers of neuroinflammation and platelet-neuron associations from the pre-symptomatic stage. We propose that fibrinogen leakage across the BBB is a signal for platelet infiltration and that platelets represent a major and early participant in neurodegeneration. This concept is compatible with the new appreciation of platelets as immune cells and of neuronal damage driven by inflammatory cells sequestered in the meninges.
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Affiliation(s)
- Jacqueline Monique Orian
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Vic. 3086, Australia.
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2
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De Jager P, Zeng L, Khan A, Lama T, Chitnis T, Weiner H, Wang G, Fujita M, Zipp F, Taga M, Kiryluk K. GWAS highlights the neuronal contribution to multiple sclerosis susceptibility. RESEARCH SQUARE 2025:rs.3.rs-5644532. [PMID: 39866869 PMCID: PMC11760239 DOI: 10.21203/rs.3.rs-5644532/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative disease affecting the brain and spinal cord. Genetic studies have identified many risk loci, that were thought to primarily impact immune cells and microglia. Here, we performed a multi-ancestry genome-wide association study with 20,831 MS and 729,220 control participants, identifying 236 susceptibility variants outside the Major Histocompatibility Complex, including four novel loci. We derived a polygenic score for MS and, optimized for European ancestry, it is informative for African-American and Latino participants. Integrating single-cell data from blood and brain tissue, we identified 76 genes affected by MS risk variants. Notably, while T cells showed the strongest enrichment, inhibitory neurons emerged as a key cell type. The expression of IL7 and STAT3 are affected only in inhibitory neurons, highlighting the importance of neuronal and glial dysfunction in MS susceptibility.
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Affiliation(s)
| | - Lu Zeng
- Columbia University Irving Medical Center
| | | | | | | | | | | | | | - Frauke Zipp
- University Medical Center of the Johannes Gutenberg University Mainz
| | - Mariko Taga
- Center for Translational & Computational Neuroimmunology
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3
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Sastri KT, Gupta NV, Kannan A, Dutta S, Ali M Osmani R, V B, Ramkishan A, S S. The next frontier in multiple sclerosis therapies: Current advances and evolving targets. Eur J Pharmacol 2024; 985:177080. [PMID: 39491741 DOI: 10.1016/j.ejphar.2024.177080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 10/11/2024] [Accepted: 10/28/2024] [Indexed: 11/05/2024]
Abstract
Recent advancements in research have significantly enhanced our comprehension of the intricate immune components that contribute to multiple sclerosis (MS) pathogenesis. By conducting an in-depth analysis of complex molecular interactions involved in the immunological cascade of the disease, researchers have successfully identified novel therapeutic targets, leading to the development of innovative therapies. Leveraging pioneering technologies in proteomics, genomics, and the assessment of environmental factors has expedited our understanding of the vulnerability and impact of these factors on the progression of MS. Furthermore, these advances have facilitated the detection of significant biomarkers for evaluating disease activity. By integrating these findings, researchers can design novel molecules to identify new targets, paving the way for improved treatments and enhanced patient care. Our review presents recent discoveries regarding the pathogenesis of MS, highlights their genetic implications, and proposes an insightful approach for engaging with newer therapeutic targets in effectively managing this debilitating condition.
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Affiliation(s)
- K Trideva Sastri
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Shivarathreeshwara Nagara, Bannimantap, Mysuru, India.
| | - N Vishal Gupta
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Shivarathreeshwara Nagara, Bannimantap, Mysuru, India.
| | - Anbarasu Kannan
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysuru, India
| | - Suman Dutta
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK
| | - Riyaz Ali M Osmani
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Shivarathreeshwara Nagara, Bannimantap, Mysuru, India
| | - Balamuralidhara V
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Shivarathreeshwara Nagara, Bannimantap, Mysuru, India
| | - A Ramkishan
- Deputy Drugs Controller (India), Central Drugs Standard Control Organization, Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India, India
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4
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Ackun-Farmmer MA, Willson Shirkey M, Oakes RS, Shah SA, Edwards C, Kapnick S, Carey ST, Yanes A, Bromberg J, Jewell CM. Engineered Immune Constructs Alter Antigen-Specific Immune Tolerance and Confer Durable Protection in Myelin-Driven Autoimmunity. ACS NANO 2024; 18:31780-31793. [PMID: 39520377 DOI: 10.1021/acsnano.4c06667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
Autoimmune diseases are broadly characterized as a failure in immune tolerance. In multiple sclerosis (MS), autoreactive immune cells attack the protective myelin sheath lining neurons in the central nervous system. Therapeutic strategies that selectively and durably restore immune tolerance without broad immunosuppression are urgently needed for MS. Our lab has developed assemblies of immune constructs built entirely from myelin antigen (MOG35-55 or PLP139-151) and regulatory innate immune cues (GpG) using layer-by-layer self-assembly. Here, we present mechanistic and translational data showing these assemblies confer therapeutic benefits in a range of clinically relevant disease contexts, including progressive disease in male mice and in relapsing-remitting disease that mimics the intermittent bouts of disease and remission most MS patients initially experience. Here, the antigen component in the complexes is matched to the disease-causing antigen, resulting in a decrease in paralysis in these models. We show that subcutaneous delivery of assemblies durably prevents diseases and drives tolerance by regulatory remodeling of the draining lymph node. Importantly, we show that subcutaneously delivered assemblies recruit and expand antigen-specific regulatory T cells (TREGS) in draining lymph nodes. Finally, we find a shift of these recruited TREGS from a resting to an activated phenotype. Taken together, these data inform the design of therapeutics for antigen-specific tolerance that could combat autoimmunity by exploiting the role of innate pathways in a disease.
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Affiliation(s)
- Marian A Ackun-Farmmer
- Robert E. Fischell Institute for Biomedical Devices, 8278 Paint Branch Drive, College Park, Maryland 20742, United States
| | - Marina Willson Shirkey
- Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, United States
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201, United States
- Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, Maryland 21201, United States
| | - Robert S Oakes
- Robert E. Fischell Institute for Biomedical Devices, 8278 Paint Branch Drive, College Park, Maryland 20742, United States
- Department of Veterans Affairs, VA Maryland Health Care System, 10. N Green Street, Baltimore, Maryland 21201, United States
| | - Shrey Alpeshkumar Shah
- Robert E. Fischell Institute for Biomedical Devices, 8278 Paint Branch Drive, College Park, Maryland 20742, United States
| | - Camilla Edwards
- Robert E. Fischell Institute for Biomedical Devices, 8278 Paint Branch Drive, College Park, Maryland 20742, United States
| | - Senta Kapnick
- Robert E. Fischell Institute for Biomedical Devices, 8278 Paint Branch Drive, College Park, Maryland 20742, United States
- Department of Veterans Affairs, VA Maryland Health Care System, 10. N Green Street, Baltimore, Maryland 21201, United States
| | - Sean T Carey
- Robert E. Fischell Institute for Biomedical Devices, 8278 Paint Branch Drive, College Park, Maryland 20742, United States
| | - Alexis Yanes
- Robert E. Fischell Institute for Biomedical Devices, 8278 Paint Branch Drive, College Park, Maryland 20742, United States
| | - Jonathan Bromberg
- Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, United States
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201, United States
- Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, Maryland 21201, United States
| | - Christopher M Jewell
- Robert E. Fischell Institute for Biomedical Devices, 8278 Paint Branch Drive, College Park, Maryland 20742, United States
- Department of Veterans Affairs, VA Maryland Health Care System, 10. N Green Street, Baltimore, Maryland 21201, United States
- Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, Maryland 21201, United States
- Marlene and Stewart Greenebaum Cancer Center, 22 S. Greene Street, Suite N9E17, Baltimore, Maryland 21201, United States
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Drosu N, Anderson M, Bilodeau PA, Nishiyama S, Mikami T, Bobrowski-Khoury N, Cabot J, Housman D, Levy M. CD4 T cells restricted to DRB1*15:01 recognize two Epstein-Barr virus glycoproteins capable of intracellular antigen presentation. Proc Natl Acad Sci U S A 2024; 121:e2416097121. [PMID: 39432795 PMCID: PMC11536159 DOI: 10.1073/pnas.2416097121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 09/06/2024] [Indexed: 10/23/2024] Open
Abstract
Both genetic and environmental factors contribute to multiple sclerosis (MS) risk. Infection with the Epstein-Barr virus (EBV) is the strongest environmental risk factor, and HLA-DR15 is the strongest genetic risk factor for MS. We employed computational methods and in vitro assays for CD4 T cell activation to investigate the DR15-restricted response to EBV. Using a machine learning-based HLA ligand predictor, the EBV glycoprotein B (gB) was predicted to be enriched in epitopes restricted to presentation by DRB1*15:01. In DR15-positive individuals, two epitopes comprised the major CD4 T cell response to gB. Surprisingly, the expression of recombinant gB in a DR15-homozygous B cell line or primary autologous B cells elicited a CD4 T cell response, indicating that intracellular gB was loaded onto HLA class II molecules. By deleting the signal sequence of gB, we determined that this pathway for direct activation of CD4 T cells was dependent on trafficking to the endoplasmic reticulum (ER) within the B cell. We screened seven recombinant EBV antigens from the ER compartment for immune responses in DR15-negative vs. DR15-homozygous individuals. In addition to gB, gH was a key CD4 T cell target in individuals homozygous for DR15. Compared to non-DR15 controls, DR15-homozygotes had significantly higher T cell responses to both gB and gH but not to EBV latent or lytic antigens overall. Responses to gB and gH were slightly elevated in DR15 homozygotes with MS. Our results link MS environmental and genetic risk factors by demonstrating that HLA-DR15 dictates CD4 T cell immunity to EBV antigens.
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Affiliation(s)
- Natalia Drosu
- Department of Neurology, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA02139
| | - Monique Anderson
- Department of Neurology, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114
| | - Philippe A. Bilodeau
- Department of Neurology, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114
| | - Shuhei Nishiyama
- Department of Neurology, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114
| | - Takahisa Mikami
- Department of Neurology, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114
| | - Natasha Bobrowski-Khoury
- Department of Neurology, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114
| | - Jackson Cabot
- Department of Neurology, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114
| | - David Housman
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA02139
| | - Michael Levy
- Department of Neurology, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114
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Valiukevicius P, Kaikaryte K, Gedvilaite-Vaicechauskiene G, Balnyte R, Liutkeviciene R. CXCL12 Gene Polymorphisms and Serum Levels: Associations with Multiple Sclerosis Prevalence and Clinical Parameters in Lithuania. Int J Mol Sci 2024; 25:9554. [PMID: 39273501 PMCID: PMC11395108 DOI: 10.3390/ijms25179554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 08/28/2024] [Accepted: 09/01/2024] [Indexed: 09/15/2024] Open
Abstract
Our study aimed to investigate the associations between CXCL12 rs1029153, rs1801157, and rs2297630 single-nucleotide polymorphisms (SNPs), CXCL12 protein levels, MS prevalence, and clinical parameters. This study included 250 individuals diagnosed with MS and 250 sex- and age-matched healthy control individuals from Lithuania. The SNPs were genotyped with real-time PCR-based assays. The CXCL12 protein concentration was evaluated in serum using the ELISA method. Of the studied CXCL12 SNPs, we found that the rs1801157 CT genotype in the males was associated with 2.3 times reduced MS odds when compared with the CC genotype according to the overdominant and codominant models (p = 0.011 and p = 0.012, respectively). There was a tendency, which did not reach adjusted statistical significance, for a lower CXCL12 protein concentration in the healthy individuals with the rs1801157 CT genotype (p = 0.028). Sensory symptoms were rarer in the women with the rs1801157 TT genotype (p = 0.004); however, this genotype was also associated with a shorter MS disease duration (p = 0.007). CXCL12 rs1801157 was associated with reduced odds of MS occurrence in the male individuals. In women, rs1801157 was associated with a sensory symptom prevalence.
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Affiliation(s)
- Paulius Valiukevicius
- Faculty of Medicine, Medical Academy, Lithuanian University of Health Sciences, A. Mickeviciaus 9, 44307 Kaunas, Lithuania
| | - Kriste Kaikaryte
- Laboratory of Ophthalmology, Neuroscience Institute, Medical Academy, Lithuanian University of Health Sciences, Eiveniu 2, 50161 Kaunas, Lithuania
| | - Greta Gedvilaite-Vaicechauskiene
- Laboratory of Ophthalmology, Neuroscience Institute, Medical Academy, Lithuanian University of Health Sciences, Eiveniu 2, 50161 Kaunas, Lithuania
| | - Renata Balnyte
- Department of Neurology, Medical Academy, Lithuanian University of Health Sciences, Eiveniu 2, 50161 Kaunas, Lithuania
| | - Rasa Liutkeviciene
- Department of Ophthalmology, Lithuanian University of Health Sciences, Eiveniu 2, 50161 Kaunas, Lithuania
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7
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Griñán-Ferré C, Bellver-Sanchis A, Guerrero A, Pallàs M. Advancing personalized medicine in neurodegenerative diseases: The role of epigenetics and pharmacoepigenomics in pharmacotherapy. Pharmacol Res 2024; 205:107247. [PMID: 38834164 DOI: 10.1016/j.phrs.2024.107247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 04/23/2024] [Accepted: 05/30/2024] [Indexed: 06/06/2024]
Abstract
About 80 % of brain disorders have a genetic basis. The pathogenesis of most neurodegenerative diseases is associated with a myriad of genetic defects, epigenetic alterations (DNA methylation, histone/chromatin remodeling, miRNA dysregulation), and environmental factors. The emergence of new sequencing technologies and tools to study the epigenome has led to identifying predictive biomarkers for earlier diagnosis, opening up the possibility of prophylactical interventions. As a result, advances in pharmacogenetics and pharmacoepigenomics now allow for personalized treatments based on the profile of each patient and the specific genetic and epigenetic mechanisms involved. This Review highlights the complexity of neurodegenerative diseases and the variability in patient responses to pharmacotherapy, emphasizing the influence of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of drugs used to treat those conditions. We specifically discuss the potential modulatory effect of several genetic polymorphisms associated with an increased risk of developing different neurodegenerative diseases. We explore genetic and genomic technologies and the potential of analyzing individual-specific drug metabolism to predict and influence drug response and associated clinical outcomes. We also provide insights into the mechanism of action of the drugs under investigation and their potential impact on disease-modifying pathways. Finally, the Review underscores the great potential of this field to enhance the effectiveness and safety of drug treatments through personalized medicine.
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Affiliation(s)
- Christian Griñán-Ferré
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Avda. Joan XXIII, 27, Barcelona 08028, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
| | - Aina Bellver-Sanchis
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Avda. Joan XXIII, 27, Barcelona 08028, Spain
| | - Ana Guerrero
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Avda. Joan XXIII, 27, Barcelona 08028, Spain
| | - Mercè Pallàs
- Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Avda. Joan XXIII, 27, Barcelona 08028, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
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8
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Al Malik YM. Tumefactive demyelinating lesions: A literature review of recent findings. NEUROSCIENCES (RIYADH, SAUDI ARABIA) 2024; 29:153-160. [PMID: 38981633 PMCID: PMC11305340 DOI: 10.17712/nsj.2024.3.20230111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2024]
Abstract
Tumefactive demyelinating lesion is a variant of multiple sclerosis that is a diagnostic challenge. Tumefactive demyelinating lesion requires extensive work-up as its clinical and radiological features are often indistinguishable from other central nervous system lesions, such as tumors. Diagnosis is further complicated by the increasing recognition that tumefactive demyelinating lesions can occur alongside, evolve into, or develop from numerous conditions other than multiple sclerosis, pointing to a possible overlapping etiology. We review herein relevant studies from 2017 onwards to provide a current view on the pathogenesis, clinical and imaging findings, novel diagnostic techniques for differential diagnoses, and management of tumefactive demyelinating lesions.
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Affiliation(s)
- Yaser M. Al Malik
- From the College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), from King Abdullah International Medical Research Center, and from the Divison of Neurology, King Abdulaziz Medical City, Ministry of the National Guard - Health Affairs, Riyadh, Kingdom of Saudi Arabia
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9
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Kettunen P, Koistinaho J, Rolova T. Contribution of CNS and extra-CNS infections to neurodegeneration: a narrative review. J Neuroinflammation 2024; 21:152. [PMID: 38845026 PMCID: PMC11157808 DOI: 10.1186/s12974-024-03139-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 05/23/2024] [Indexed: 06/09/2024] Open
Abstract
Central nervous system infections have been suggested as a possible cause for neurodegenerative diseases, particularly sporadic cases. They trigger neuroinflammation which is considered integrally involved in neurodegenerative processes. In this review, we will look at data linking a variety of viral, bacterial, fungal, and protozoan infections to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis and unspecified dementia. This narrative review aims to bring together a broad range of data currently supporting the involvement of central nervous system infections in the development of neurodegenerative diseases. The idea that no single pathogen or pathogen group is responsible for neurodegenerative diseases will be discussed. Instead, we suggest that a wide range of susceptibility factors may make individuals differentially vulnerable to different infectious pathogens and subsequent pathologies.
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Affiliation(s)
- Pinja Kettunen
- Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Jari Koistinaho
- Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
| | - Taisia Rolova
- Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
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10
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Thapa S, Bhattarai A, Shah S, Timsina S, Chand S, Jakimovski D. Helicobacter pylori infection and risk of multiple sclerosis: an updated meta-analysis. Neurol Sci 2024; 45:2539-2548. [PMID: 38243036 DOI: 10.1007/s10072-024-07328-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 01/11/2024] [Indexed: 01/21/2024]
Abstract
Numerous studies have proposed that Helicobacter pylori infection may possess a protective effect in terms of future risk of multiple sclerosis (MS), however is poorly evidenced. We performed a systematic review and meta-analysis to obtain the pooled results regarding the prevalence of H. pylori infection in persons with multiple sclerosis (pwMS) and healthy controls. A comprehensive database search was performed in PubMed, Embase, and medRxiv for all relevant literature published from the inception of the databases until the August 1, 2022. The retrieved articles were first screened by title and abstract, followed by full-text screening based on the pre-established eligibility criteria. The risk of bias was assessed using the ROBINS-I tool. Data on the seroprevalence of H. pylori in pwMS and healthy controls was extracted, and a meta-analysis was performed in Review Manager Version 5.4.1. Sub-group analysis was performed in accordance with the geographical distribution (Eastern and Western countries) and the method of detection of H. pylori infection enzyme-linked-immunoassay (ELISA), Immunofluorescence, Immunochromatography). Furthermore, sensitivity analyses and publication bias were determined. The preliminary database search retrieved a total of 822 studies. Seventeen case-control studies with a total of 2721 pwMS and 2245 controls were included as a final sample size for the meta-analysis. The overall risk of bias was moderate. Overall, the rate of H. pylori infection in pwMS was not significantly different than in healthy controls (OR: 0.79 (95% CI = 0.58-1.08); I2 = 79%, p = 0.14). Subgroup analysis revealed that the rate of H. pylori infection among PwMS was not significant in both Eastern and Western countries (OR: 0.75 (95% CI = 0.52-1.08); I2 = 81%, p = 0.12). In contrast, data revealed that the prevalence of H. pylori infection in pwMS was significantly lower than that of control based on studies utilizing ELISA assays detection (OR: 0.71 (95% CI = 0.50-1.00); I2 = 81%, p = 0.05), while no significant difference was seen on studies using other assays than ELISA (OR: 1.19 (95% CI = 0.81-1.77); I2 = 0%, p = 0.38). Our findings of statistically indifferent prevalence of H. pylori infection as compared between pwMS and healthy controls suggested the absence of protective effect for risk of MS following H. pylori infection.
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Affiliation(s)
- Sangharsha Thapa
- Jacobs Comprehensive MS Treatment and Research Center,, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Abhinav Bhattarai
- Institute of Medicine, Tribhuvan University, Maharajgunj, 44600, Nepal
| | - Sangam Shah
- Institute of Medicine, Tribhuvan University, Maharajgunj, 44600, Nepal
| | - Sakchhyam Timsina
- Institute of Medicine, Tribhuvan University, Maharajgunj, 44600, Nepal
| | - Swati Chand
- Rochester General Hospital, Rochester, NY, USA
| | - Dejan Jakimovski
- Jacobs Comprehensive MS Treatment and Research Center,, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
- Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 100 High Street , Buffalo, NY, 14203, USA.
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11
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Akaishi T, Misu T, Takahashi T, Fujihara K, Fujimori J, Nakashima I, Aoki M. Stochastic models for the onset and disease course of multiple sclerosis. Clin Neurol Neurosurg 2024; 239:108224. [PMID: 38447482 DOI: 10.1016/j.clineuro.2024.108224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 02/29/2024] [Accepted: 03/02/2024] [Indexed: 03/08/2024]
Abstract
OBJECTIVE Exact causes and mechanisms regulating the onset and progression in many chronic diseases, including multiple sclerosis (MS), remain uncertain. Until now, the potential role of random process based on stochastic models in the temporal course of chronic diseases remains largely unevaluated. Therefore, the present study investigated the applicability of stochastic models for the onset and disease course of MS. METHODS Stochastic models with random temporal process in disease activity, underlying clinical relapse and/or subclinical brain atrophy, were developed. The models incorporated parameters regarding the distribution of temporal changes in disease activity and the drift constant. RESULTS By adjusting the parameters (temporal change dispersion and drift constant) and the threshold for the onset of disease, the stochastic disease progression models could reproduce various types of subsequent disease course, such as clinically isolated syndrome (monophasic), relapsing-remitting MS, primary-progressive MS, and secondary-progressive MS. Furthermore, the disease prevalence and distribution of onset age could be also reproduced with stochastic models by adjusting the parameters. The models could further explain why approximately half of the patients with relapsing-remitting MS will eventually experience a transition to secondary-progressive MS. CONCLUSION Stochastic models with random temporal changes in disease activity could reproduce the characteristic onset age distribution and disease course forms in MS. Further studies by using real-world data to underscore the significance of random process in the occurrence and progression of MS are warranted.
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Affiliation(s)
- Tetsuya Akaishi
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Tatsuro Misu
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Toshiyuki Takahashi
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology, National Hospital Organization Yonezawa National Hospital, Yonezawa, Japan
| | - Kazuo Fujihara
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan; Multiple Sclerosis Therapeutics, Fukushima Medical University, Fukushima, Japan
| | - Juichi Fujimori
- Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Ichiro Nakashima
- Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Masashi Aoki
- Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan
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12
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Dejbakht M, Akhzari M, Jalili S, Faraji F, Barazesh M. Multiple Sclerosis: New Insights into Molecular Pathogenesis and Novel Platforms for Disease Treatment. Curr Drug Res Rev 2024; 16:175-197. [PMID: 37724675 DOI: 10.2174/2589977516666230915103730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 06/23/2023] [Accepted: 07/03/2023] [Indexed: 09/21/2023]
Abstract
BACKGROUND Multiple sclerosis (MS), a chronic inflammatory disorder, affects the central nervous system via myelin degradation. The cause of MS is not fully known, but during recent years, our knowledge has deepened significantly regarding the different aspects of MS, including etiology, molecular pathophysiology, diagnosis and therapeutic options. Myelin basic protein (MBP) is the main myelin protein that accounts for maintaining the stability of the myelin sheath. Recent evidence has revealed that MBP citrullination or deamination, which is catalyzed by Ca2+ dependent peptidyl arginine deiminase (PAD) enzyme leads to the reduction of positive charge, and subsequently proteolytic cleavage of MBP. The overexpression of PAD2 in the brains of MS patients plays an essential role in new epitope formation and progression of the autoimmune disorder. Some drugs have recently entered phase III clinical trials with promising efficacy and will probably obtain approval in the near future. As different therapeutic platforms develop, finding an optimal treatment for each individual patient will be more challenging. AIMS This review provides a comprehensive insight into MS with a focus on its pathogenesis and recent advances in diagnostic methods and its present and upcoming treatment modalities. CONCLUSION MS therapy alters quickly as research findings and therapeutic options surrounding MS expand. McDonald's guidelines have created different criteria for MS diagnosis. In recent years, ever-growing interest in the development of PAD inhibitors has led to the generation of many reversible and irreversible PAD inhibitors against the disease with satisfactory therapeutic outcomes.
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Affiliation(s)
- Majid Dejbakht
- Department of Cellular and Molecular Research Center, Gerash University of Medical Sciences, Gerash, Iran
| | - Morteza Akhzari
- School of Nursing, Larestan University of Medical Sciences, Larestan, Iran
| | - Sajad Jalili
- Department of Orthopedics, School of Medicine, Ahvaz Jundishapour University of Medical Sciences, Ahvaz, Iran
| | - Fouziyeh Faraji
- Department of Cellular and Molecular Research Center, Gerash University of Medical Sciences, Gerash, Iran
| | - Mahdi Barazesh
- Department of Biotechnology, Cellular and Molecular Research Center, School of Paramedical, Gerash University of Medical Sciences, Gerash, Iran
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13
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Maxwell DL, Orian JM. Cerebellar pathology in multiple sclerosis and experimental autoimmune encephalomyelitis: current status and future directions. J Cent Nerv Syst Dis 2023; 15:11795735231211508. [PMID: 37942276 PMCID: PMC10629308 DOI: 10.1177/11795735231211508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 10/15/2023] [Indexed: 11/10/2023] Open
Abstract
Recent decades have witnessed significant progress in understanding mechanisms driving neurodegeneration and disease progression in multiple sclerosis (MS), but with a focus on the cerebrum. In contrast, there have been limited studies of cerebellar disease, despite the common occurrence of cerebellar symptoms in this disorder. These rare studies, however, highlight the early cerebellar involvement in disease development and an association between the early occurrence of cerebellar lesions and risk of worse prognosis. In parallel developments, it has become evident that far from being a region specialized in movement control, the cerebellum plays a crucial role in cognitive function, via circuitry connecting the cerebellum to association areas of the cerebrum. This complexity, coupled with challenges in imaging of the cerebellum have been major obstacles in the appreciation of the spatio-temporal evolution of cerebellar damage in MS and correlation with disability and progression. MS studies based on animal models have relied on an induced neuroinflammatory disease known as experimental autoimmune encephalomyelitis (EAE), in rodents and non-human primates (NHP). EAE has played a critical role in elucidating mechanisms underpinning tissue damage and been validated for the generation of proof-of-concept for cerebellar pathological processes relevant to MS. Additionally, rodent and NHP studies have formed the cornerstone of current knowledge of functional anatomy and cognitive processes. Here, we propose that improved insight into consequences of cerebellar damage in MS at the functional, cellular and molecular levels would be gained by more extensive characterization of EAE cerebellar pathology combined with the power of experimental paradigms in the field of cognition. Such combinatorial approaches would lead to improved potential for the development of MS sensitive markers and evaluation of candidate therapeutics.
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Affiliation(s)
- Dain L. Maxwell
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, Australia
- Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, Australia
| | - Jacqueline M. Orian
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, Australia
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14
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Wang Y, Wang J, Feng J. Multiple sclerosis and pregnancy: Pathogenesis, influencing factors, and treatment options. Autoimmun Rev 2023; 22:103449. [PMID: 37741528 DOI: 10.1016/j.autrev.2023.103449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 09/18/2023] [Indexed: 09/25/2023]
Abstract
Multiple sclerosis (MS) is an autoimmune-mediated degenerative disease of the central nervous system, characterized by inflammatory demyelination. It is primarily found in women of childbearing age, making pregnancy a significant concern for both patients with MS and clinicians. To assist these patients in achieving their desire for pregnancy, reducing MS relapses during all stages of pregnancy, preventing the progression of MS, mitigating the impact of MS treatment on the course and outcome of pregnancy, and a thorough understanding of the relationship between pregnancy and MS, as well as specific management and the application of relevant medications for MS patients at each stage of pregnancy, are essential. This article provides an update on pregnancy-related issues in women with MS, including the general recommendations for management at each stage of pregnancy.
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Affiliation(s)
- Yinxiang Wang
- Department of Neurology, Shengjing Hospital of China Medical University, 36 Sanhao St., Shenyang 110004, China
| | - Jue Wang
- Department of Neurology, Shengjing Hospital of China Medical University, 36 Sanhao St., Shenyang 110004, China
| | - Juan Feng
- Department of Neurology, Shengjing Hospital of China Medical University, 36 Sanhao St., Shenyang 110004, China.
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15
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Villani R, Serviddio G, Avolio C, Cassano T, D'Amico E. Autoimmune liver disease and multiple sclerosis: state of the art and future perspectives. Clin Exp Med 2023; 23:3321-3338. [PMID: 37421590 PMCID: PMC10618321 DOI: 10.1007/s10238-023-01128-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 06/23/2023] [Indexed: 07/10/2023]
Abstract
Clinical observations suggest that the prevalence of autoimmune diseases is changing over time. Both autoimmune liver diseases and multiple sclerosis have shown a significant increase in the last decades. Although the coexistence of autoimmune diseases within individuals and families is a common phenomenon, the extent to which liver disease and multiple sclerosis co-occur is not clear. Case reports and few studies have reported the possible coexistence of multiple sclerosis with thyroid diseases, inflammatory bowel disease, psoriasis, and rheumatoid arthritis. It is unknown whether there is a definite association between multiple sclerosis and autoimmune liver diseases. We reviewed the literature to summarize the available studies on the association between different autoimmune liver diseases (autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis) and treated or untreated multiple sclerosis.
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Affiliation(s)
- Rosanna Villani
- Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
| | - Gaetano Serviddio
- Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Carlo Avolio
- Department of Medical and Surgical Sciences, Multiple Sclerosis Center, University of Foggia, Foggia, Italy
| | - Tommaso Cassano
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Emanuele D'Amico
- Department of Medical and Surgical Sciences, Multiple Sclerosis Center, University of Foggia, Foggia, Italy
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16
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Pasella M, Pisano F, Cannas B, Fanni A, Cocco E, Frau J, Lai F, Mocci S, Littera R, Giglio SR. Decision trees to evaluate the risk of developing multiple sclerosis. Front Neuroinform 2023; 17:1248632. [PMID: 37649987 PMCID: PMC10465164 DOI: 10.3389/fninf.2023.1248632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 07/28/2023] [Indexed: 09/01/2023] Open
Abstract
Introduction Multiple sclerosis (MS) is a persistent neurological condition impacting the central nervous system (CNS). The precise cause of multiple sclerosis is still uncertain; however, it is thought to arise from a blend of genetic and environmental factors. MS diagnosis includes assessing medical history, conducting neurological exams, performing magnetic resonance imaging (MRI) scans, and analyzing cerebrospinal fluid. While there is currently no cure for MS, numerous treatments exist to address symptoms, decelerate disease progression, and enhance the quality of life for individuals with MS. Methods This paper introduces a novel machine learning (ML) algorithm utilizing decision trees to address a key objective: creating a predictive tool for assessing the likelihood of MS development. It achieves this by combining prevalent demographic risk factors, specifically gender, with crucial immunogenetic risk markers, such as the alleles responsible for human leukocyte antigen (HLA) class I molecules and the killer immunoglobulin-like receptors (KIR) genes responsible for natural killer lymphocyte receptors. Results The study included 619 healthy controls and 299 patients affected by MS, all of whom originated from Sardinia. The gender feature has been disregarded due to its substantial bias in influencing the classification outcomes. By solely considering immunogenetic risk markers, the algorithm demonstrates an ability to accurately identify 73.24% of MS patients and 66.07% of individuals without the disease. Discussion Given its notable performance, this system has the potential to support clinicians in monitoring the relatives of MS patients and identifying individuals who are at an increased risk of developing the disease.
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Affiliation(s)
- Manuela Pasella
- Department of Electrical and Electronic Engineering, University of Cagliari, Cagliari, Italy
| | - Fabio Pisano
- Department of Electrical and Electronic Engineering, University of Cagliari, Cagliari, Italy
| | - Barbara Cannas
- Department of Electrical and Electronic Engineering, University of Cagliari, Cagliari, Italy
| | - Alessandra Fanni
- Department of Electrical and Electronic Engineering, University of Cagliari, Cagliari, Italy
| | - Eleonora Cocco
- Department of Medical Science and Public Health, Centro Sclerosi Multipla, University of Cagliari, Cagliari, Italy
| | - Jessica Frau
- Department of Medical Science and Public Health, Centro Sclerosi Multipla, University of Cagliari, Cagliari, Italy
| | - Francesco Lai
- Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Stefano Mocci
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
- Centre for Research University Services, University of Cagliari, Monserrato, Italy
| | - Roberto Littera
- AART-ODV (Association for the Advancement of Research on Transplantation), Cagliari, Italy
- Medical Genetics, R. Binaghi Hospital, ASSL Cagliari, ATS Sardegna, Cagliari, Italy
| | - Sabrina Rita Giglio
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
- Centre for Research University Services, University of Cagliari, Monserrato, Italy
- AART-ODV (Association for the Advancement of Research on Transplantation), Cagliari, Italy
- Medical Genetics, R. Binaghi Hospital, ASSL Cagliari, ATS Sardegna, Cagliari, Italy
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17
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Afrasiabi A, Ahlenstiel C, Swaminathan S, Parnell GP. The interaction between Epstein-Barr virus and multiple sclerosis genetic risk loci: insights into disease pathogenesis and therapeutic opportunities. Clin Transl Immunology 2023; 12:e1454. [PMID: 37337612 PMCID: PMC10276892 DOI: 10.1002/cti2.1454] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 05/30/2023] [Accepted: 06/05/2023] [Indexed: 06/21/2023] Open
Abstract
Multiple sclerosis (MS) is a chronic neurodegenerative autoimmune disease, characterised by the demyelination of neurons in the central nervous system. Whilst it is unclear what precisely leads to MS, it is believed that genetic predisposition combined with environmental factors plays a pivotal role. It is estimated that close to half the disease risk is determined by genetic factors. However, the risk of developing MS cannot be attributed to genetic factors alone, and environmental factors are likely to play a significant role by themselves or in concert with host genetics. Epstein-Barr virus (EBV) infection is the strongest known environmental risk factor for MS. There has been increasing evidence that leaves little doubt that EBV is necessary, but not sufficient, for developing MS. One plausible explanation is EBV may alter the host immune response in the presence of MS risk alleles and this contributes to the pathogenesis of MS. In this review, we discuss recent findings regarding how EBV infection may contribute to MS pathogenesis via interactions with genetic risk loci and discuss possible therapeutic interventions.
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Affiliation(s)
- Ali Afrasiabi
- EBV Molecular Lab, Centre for Immunology and Allergy Research, Westmead Institute for Medical ResearchUniversity of SydneySydneyNSWAustralia
- The Graduate School of Biomedical EngineeringUniversity of New South WalesSydneyNSWAustralia
| | - Chantelle Ahlenstiel
- Kirby InstituteUniversity of New South WalesSydneyNSWAustralia
- RNA InstituteUniversity of New South WalesSydneyNSWAustralia
| | - Sanjay Swaminathan
- EBV Molecular Lab, Centre for Immunology and Allergy Research, Westmead Institute for Medical ResearchUniversity of SydneySydneyNSWAustralia
- Department of MedicineWestern Sydney UniversitySydneyNSWAustralia
| | - Grant P Parnell
- EBV Molecular Lab, Centre for Immunology and Allergy Research, Westmead Institute for Medical ResearchUniversity of SydneySydneyNSWAustralia
- Biomedical Informatics and Digital Health, School of Medical Sciences, Faculty of Medicine and HealthThe University of SydneySydneyNSWAustralia
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18
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Vesic K, Gavrilovic A, Mijailović NR, Borovcanin MM. Neuroimmune, clinical and treatment challenges in multiple sclerosis-related psychoses. World J Psychiatry 2023; 13:161-170. [PMID: 37123101 PMCID: PMC10130959 DOI: 10.5498/wjp.v13.i4.161] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/16/2023] [Accepted: 03/23/2023] [Indexed: 04/18/2023] Open
Abstract
In recent years, epidemiological and genetic studies have shown an association between autoimmune diseases and psychosis. The question arises whether patients with schizophrenia are more likely to develop multiple sclerosis (MS) later in life. It is well known that the immune system plays an important role in the etiopathogenesis of both disorders. Immune disturbances may be similar or very different in terms of different types of immune responses, disturbed myelination, and/or immunogenetic predispositions. A psychotic symptom may be a consequence of the MS diagnosis itself or a separate entity. In this review article, we discussed the timing of onset of psychotic symptoms and MS and whether the use of corticosteroids as therapy for acute relapses in MS is unfairly neglected in patients with psychiatric comorbidities. In addition, we discussed that the anti-inflammatory potential of antipsychotics could be useful and should be considered, especially in the treatment of psychosis that coexists with MS. Autoimmune disorders could precipitate psychotic symptoms, and in this context, autoimmune psychosis must be considered as a persistent symptomatology that requires continuous and specific treatment.
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Affiliation(s)
- Katarina Vesic
- Department of Neurology, University of Kragujevac, Faculty of Medical Sciences, Kragujevac 34000, Sumadija, Serbia
| | - Aleksandar Gavrilovic
- Department of Neurology, University of Kragujevac, Faculty of Medical Sciences, Kragujevac 34000, Sumadija, Serbia
| | - Nataša R Mijailović
- Department of Pharmacy, University of Kragujevac, Faculty of Medical Sciences, Kragujevac 34000, Sumadija, Serbia
| | - Milica M Borovcanin
- Department of Psychiatry, University of Kragujevac, Faculty of Medical Sciences, Kragujevac 34000, Sumadija, Serbia
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19
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Ackun-Farmmer MA, Jewell CM. Delivery route considerations for designing antigen-specific biomaterial strategies to combat autoimmunity. ADVANCED NANOBIOMED RESEARCH 2023; 3:2200135. [PMID: 36938103 PMCID: PMC10019031 DOI: 10.1002/anbr.202200135] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Disease modifying drugs and biologics used to treat autoimmune diseases, although promising, are non-curative. As the field moves towards development of new approaches to treat autoimmune disease, antigen-specific therapies immunotherapies (ASITs) have emerged. Despite clinical approval of ASITs for allergies, clinical trials using soluble ASITs for autoimmunity have been largely unsuccessful. A major effort to address this shortcoming is the use of biomaterials to harness the features unique to specific delivery routes. This review focuses on biomaterials being developed for delivery route-specific strategies to induce antigen-specific responses in autoimmune diseases such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis, and celiac disease. We first discuss the delivery strategies used in ongoing and completed clinical trials in autoimmune ASITs. Next, we highlight pre-clinical biomaterial approaches from the most recent 3 years in the context of these same delivery route considerations. Lastly, we provide discussion on the gaps remaining in biomaterials development and comment on the need to consider delivery routes in the process of designing biomaterials for ASITs.
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Affiliation(s)
- Marian A Ackun-Farmmer
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA
| | - Christopher M Jewell
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA
- US Department of Veterans Affairs, VA Maryland Health Care System, Baltimore, MD, 21201, USA
- Robert E. Fischell Institute for Biomedical Devices, College Park, MD, 20742, USA
- Department of Microbiology and Immunology, University of Maryland Medical School, Baltimore, MD, 21201, USA
- Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, 21201, USA
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20
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Knowledge about multiple sclerosis among Palestinian community dwellers in the West Bank. J Public Health (Oxf) 2022. [DOI: 10.1007/s10389-022-01803-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
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21
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Al-Kafaji G, Alwehaidah MS, Alsabbagh MM, Alharbi MA, Bakhiet M. Mitochondrial DNA haplogroup analysis in Saudi Arab patients with multiple sclerosis. PLoS One 2022; 17:e0279237. [PMID: 36534684 PMCID: PMC9762579 DOI: 10.1371/journal.pone.0279237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 12/03/2022] [Indexed: 12/24/2022] Open
Abstract
Previous studies have suggested that mitochondrial DNA (mtDNA) variants are associated with multiple sclerosis (MS), a complex neurodegenerative immune-mediated disease of the central nervous system. Since mtDNA is maternally inherited without recombination, specific mtDNA variants defining genetic background are associated with the susceptibility to human diseases. To assess the contribution of mtDNA haplogroups to the predisposition of MS in an Arab population, we analysed sequencing data of mitochondrial genomes from 47 native Saudi Arab individuals including 23 patients with relapsing-remitting MS (RRMS) and 24 healthy controls. All patients and controls could be classified into ten haplogroups. The European-specific haplogroup U was more prevalent in patients than in the controls (26.1% vs. 4.2%), whereas haplogroup T was only present in patients and haplogroups HV and N were only found in controls. Haplogroup U was significantly association with increased risk of MS (odds ratio = 6.26, p<0.05), although the association did not maintain significance after adjustment for multiple comparisons. Haplotype U was more prevalent in patients with younger age of onset (p = 0.006), but there was no relationship between haplotype U and disease severity, disease duration or EDSS and age-matched carriers and non-carriers of haplogroup U (p>0.05). Definition site of haplogroup U include the variant m.12308A>G in MT-TL2 gene which was found to affect highly conserved position within the variable arm of tRNALeu(CUN) and thus may impact mitochondrial protein synthesis, and two other variants namely m.11467A>G in MT-ND4 gene and m.12372G>A in MT-ND5 gene which were previously linked with mitochondrial function. Despite the small number of subjects, which may limit the statistical power of the study, our results showed for the first time a possible contribution of haplogroup U to the predisposition to MS in an Arab population. These findings warrant further validation in a large cohort to distinguish a genuine effect specific to MS from a chance finding due to small sampling.
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Affiliation(s)
- Ghada Al-Kafaji
- Department of Molecular Medicine and Al-Jawhara Centre for Molecular Medicine, Genetics, and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
- * E-mail:
| | - Materah Salem Alwehaidah
- Department of Medical Laboratory, Faculty of Allied Health, Kuwait University, Kuwait City, Kuwait
| | - Manahel Mahmood Alsabbagh
- Department of Molecular Medicine and Al-Jawhara Centre for Molecular Medicine, Genetics, and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
| | - Maram A. Alharbi
- College of Forensic Sciences, Naif Arab University for Security Sciences, Riyadh, Kingdom of Saudi Arabia
| | - Moiz Bakhiet
- Department of Molecular Medicine and Al-Jawhara Centre for Molecular Medicine, Genetics, and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
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22
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Costantini E, Masciarelli E, Casorri L, Di Luigi M, Reale M. Medicinal herbs and multiple sclerosis: Overview on the hard balance between new therapeutic strategy and occupational health risk. Front Cell Neurosci 2022; 16:985943. [PMID: 36439198 PMCID: PMC9688751 DOI: 10.3389/fncel.2022.985943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 10/20/2022] [Indexed: 11/11/2022] Open
Abstract
Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination and axonal loss of the central nervous system (CNS). Despite its spread throughout the world, the mechanisms that determine its onset are still to be defined. Immunological, genetic, viral, and environmental factors and exposure to chemicals may trigger MS. Many studies have highlighted the anti-inflammatory and anti-oxidant effects of medicinal herbs, which make them a natural and complementary treatment for neurodegenerative diseases. A severe reduction of several MS symptoms occurs with herbal therapy. Thus, the request for medicinal plants with potential beneficial effects, for MS patients, is constantly increasing. Consequently, a production increase needs. Unfortunately, many medicinal herbs were untested and their action mechanism, possible adverse effects, contraindications, or interactions with other drugs, are poorly or not investigated. Keeping in mind the pathological mechanisms of MS and the oxidative damages and mitochondrial dysfunctions induced by pesticides, it is important to understand if pesticides used to increase agricultural productivity and their residues in medicinal plants, may increase the risk of developing MS in both workers and consumers. Studies providing some indication about the relationship between environmental exposure to pesticides and MS disease incidence are few, fragmentary, and discordant. The aim of this article is to provide a glance at the therapeutic potential of medicinal plants and at the risk for MS onset of pesticides used by medicinal plant growers and present in medicinal herbs.
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Affiliation(s)
- Erica Costantini
- Department of Medicine and Science of Aging, G. d’Annunzio University of Chieti–Pescara, Chieti, Italy
| | - Eva Masciarelli
- Department of Technological Innovations and Safety of Plants, Products and Anthropic Settlements, National Institute for Insurance Against Accidents at Work, Rome, Italy
| | - Laura Casorri
- Department of Technological Innovations and Safety of Plants, Products and Anthropic Settlements, National Institute for Insurance Against Accidents at Work, Rome, Italy
| | - Marco Di Luigi
- Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, INAIL Research Center, National Institute for Insurance Against Accidents at Work, Rome, Italy
| | - Marcella Reale
- Department of Innovative Technologies in Medicine and Dentistry, G. d’Annunzio University of Chieti–Pescara, Chieti, Italy
- *Correspondence: Marcella Reale,
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23
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Borziak K, Finkelstein J. X-linked genetic risk factors that promote autoimmunity and dampen remyelination are associated with multiple sclerosis susceptibility. Mult Scler Relat Disord 2022; 66:104065. [PMID: 35905688 DOI: 10.1016/j.msard.2022.104065] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/14/2022] [Accepted: 07/17/2022] [Indexed: 01/21/2023]
Abstract
BACKGROUND Multiple sclerosis (MS) is a chronic neurodegenerative disease, which has a strong genetic component and is more prevalent in women. MS is caused by an autoimmunity initiated inflammatory response which leads to axon demyelination, followed by axon loss, plaque formation and neurodegeneration. The goal of this article was to explore X-linked genetic factors that are associated with MS susceptibility. METHODS Using UK Biobank microarray, we analyzed the prevalence of alleles on the X chromosome to identify variants potentially involved in MS. Overall, 488,225 patients across 18,857 markers were analyzed using PLINK. RESULTS Our results identify 20 SNPs that are significantly more abundant in persons with MS. The genes associated with these SNPs belong to immunity (LAMP2, AVPR2, MTMR8, F8, BCOR, PORCN, and ELF4) and remyelination (NSDHL, HS6ST2, RBM10, TAZ, and AR) pathways that are potentially of great significance for understanding the onset and progression of multiple sclerosis. We further identified a significant 20-fold increase in incidence of MS cases in women with co-occurrences of SNPs associated with myelination and immunity functions. CONCLUSIONS Our analysis provides novel insights into the roles of X-linked genes in the onset and presentation of multiple sclerosis, identifying 20 SNPs in 14 genes involved primarily in immunity and myelination functions that are significantly more abundant in persons with MS. Our co-occurrence analysis suggests that concurrent disruption of both myelination and immune systems significantly increases the risk of MS onset in women.
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Affiliation(s)
- Kirill Borziak
- Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 United States.
| | - Joseph Finkelstein
- Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 United States
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24
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Zhang X, Song Y, Chen X, Zhuang X, Wei Z, Yi L. Integration of Genetic and Immune Infiltration Insights into Data Mining of Multiple Sclerosis Pathogenesis. COMPUTATIONAL INTELLIGENCE AND NEUROSCIENCE 2022; 2022:1661334. [PMID: 35795733 PMCID: PMC9252675 DOI: 10.1155/2022/1661334] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 06/07/2022] [Accepted: 06/08/2022] [Indexed: 11/17/2022]
Abstract
Background Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. MS pathogenesis is closely related to the environment, genetic, and immune system, but the underlying interactions have not been clearly elucidated. This study aims to unveil the genetic basis and immune landscape of MS pathogenesis with bioinformatics. Methods Gene matrix was retrieved from the gene expression database NCBI-GEO. Then, bioinformatics was used to standardize the samples and obtain differentially expressed genes (DEGs). The protein-protein interaction network was constructed with DEGs on the STRING website. Cytohubba plug-in and MCODE plug-in were used to mine hub genes. Meanwhile, the CIBERSORTX algorithm was used to explore the characteristics of immune cell infiltration in MS brain tissues. Spearman correlation analysis was performed between genes and immune cells, and the correlation between genes and different types of brain tissues was also analyzed using the WGCNA method. Results A total of 90 samples from 2 datasets were included, and 882 DEGs and 10 hub genes closely related to MS were extracted. Functional enrichment analysis suggested the role of immune response in MS. Besides, CIBERSORTX algorithm results showed that MS brain tissues contained a variety of infiltrating immune cells. Correlation analysis suggested that the hub genes were highly relevant to chronic active white matter lesions. Certain hub genes played a role in the activation of immune cells such as macrophages and natural killer cells. Conclusions Our study shall provide guidance for the further study of the genetic basis and immune infiltration mechanism of MS.
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Affiliation(s)
- Xiaoyun Zhang
- Department of Rehabilitation, Shenzhen Longhua District Central Hospital, Shenzhen 518000, China
| | - Ying Song
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen 518000, China
| | - Xiao Chen
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen 518000, China
| | - Xiaojia Zhuang
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen 518000, China
| | - Zhiqiang Wei
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen 518000, China
| | - Li Yi
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen 518000, China
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25
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Engelenburg HJ, Lucassen PJ, Sarafian JT, Parker W, Laman JD. Multiple sclerosis and the microbiota. Evol Med Public Health 2022; 10:277-294. [PMID: 35747061 PMCID: PMC9211007 DOI: 10.1093/emph/eoac009] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 03/04/2022] [Indexed: 11/13/2022] Open
Abstract
Abstract
Multiple sclerosis (MS), a neurological autoimmune disorder, has recently been linked to neuro-inflammatory influences from the gut. In this review, we address the idea that evolutionary mismatches could affect the pathogenesis of MS via the gut microbiota. The evolution of symbiosis as well as the recent introduction of evolutionary mismatches is considered, and evidence regarding the impact of diet on the MS-associated microbiota is evaluated. Distinctive microbial community compositions associated with the gut microbiota of MS patients are difficult to identify, and substantial study-to-study variation and even larger variations between individual profiles of MS patients are observed. Furthermore, although some dietary changes impact the progression of MS, MS-associated features of microbiota were found to be not necessarily associated with diet per se. In addition, immune function in MS patients potentially drives changes in microbial composition directly, in at least some individuals. Finally, assessment of evolutionary histories of animals with their gut symbionts suggests that the impact of evolutionary mismatch on the microbiota is less concerning than mismatches affecting helminths and protists. These observations suggest that the benefits of an anti-inflammatory diet for patients with MS may not be mediated by the microbiota per se. Furthermore, any alteration of the microbiota found in association with MS may be an effect rather than a cause. This conclusion is consistent with other studies indicating that a loss of complex eukaryotic symbionts, including helminths and protists, is a pivotal evolutionary mismatch that potentiates the increased prevalence of autoimmunity within a population.
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Affiliation(s)
- Hendrik J Engelenburg
- Department of Pathology and Medical Biology, University Medical Center Groningen , Groningen, The Netherlands
- Brain Plasticity Group, Swammerdam Institute for Life Sciences, University of Amsterdam , Amsterdam, The Netherlands
| | - Paul J Lucassen
- Brain Plasticity Group, Swammerdam Institute for Life Sciences, University of Amsterdam , Amsterdam, The Netherlands
- Center for Urban Mental Health, University of Amsterdam , Amsterdam, The Netherlands
| | | | | | - Jon D Laman
- Department of Pathology and Medical Biology, University Medical Center Groningen , Groningen, The Netherlands
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Capturing SNP Association across the NK Receptor and HLA Gene Regions in Multiple Sclerosis by Targeted Penalised Regression Models. Genes (Basel) 2021; 13:genes13010087. [PMID: 35052430 PMCID: PMC8774935 DOI: 10.3390/genes13010087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/22/2021] [Accepted: 12/24/2021] [Indexed: 11/17/2022] Open
Abstract
Conventional genome-wide association studies (GWASs) of complex traits, such as Multiple Sclerosis (MS), are reliant on per-SNP p-values and are therefore heavily burdened by multiple testing correction. Thus, in order to detect more subtle alterations, ever increasing sample sizes are required, while ignoring potentially valuable information that is readily available in existing datasets. To overcome this, we used penalised regression incorporating elastic net with a stability selection method by iterative subsampling to detect the potential interaction of loci with MS risk. Through re-analysis of the ANZgene dataset (1617 cases and 1988 controls) and an IMSGC dataset as a replication cohort (1313 cases and 1458 controls), we identified new association signals for MS predisposition, including SNPs above and below conventional significance thresholds while targeting two natural killer receptor loci and the well-established HLA loci. For example, rs2844482 (98.1% iterations), otherwise ignored by conventional statistics (p = 0.673) in the same dataset, was independently strongly associated with MS in another GWAS that required more than 40 times the number of cases (~45 K). Further comparison of our hits to those present in a large-scale meta-analysis, confirmed that the majority of SNPs identified by the elastic net model reached conventional statistical GWAS thresholds (p < 5 × 10−8) in this much larger dataset. Moreover, we found that gene variants involved in oxidative stress, in addition to innate immunity, were associated with MS. Overall, this study highlights the benefit of using more advanced statistical methods to (re-)analyse subtle genetic variation among loci that have a biological basis for their contribution to disease risk.
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Moussa M, Abou Chakra M, Papatsoris AG, Dabboucy B, Hsieh M, Dellis A, Fares Y. Perspectives on urological care in multiple sclerosis patients. Intractable Rare Dis Res 2021; 10:62-74. [PMID: 33996350 PMCID: PMC8122310 DOI: 10.5582/irdr.2021.01029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. Lower urinary tract dysfunction due to MS includes a dysfunction of the storage phase or dysfunction of the voiding phase or a detrusor-sphincter dyssynergia. Baseline evaluation includes a voiding chart, an ultrasound scan of the urinary tract, urine culture, and an urodynamic study. For storage symptoms, antimuscarinics are the first-line treatment, and clean intermittent catheterization (CIC) is indicated if there is concomitant incomplete bladder emptying. Intradetrusor injections with botulinum toxin A (BTX-A), are recommended for refractory cases. Urinary diversion is rarely indicated. For patients with voiding symptoms, CIC and alpha-blockers are usually offered. Sexual dysfunction in patients with MS is multifactorial. Phosphodiesterase type 5 inhibitors are first-line therapies for MS-associated erectile dysfunction in both male and female patients. This review summarizes the epidemiology, pathogenesis, risk factors, genetic, clinical manifestations, diagnostic tests, and management of MS. Lastly, the urologic outcomes and therapies are reviewed.
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Affiliation(s)
- Mohamad Moussa
- Chairman of Urology Department, Lebanese University & Al Zahraa Hospital, University Medical Center, Beirut, Lebanon
| | - Mohamad Abou Chakra
- Urology Department, Lebanese University, Beirut, Lebanon
- Address correspondence to:Mohamad Abou Chakra, Faculty of Medicine, Department of Urology, Lebanese University. Beirut, Lebanon. E-mail:
| | - Athanasios G. Papatsoris
- 2nd Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Baraa Dabboucy
- Department of Neurosurgery, Lebanese University, Beirut, Lebanon
| | - Michael Hsieh
- Division of Urology, Children's National Hospital, Washington, USA
- Department of Urology, The George Washington University, Washington, USA
| | - Athanasios Dellis
- Department of Urology/General Surgery, Areteion Hospital, Athens, Greece
| | - Youssef Fares
- Department of Neurosurgery, Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
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Bolton C. An evaluation of the recognised systemic inflammatory biomarkers of chronic sub-optimal inflammation provides evidence for inflammageing (IFA) during multiple sclerosis (MS). Immun Ageing 2021; 18:18. [PMID: 33853634 PMCID: PMC8045202 DOI: 10.1186/s12979-021-00225-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 03/12/2021] [Indexed: 01/11/2023]
Abstract
The pathogenesis of the human demyelinating disorder multiple sclerosis (MS) involves the loss of immune tolerance to self-neuroantigens. A deterioration in immune tolerance is linked to inherent immune ageing, or immunosenescence (ISC). Previous work by the author has confirmed the presence of ISC during MS. Moreover, evidence verified a prematurely aged immune system that may change the frequency and profile of MS through an altered decline in immune tolerance. Immune ageing is closely linked to a chronic systemic sub-optimal inflammation, termed inflammageing (IFA), which disrupts the efficiency of immune tolerance by varying the dynamics of ISC that includes accelerated changes to the immune system over time. Therefore, a shifting deterioration in immunological tolerance may evolve during MS through adversely-scheduled effects of IFA on ISC. However, there is, to date, no collective proof of ongoing IFA during MS. The Review addresses the constraint and provides a systematic critique of compelling evidence, through appraisal of IFA-related biomarker studies, to support the occurrence of a sub-optimal inflammation during MS. The findings justify further work to unequivocally demonstrate IFA in MS and provide additional insight into the complex pathology and developing epidemiology of the disease.
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Associations of serum short-chain fatty acids with circulating immune cells and serum biomarkers in patients with multiple sclerosis. Sci Rep 2021; 11:5244. [PMID: 33664396 PMCID: PMC7933417 DOI: 10.1038/s41598-021-84881-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 02/22/2021] [Indexed: 02/06/2023] Open
Abstract
Altered composition of gut bacteria and changes to the production of their bioactive metabolites, the short-chain fatty acids (SCFAs), have been implicated in the development of multiple sclerosis (MS). However, the immunomodulatory actions of SCFAs and intermediaries in their ability to influence MS pathogenesis are uncertain. In this study, levels of serum SCFAs were correlated with immune cell abundance and phenotype as well as with other relevant serum factors in blood samples taken at first presentation of Clinically Isolated Syndrome (CIS; an early form of MS) or MS and compared to healthy controls. There was a small but significant reduction in propionate levels in the serum of patients with CIS or MS compared with healthy controls. The frequencies of circulating T follicular regulatory cells and T follicular helper cells were significantly positively correlated with serum levels of propionate. Levels of butyrate associated positively with frequencies of IL-10-producing B-cells and negatively with frequencies of class-switched memory B-cells. TNF production by polyclonally-activated B-cells correlated negatively with acetate levels. Levels of serum SCFAs associated with changes in circulating immune cells and biomarkers implicated in the development of MS.
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30
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Ong LTC, Schibeci SD, Fewings NL, Booth DR, Parnell GP. Age-dependent VDR peak DNA methylation as a mechanism for latitude-dependent multiple sclerosis risk. Epigenetics Chromatin 2021; 14:9. [PMID: 33541415 PMCID: PMC7863270 DOI: 10.1186/s13072-021-00383-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 01/28/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The mechanisms linking UV radiation and vitamin D exposure to the risk of acquiring the latitude and critical period-dependent autoimmune disease, multiple sclerosis, is unclear. We examined the effect of vitamin D on DNA methylation and DNA methylation at vitamin D receptor binding sites in adult and paediatric myeloid cells. This was accomplished through differentiating CD34+ haematopoietic progenitors into CD14+ mononuclear phagocytes, in the presence and absence of calcitriol. RESULTS Few DNA methylation changes occurred in cells treated with calcitriol. However, several VDR-binding sites demonstrated increased DNA methylation in cells of adult origin when compared to cells of paediatric origin. This phenomenon was not observed at other transcription factor binding sites. Genes associated with these sites were enriched for intracellular signalling and cell activation pathways involved in myeloid cell differentiation and adaptive immune system regulation. CONCLUSION These results suggest vitamin D exposure at critical periods during development may contribute to latitude-related differences in autoimmune disease incidence.
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Affiliation(s)
- Lawrence T C Ong
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Rd, Westmead, NSW, 2145, Australia. .,Department of Immunology, Westmead Hospital, Cnr Darcy and Hawkesbury Rds, Westmead, NSW, 2145, Australia.
| | - Stephen D Schibeci
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Rd, Westmead, NSW, 2145, Australia
| | - Nicole L Fewings
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Rd, Westmead, NSW, 2145, Australia
| | - David R Booth
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Rd, Westmead, NSW, 2145, Australia
| | - Grant P Parnell
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, The University of Sydney, 176 Hawkesbury Rd, Westmead, NSW, 2145, Australia
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31
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Delfan N, Galehdari H, Ghanbari Mardasi F, Zabihi R, Latifi Pakdehi T, Seifi T, Majdinasab N. Association of HLA-DR2-Related Haplotype (HLA-DRB5*01-DRB1*1501-DQB1*0602) in Patients with Multiple Sclerosis in Khuzestan Province. IRANIAN JOURNAL OF CHILD NEUROLOGY 2021; 15:35-46. [PMID: 34282361 PMCID: PMC8272550 DOI: 10.22037/ijcn.v14i4.18795] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Accepted: 01/01/2020] [Indexed: 11/18/2022]
Abstract
OBJECTIVE Multiple sclerosis (MS) is a partially heritable autoimmune disease. HLA-DR2 is the largest identified genetic risk factor for MS. The largest identified genetic risk factor is haplotype from the MHC class II HLA-DR2, which increases the disease risk. The HLA-DR2 distribution in MS patients has been confirmed, but contradictory outcomes have been found. Moreover, the HLA-DR2 effect on ethnicity and gender is unclear. There are no data regarding the HLA-DR2 (HLA-DRB1*1501-DRB5*01-DQB1*0602) association with MS in Khuzestan Province, Iran. This study aimed to investigate the association of HLA-DR2 with MS regarding both sex and ethnicity in this province. MATERIALS & METHODS A total of 399 individuals were recruited. HLA typing was conducted using the polymerase chain reaction amplification with sequence-specific primers technology. The HLA-DR2 association with MS was analyzed, and also its probable association with gender, ethnicity, the expanded disability status scale (EDSS), and MS clinical course was examined using the Chi-square test. RESULTS HLA-DRB5*01 - -DQB1*0602 - as the most common HLA haplotype was found in both patient and control groups. In contrast, the DRB5*01 + -DRB1*1501 + -DQB1*0602 - frequency was very low in the groups. It was observed that haplotypes had no association with MS susceptibility. Most of the haplotypes showed no association with ethnicity, sex, EDSS, and MS course except for the HLA-DRB5*01 + -DRB1*1501 + -DQB1*0602 - haplotype that was positively associated with EDSS steps 5 to 10 (p=0.014) and non-RRMS (p=0.023). CONCLUSION There was no association between HLA-DR2 and MS susceptibility. However, the higher HLA-DRB5*01 + -DRB1*1501 + -DQB1*0602 - frequency may play a role in MS development. Also, HLA-DR2 did not increase significantly concerning clinical course, ethnicity, sex, and EDSS. This study further supports the importance of replication studies as susceptible loci that might differ in various ethnicities. Therefore, it is concluded that the association between HLA-DR2 and MS is more allelic than haplotypic in Khuzestan.
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Affiliation(s)
- Nooshin Delfan
- Department of Genetics, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz Iran
| | - Hamid Galehdari
- Department of Genetics, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz Iran
| | | | - Rezvan Zabihi
- Department of Genetics, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz Iran
| | - Tahereh Latifi Pakdehi
- Department of Genetics, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz Iran
| | - Tahereh Seifi
- Department of Genetics, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz Iran
| | - Nastaran Majdinasab
- Department of Neurology, Jondishapour University of Medical Sciences, Musculoskeletal Rehabilitation Research Center, Ahvaz, Iran
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Houen G, Trier NH, Frederiksen JL. Epstein-Barr Virus and Multiple Sclerosis. Front Immunol 2020; 11:587078. [PMID: 33391262 PMCID: PMC7773893 DOI: 10.3389/fimmu.2020.587078] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 11/18/2020] [Indexed: 12/11/2022] Open
Abstract
Multiple sclerosis (MS) is a neurologic disease affecting myelinated nerves in the central nervous system (CNS). The disease often debuts as a clinically isolated syndrome, e.g., optic neuritis (ON), which later develops into relapsing-remitting (RR) MS, with temporal attacks or primary progressive (PP) MS. Characteristic features of MS are inflammatory foci in the CNS and intrathecal synthesis of immunoglobulins (Igs), measured as an IgG index, oligoclonal bands (OCBs), or specific antibody indexes. Major predisposing factors for MS are certain tissue types (e.g., HLA DRB1*15:01), vitamin D deficiency, smoking, obesity, and infection with Epstein-Barr virus (EBV). Many of the clinical signs of MS described above can be explained by chronic/recurrent EBV infection and current models of EBV involvement suggest that RRMS may be caused by repeated entry of EBV-transformed B cells to the CNS in connection with attacks, while PPMS may be caused by more chronic activity of EBV-transformed B cells in the CNS. In line with the model of EBV's role in MS, new treatments based on monoclonal antibodies (MAbs) targeting B cells have shown good efficacy in clinical trials both for RRMS and PPMS, while MAbs inhibiting B cell mobilization and entry to the CNS have shown efficacy in RRMS. Thus, these agents, which are now first line therapy in many patients, may be hypothesized to function by counteracting a chronic EBV infection.
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Affiliation(s)
- Gunnar Houen
- Institute of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
- Department of Neurology, Rigshospitalet, Glostrup, Denmark
| | | | - Jette Lautrup Frederiksen
- Department of Neurology, Rigshospitalet, Glostrup, Denmark
- Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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33
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Jmii H, Fisson S, Aouni M, Jaidane H. Type B coxsackieviruses and central nervous system disorders: critical review of reported associations. Rev Med Virol 2020; 31:e2191. [PMID: 33159700 DOI: 10.1002/rmv.2191] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/12/2020] [Accepted: 10/19/2020] [Indexed: 11/07/2022]
Abstract
Type B coxsackieviruses (CV-B) frequently infect the central nervous system (CNS) causing neurological diseases notably meningitis and encephalitis. These infections occur principally among newborns and children. Epidemiological studies of patients with nervous system disorders demonstrate the presence of infectious virus, its components, or anti-CV-B antibodies. Some experimental studies conducted in vitro and in vivo support the potential association between CV-B and idiopathic neurodegenerative diseases such as amyotrophic lateral sclerosis and psychiatric illness such as schizophrenia. However, mechanisms explaining how CV-B infections may contribute to the genesis of CNS disorders remain unclear. The proposed mechanisms focus on the immune response following the viral infection as a contributor to pathogenesis. This review describes these epidemiological and experimental studies, the modes of transmission of CV-B with an emphasis on congenital transmission, the routes used by CV-B to reach the brain parenchyma, and plausible mechanisms by which CV-B may induce CNS diseases, with a focus on potential immunopathogenesis.
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Affiliation(s)
- Habib Jmii
- Laboratory of Transmissible Diseases and Biologically Active Substances LR99ES27, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
- Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Sylvain Fisson
- Généthon, Inserm UMR_S951, Univ Evry, University Paris Saclay, Evry, France
- Sorbonne University, INSERM, CNRS, Institut de la Vision, Paris, France
| | - Mahjoub Aouni
- Laboratory of Transmissible Diseases and Biologically Active Substances LR99ES27, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | - Hela Jaidane
- Laboratory of Transmissible Diseases and Biologically Active Substances LR99ES27, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
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34
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Deeba E, Lambrianides A, Pantzaris M, Krashias G, Christodoulou C. The expression profile of virus-recognizing toll-like receptors in natural killer cells of Cypriot multiple sclerosis patients. BMC Res Notes 2020; 13:460. [PMID: 32993761 PMCID: PMC7526110 DOI: 10.1186/s13104-020-05300-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 09/22/2020] [Indexed: 11/14/2022] Open
Abstract
Objective The exact aetiology of multiple sclerosis (MS) remains elusive, although several environmental and genetic risk factors have been implicated to varying degrees. Among the environmental risk factors, viral infections have been suggested as strong candidates contributing to MS pathology/progression. Viral recognition and control are largely tasked to the NK cells via TLR recognition and various cytotoxic and immunoregulatory functions. Additionally, the complex roles of different TLRs in MS pathology are highlighted in multiple, often contradictory, studies. The present work aims to analyse the TLR expression profile of NK cells isolated from MS patients. Highly purified CD56+CD3− NK cells isolated from peripheral blood of MS patients (n = 19) and healthy controls (n = 20) were analysed via flow cytometry for their expression of viral antigen-recognizing TLRs (TLR2, TLR3, TLR7, and TLR9). Results No difference was noted in TLR expression between MS patients and healthy controls. These results aim to supplement previous findings which study expressional or functional differences in TLRs present in various subsets of the immune system in MS, thus aiding in a better understanding of MS as a complex multifaceted disease.
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Affiliation(s)
- Elie Deeba
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 International Airport Avenue, 2370, Nicosia, Cyprus
| | - Anastasia Lambrianides
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 International Airport Avenue, 2370, Nicosia, Cyprus.,Neurology Clinic C, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Marios Pantzaris
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 International Airport Avenue, 2370, Nicosia, Cyprus.,Neurology Clinic C, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - George Krashias
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 International Airport Avenue, 2370, Nicosia, Cyprus. .,Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, P.O.Box 23462, 1683, Nicosia, Cyprus.
| | - Christina Christodoulou
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 International Airport Avenue, 2370, Nicosia, Cyprus.,Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, P.O.Box 23462, 1683, Nicosia, Cyprus
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Dwyer CM, Nguyen LTT, Healy LM, Dutta R, Ludwin S, Antel J, Binder MD, Kilpatrick TJ. Multiple Sclerosis as a Syndrome-Implications for Future Management. Front Neurol 2020; 11:784. [PMID: 32982904 PMCID: PMC7483755 DOI: 10.3389/fneur.2020.00784] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 06/25/2020] [Indexed: 12/25/2022] Open
Abstract
We propose that multiple sclerosis (MS) is best characterized as a syndrome rather than a single disease because different pathogenetic mechanisms can result in the constellation of symptoms and signs by which MS is clinically characterized. We describe several cellular mechanisms that could generate inflammatory demyelination through disruption of homeostatic interactions between immune and neural cells. We illustrate that genomics is important in identifying phenocopies, in particular for primary progressive MS. We posit that molecular profiling, rather than traditional clinical phenotyping, will facilitate meaningful patient stratification, as illustrated by interactions between HLA and a regulator of homeostatic phagocytosis, MERTK. We envisage a personalized approach to MS management where genetic, molecular, and cellular information guides management.
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Affiliation(s)
- Christopher M Dwyer
- Florey Institute of Neuroscience and Mental Health, Florey Department, The University of Melbourne, Parkville, VIC, Australia.,Department of Neurology, Royal Melbourne Hospital, Parkville, VIC, Australia
| | - Linda Thien-Trang Nguyen
- Florey Institute of Neuroscience and Mental Health, Florey Department, The University of Melbourne, Parkville, VIC, Australia
| | - Luke M Healy
- Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
| | - Ranjan Dutta
- Department of Neurosciences, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Samuel Ludwin
- Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
| | - Jack Antel
- Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
| | - Michele D Binder
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia.,Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, Australia
| | - Trevor J Kilpatrick
- Florey Institute of Neuroscience and Mental Health, Florey Department, The University of Melbourne, Parkville, VIC, Australia.,Department of Neurology, Royal Melbourne Hospital, Parkville, VIC, Australia
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36
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Libner CD, Salapa HE, Levin MC. The Potential Contribution of Dysfunctional RNA-Binding Proteins to the Pathogenesis of Neurodegeneration in Multiple Sclerosis and Relevant Models. Int J Mol Sci 2020; 21:E4571. [PMID: 32604997 PMCID: PMC7369711 DOI: 10.3390/ijms21134571] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/22/2020] [Accepted: 06/23/2020] [Indexed: 12/19/2022] Open
Abstract
Neurodegeneration in multiple sclerosis (MS) is believed to underlie disease progression and permanent disability. Many mechanisms of neurodegeneration in MS have been proposed, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, and RNA-binding protein dysfunction. The purpose of this review is to highlight mechanisms of neurodegeneration in MS and its models, with a focus on RNA-binding protein dysfunction. Studying RNA-binding protein dysfunction addresses a gap in our understanding of the pathogenesis of MS, which will allow for novel therapies to be generated to attenuate neurodegeneration before irreversible central nervous system damage occurs.
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Affiliation(s)
- Cole D. Libner
- Department of Health Sciences, University of Saskatchewan, Saskatoon, SK S7N 5A2, Canada;
- Office of Saskatchewan Multiple Sclerosis Clinical Research Chair, CMSNRC (Cameco MS Neuroscience. Research Center), University of Saskatchewan, Saskatoon, SK S7K 0M7, Canada;
| | - Hannah E. Salapa
- Office of Saskatchewan Multiple Sclerosis Clinical Research Chair, CMSNRC (Cameco MS Neuroscience. Research Center), University of Saskatchewan, Saskatoon, SK S7K 0M7, Canada;
- Department of Medicine, Neurology Division, University of Saskatchewan, Saskatoon, SK S7N 5A2, Canada
| | - Michael C. Levin
- Office of Saskatchewan Multiple Sclerosis Clinical Research Chair, CMSNRC (Cameco MS Neuroscience. Research Center), University of Saskatchewan, Saskatoon, SK S7K 0M7, Canada;
- Department of Medicine, Neurology Division, University of Saskatchewan, Saskatoon, SK S7N 5A2, Canada
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Das J, Gill A, Lo C, Chan-Lam N, Price S, Wharton SB, Jessop H, Sharrack B, Snowden JA. A Case of Multiple Sclerosis-Like Relapsing Remitting Encephalomyelitis Following Allogeneic Hematopoietic Stem Cell Transplantation and a Review of the Published Literature. Front Immunol 2020; 11:668. [PMID: 32431694 PMCID: PMC7214636 DOI: 10.3389/fimmu.2020.00668] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 03/24/2020] [Indexed: 12/21/2022] Open
Abstract
Complications involving the central nervous system (CNS) occur in 9–14% of patients following allogeneic hematopoietic stem cell transplantation (HSCT), including stroke-like episodes, demyelination, encephalitis, and nonspecific neurological symptoms. Here we report a case of multiple sclerosis (MS) like relapsing remitting encephalomyelitis following allogeneic HSCT, which did not respond to disease modifying therapies (DMTs) and “domino” autologous HSCT. A 53-year-old male was treated with allogeneic HSCT for lymphoid blast transformation of chronic myeloid leukemia. Ten months later he presented with confusion, slurred speech, left sided facial weakness and ataxia. A magnetic resonance imaging brain scan showed multiple enhancing tumefactive lesions. Neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) antibodies were negative. After extensive investigations for infections, autoimmune disorders and recurrence of malignancy, he underwent brain biopsy, which showed a macrophage rich lesion with severe myelin loss but axonal preservation indicating a demyelinating pathology. Although his symptoms improved with corticosteroids, he relapsed five months later. In the absence of any systemic features suggesting graft versus host disease (GvHD), his presentation was thought to be compatible with MS. The illness followed an aggressive course that did not respond to glatiramer acetate and natalizumab. He was therefore treated with “domino” autologous HSCT, which also failed to induce long-term remission. Despite further treatment with ocrelizumab, he died of progressive disease. An autopsy limited to the examination of brain revealed multifocal destructive leukoencephalopathy with severe myelin and axonal loss. Immunohistochemistry showed macrophage located in the perivascular area, with no T or B lymphocytes. The appearance was unusual and not typical for chronic MS plaques. Reported cases of CNS demyelination following allogeneic HSCT are very limited in the literature, especially in relation to histopathological examination. Although the clinical disease course of our patient following allogeneic HSCT resembled an “MS-like” relapsing remitting encephalomyelitis, the autopsy examination did not show any evidence of active inflammation. The impact of DMTs and HSCT on the histological appearance of “MS-like” CNS pathologies is unknown. Therefore, reporting this and similar cases will improve our awareness and understanding of underlying disease mechanisms.
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Affiliation(s)
- Joyutpal Das
- Department of Neurology, Salford Royal NHS Foundation Trust, Manchester, United Kingdom.,Department of Neurology, Royal Hallamshire Hospital, Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Atta Gill
- Department of Haematology, Royal Hallamshire Hospital, Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Christine Lo
- Department of Neurology, Royal Hallamshire Hospital, Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.,Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom
| | - Natalie Chan-Lam
- Department of Haematology, Royal Hallamshire Hospital, Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Siân Price
- Department of Neurology, Royal Hallamshire Hospital, Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Stephen B Wharton
- Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom.,Department of Histopathology, Royal Hallamshire Hospital, Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Helen Jessop
- Department of Haematology, Royal Hallamshire Hospital, Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Basil Sharrack
- Department of Neurology, Royal Hallamshire Hospital, Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.,Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom
| | - John A Snowden
- Department of Haematology, Royal Hallamshire Hospital, Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
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Varytė G, Zakarevičienė J, Ramašauskaitė D, Laužikienė D, Arlauskienė A. Pregnancy and Multiple Sclerosis: An Update on the Disease Modifying Treatment Strategy and a Review of Pregnancy's Impact on Disease Activity. MEDICINA (KAUNAS, LITHUANIA) 2020; 56:E49. [PMID: 31973138 PMCID: PMC7074401 DOI: 10.3390/medicina56020049] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 12/17/2019] [Accepted: 01/16/2020] [Indexed: 01/28/2023]
Abstract
Pregnancy rates are rapidly increasing among women of reproductive age diagnosed with multiple sclerosis (MS). Through pre-conception, pregnancy and post-partum periods, there is a need for disease control management, to decrease chances of MS relapses while avoiding potential risks to the mother and the fetus. However, pregnancy is not always compatible with the available highly effective MS treatments. This narrative review provides the aspects of pregnancy's outcomes and the impact on disease activity, choices of anesthesia and the management of relapses during the pregnancy and breastfeeding period. Available disease modifying treatment is discussed in the article with new data supporting the strategy of continuing natalizumab after conception, as it is related to a decreased risk of MS relapses during the pregnancy and postpartum period.
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Affiliation(s)
- Guoda Varytė
- Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
| | - Jolita Zakarevičienė
- Clinic of Obstetrics and Gynaecology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania; (J.Z.); (D.R.); (D.L.); (A.A.)
| | - Diana Ramašauskaitė
- Clinic of Obstetrics and Gynaecology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania; (J.Z.); (D.R.); (D.L.); (A.A.)
| | - Dalia Laužikienė
- Clinic of Obstetrics and Gynaecology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania; (J.Z.); (D.R.); (D.L.); (A.A.)
| | - Audronė Arlauskienė
- Clinic of Obstetrics and Gynaecology, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania; (J.Z.); (D.R.); (D.L.); (A.A.)
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Incidence and temporal trends of co-occurring personality disorder diagnoses in immune-mediated inflammatory diseases. Epidemiol Psychiatr Sci 2020; 29:e84. [PMID: 31915099 PMCID: PMC7214704 DOI: 10.1017/s2045796019000854] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
AIMS Although immune-mediated inflammatory diseases (IMID) are associated with multiple mental health conditions, there is a paucity of literature assessing personality disorders (PDs) in these populations. We aimed to estimate and compare the incidence of any PD in IMID and matched cohorts over time, and identify sociodemographic characteristics associated with the incidence of PD. METHODS We used population-based administrative data from Manitoba, Canada to identify persons with incident inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA) using validated case definitions. Unaffected controls were matched 5:1 on sex, age and region of residence. PDs were identified using hospitalisation or physician claims. We used unadjusted and covariate-adjusted negative binomial regression to compare the incidence of PDs between the IMID and matched cohorts. RESULTS We identified 19 572 incident cases of IMID (IBD n = 6,119, MS n = 3,514, RA n = 10 206) and 97 727 matches overall. After covariate adjustment, the IMID cohort had an increased incidence of PDs (incidence rate ratio [IRR] 1.72; 95%CI: 1.47-2.01) as compared to the matched cohort, which remained consistent over time. The incidence of PDs was similarly elevated in IBD (IRR 2.19; 95%CI: 1.69-2.84), MS (IRR 1.79; 95%CI: 1.29-2.50) and RA (IRR 1.61; 95%CI: 1.29-1.99). Lower socioeconomic status and urban residence were associated with an increased incidence of PDs, whereas mid to older adulthood (age 45-64) was associated with overall decreased incidence. In a restricted sample with 5 years of data before and after IMID diagnosis, the incidence of PDs was also elevated before IMID diagnosis among all IMID groups relative to matched controls. CONCLUSIONS IMID are associated with an increased incidence of PDs both before and after an IMID diagnosis. These results support the relevance of shared risk factors in the co-occurrence of PDs and IMID conditions.
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The effect of galanin gene polymorphism rs948854 on the severity of multiple sclerosis: A significant association with the age of onset. Mult Scler Relat Disord 2020; 37:101439. [DOI: 10.1016/j.msard.2019.101439] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 09/04/2019] [Accepted: 10/08/2019] [Indexed: 01/15/2023]
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Saravani M, Rokni M, Mehrbani M, Amirkhosravi A, Faramarz S, Fatemi I, Esmaeili Tarzi M, Nematollahi MH. The evaluation of VEGF and HIF-1α gene polymorphisms and multiple sclerosis susceptibility. J Gene Med 2019; 21:e3132. [PMID: 31652374 DOI: 10.1002/jgm.3132] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 09/03/2019] [Accepted: 10/02/2019] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Multiple sclerosis (MS) is an autoimmune disease that leads to myelin sheath destruction. Hypoxia-inducible factor 1 (HIF-1) has several roles in cells, such as inducing inflammation and angiogenesis. Recently, several lines of evidence have indicated the role of the hypoxia response and the HIF-1 signaling pathway in an autoimmune disease such as MS. The present study aimed to evaluate the effects of HIF-1α gene polymorphisms and vascular endothelial growth factor (VEGF) (as a major target gene of HIF-1α) gene polymorphism on MS susceptibility. METHODS In total, 150 MS patients and 150 healthy age- and gender-matched people as a control group participated in the present study. The polymerase chain reaction-restriction fragment length polymorphism method was used for genotyping. RESULTS The results obtained showed that the CC genotype of the VEGF rs699947 polymorphism was significantly higher in the case group than in the control group (p = 0.004). Also, we showed a significant relationship between the VEGF rs699947 polymorphism and MS in a dominant inheritance model (p = 0.005). Regarding the VEGF rs699947 polymorphism allelic distribution, the C allele frequency was significantly higher in the control group than in the case group (71.3% versus 61%, respectively, p = 0.009) and decreased the MS susceptibility by 1.6-fold (odds ratio = 1.6, 95% confidence interval = 1.2-2.2). There was no significant difference between the two groups with respect to HIF-1α rs11549465 genotypic distribution. The HIF-1α C111A polymorphism was non-polymorphic in our study population, except in the case group where nine subjects carried the CA genotype. CONCLUSIONS We show a significant association between VEGF rs60047 polymorphism and MS susceptibility. However, our results do not show a significant association between MS and HIF-1α polymorphisms.
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Affiliation(s)
- Mohsen Saravani
- Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.,Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mohsen Rokni
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrzad Mehrbani
- Herbal and Traditional Medicines Research Center, Kerman University of Medical Sciences, Kerman, Iran.,Department of Traditional Medicine, School of Persian Medicine, Kerman University of Medical Sciences, Tehran, Iran
| | - Arian Amirkhosravi
- Food, Drug and Cosmetic Safety Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Sanaz Faramarz
- Kerman Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.,Department of Clinical Biochemistry, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Iman Fatemi
- Research Center of Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman, Iran
| | - Mojdeh Esmaeili Tarzi
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Hadi Nematollahi
- Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran.,Department of Clinical Biochemistry, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
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Olcum M, Tastan B, Kiser C, Genc S, Genc K. Microglial NLRP3 inflammasome activation in multiple sclerosis. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2019; 119:247-308. [PMID: 31997770 DOI: 10.1016/bs.apcsb.2019.08.007] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Multiple sclerosis (MS) is a chronic, autoimmune and neuroinflammatory disease of the central nervous system (CNS) mediated by autoreactive T cells directed against myelin antigens. Although the crucial role of adaptive immunity is well established in MS, the contribution of innate immunity has only recently been appreciated. Microglia are the main innate immune cells of the CNS. Similar to other myeloid cells, microglia recognize both exogenous and host-derived endogenous danger signals through pattern recognition receptors (PRRs) localized on their cell surface such as Toll Like receptor 4, or in the cytosol such as NLRP3. The second one is the sensor protein of the multi-molecular NLRP3 inflammasome complex in activated microglia that promotes the maturation and secretion of proinflammatory cytokines, interleukin-1β and interleukin-18. Overactivation of microglia and aberrant activation of the NLRP3 inflammasome have been implicated in the pathogenesis of MS. Indeed, experimental data, together with post-mortem and clinical studies have revealed an increased expression of NLRP3 inflammasome complex elements in microglia and other immune cells. In this review, we focus on microglial NLRP3 inflammasome activation in MS. First, we overview the basic knowledge about MS, microglia and the NLRP3 inflammasome. Then, we summarize studies about microglial NLRP3 inflammasome activation in MS and its animal models. We also highlight experimental therapeutic approaches that target different steps of NLRP inflammasome activation. Finally, we discuss future research avenues and new methods in this rapidly evolving area.
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Affiliation(s)
- Melis Olcum
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus Balcova, Izmir, Turkey
| | - Bora Tastan
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus Balcova, Izmir, Turkey; Izmir International Biomedicine and Genome Institute (iBG-Izmir), Dokuz Eylul University Health Campus, Balcova, Izmir, Turkey
| | - Cagla Kiser
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus Balcova, Izmir, Turkey; Izmir International Biomedicine and Genome Institute (iBG-Izmir), Dokuz Eylul University Health Campus, Balcova, Izmir, Turkey
| | - Sermin Genc
- Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus Balcova, Izmir, Turkey; Izmir International Biomedicine and Genome Institute (iBG-Izmir), Dokuz Eylul University Health Campus, Balcova, Izmir, Turkey; Department of Neuroscience, Institute of Health and Science, Dokuz Eylul University Health Campus, Balcova, Izmir, Turkey
| | - Kursad Genc
- Department of Neuroscience, Institute of Health and Science, Dokuz Eylul University Health Campus, Balcova, Izmir, Turkey
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Deerhake ME, Biswas DD, Barclay WE, Shinohara ML. Pattern Recognition Receptors in Multiple Sclerosis and Its Animal Models. Front Immunol 2019; 10:2644. [PMID: 31781124 PMCID: PMC6861384 DOI: 10.3389/fimmu.2019.02644] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Accepted: 10/25/2019] [Indexed: 12/15/2022] Open
Abstract
Pattern recognition receptors (PRRs) coordinate the innate immune response and have a significant role in the development of multiple sclerosis (MS). Accumulating evidence has identified both pathogenic and protective functions of PRR signaling in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Additionally, evidence for PRR signaling in non-immune cells and PRR responses to host-derived endogenous ligands has also revealed new pathways controlling the development of CNS autoimmunity. Many PRRs remain uncharacterized in MS and EAE, and understanding the distinct triggers and functions of PRR signaling in CNS autoimmunity requires further investigation. In this brief review, we discuss the diverse pathogenic and protective functions of PRRs in MS and EAE, and highlight major avenues for future research.
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Affiliation(s)
- M Elizabeth Deerhake
- Department of Immunology, Duke University School of Medicine, Durham, NC, United States
| | - Debolina D Biswas
- Department of Immunology, Duke University School of Medicine, Durham, NC, United States
| | - William E Barclay
- Department of Immunology, Duke University School of Medicine, Durham, NC, United States
| | - Mari L Shinohara
- Department of Immunology, Duke University School of Medicine, Durham, NC, United States.,Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, United States
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Tobore TO. Towards a comprehensive etiopathogenetic and pathophysiological theory of multiple sclerosis. Int J Neurosci 2019; 130:279-300. [PMID: 31588832 DOI: 10.1080/00207454.2019.1677648] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background: Multiple sclerosis (MS) is a neurodegenerative disease caused by dysfunction of the immune system that affects the central nervous system (CNS). It is characterized by demyelination, chronic inflammation, neuronal and oligodendrocyte loss and reactive astrogliosis. It can result in physical disability and acute neurological and cognitive problems. Despite the gains in knowledge of immunology, cell biology, and genetics in the last five decades, the ultimate etiology or specific elements that trigger MS remain unknown. The objective of this review is to propose a theoretical basis for MS etiopathogenesis.Methods: Search was done by accessing PubMed/Medline, EBSCO, and PsycINFO databases. The search string used was "(multiple sclerosis* OR EAE) AND (pathophysiology* OR etiopathogenesis)". The electronic databases were searched for titles or abstracts containing these terms in all published articles between January 1, 1960, and June 30, 2019. The search was filtered down to 362 articles which were included in this review.Results: A framework to better understand the etiopathogenesis and pathophysiology of MS can be derived from four essential factors; mitochondria dysfunction (MtD) & oxidative stress (OS), vitamin D (VD), sex hormones and thyroid hormones. These factors play a direct role in MS etiopathogenesis and have a modulatory effect on many other factors involved in the disease.Conclusions: For better MS prevention and treatment outcomes, efforts should be geared towards treating thyroid problems, sex hormone alterations, VD deficiency, sleep problems and melatonin alterations. MS patients should be encouraged to engage in activities that boost total antioxidant capacity (TAC) including diet and regular exercise and discouraged from activities that promote OS including smoking and alcohol consumption.
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Feliciano LM, Sávio ALV, de Castro Marcondes JP, da Silva GN, Salvadori DMF. Genetic Alterations in Patients with Two Clinical Phenotypes of Multiple Sclerosis. J Mol Neurosci 2019; 70:120-130. [PMID: 31686392 DOI: 10.1007/s12031-019-01408-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 09/26/2019] [Indexed: 11/26/2022]
Abstract
The etiology of multiple sclerosis (MS) is still not known, but the interaction of genetic, immunological, and environmental factors seem to be involved. This study aimed to investigate genetic alterations and the vitamin D status in patients with relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS). A total of 53 patients (29 RRMS; 24 SPMS) and 25 healthy subjects were recruited to evaluate the micronucleated cell (MNC) frequency and nuclear abnormalities in the buccal mucosa, gene expression profiling in mononuclear cells, and plasmatic vitamin D concentration in the blood. Results showed a higher frequency of cells with karyorrhexis (SPMS) and lower frequencies of nuclear pyknosis (RRMS and SPMS) and karyolysis (SPMS) in patients with MS. Significant increase in the frequency of MNC was detected in the buccal mucosa of RRMS and SPMS patients. HIF1A, IL13, IL18, MYC, and TNF were differentially expressed in MS patients, and APP was overexpressed in cells of RRMS compared to SPMS patients. No relationship was observed between vitamin D level and the differentially expressed genes. In conclusion, the cytogenetic alterations in the buccal mucosa can be important indicators of genetic instability and degenerative processes in patients with MS. Furthermore, our data introduced novel biomarkers associated with the molecular pathogenesis of MS.
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Identifying the culprits in neurological autoimmune diseases. J Transl Autoimmun 2019; 2:100015. [PMID: 32743503 PMCID: PMC7388404 DOI: 10.1016/j.jtauto.2019.100015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/27/2019] [Accepted: 09/03/2019] [Indexed: 12/16/2022] Open
Abstract
The target organ of neurological autoimmune diseases (NADs) is the central or peripheral nervous system. Multiple sclerosis (MS) is the most common NAD, whereas Guillain-Barré syndrome (GBS), myasthenia gravis (MG), and neuromyelitis optica (NMO) are less common NADs, but the incidence of these diseases has increased exponentially in the last few years. The identification of a specific culprit in NADs is challenging since a myriad of triggering factors interplay with each other to cause an autoimmune response. Among the factors that have been associated with NADs are genetic susceptibility, epigenetic mechanisms, and environmental factors such as infection, microbiota, vitamins, etc. This review focuses on the most studied culprits as well as the mechanisms used by these to trigger NADs.
Neurological autoimmune diseases are caused by a complex interaction between genes, environmental factors, and epigenetic deregulation. Infectious agents can cause an autoimmune reaction to myelin epitopes through molecular mimicry and/or bystander activation. Gut microbiota dysbiosis contributes to neurological autoimmune diseases. Smoking increases the risk of NADs through inflammatory signaling pathways, oxidative stress, and Th17 differentiation. Deficiency in vitamin D favors NAD development through direct damage to the central and peripheral nervous system.
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Rikos D, Siokas V, Aloizou AM, Tsouris Z, Aslanidou P, Koutsis G, Anagnostouli M, Bogdanos DP, Grigoriadis N, Hadjigeorgiou GM, Dardiotis E. TREM2 R47H (rs75932628) variant is unlikely to contribute to Multiple Sclerosis susceptibility and severity in a large Greek MS cohort. Mult Scler Relat Disord 2019; 35:116-118. [PMID: 31362167 DOI: 10.1016/j.msard.2019.07.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 06/28/2019] [Accepted: 07/19/2019] [Indexed: 01/10/2023]
Abstract
BACKGROUND Multiple Sclerosis is a multifactorial autoimmune disease of the central nervous system, characterized by focal inflammation, demyelination and secondary axonal injury. TREM2 is a signaling protein which participates in the innate immune system by implication to inflammation, proliferation and phagocytosis. The R47H (rs75392628) rare variant of the TREM2 gene has been related to various neurological diseases and leads to impaired signaling, lipoprotein binding, lipoprotein uptake and surface uptake. AIM To assess the role of TREM2 rs75932628 on MS risk through a genetic candidate gene association case-control study in a Greek population. METHODS 1246 MS cases and 398 controls were genotyped for this variant. RESULTS No MS or healthy subjects carried the variant. CONCLUSION This variant does not seem to play a determining role in the pathogenesis of MS, although further studies examining the presence of TREM2 mutations in other, phylogenetically different populations and the epigenetic regulation of this gene are needed in order to thoroughly investigate its role in MS.
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Affiliation(s)
- Dimitrios Rikos
- Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, University of Thessaly, Larissa, Greece
| | - Vasileios Siokas
- Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, University of Thessaly, Larissa, Greece
| | - Athina-Maria Aloizou
- Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, University of Thessaly, Larissa, Greece
| | - Zisis Tsouris
- Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, University of Thessaly, Larissa, Greece
| | - Paraskevi Aslanidou
- Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, University of Thessaly, Larissa, Greece
| | - Georgios Koutsis
- Neurogenetics Unit, 1st Department of Neurology, University of Athens, Medical School, Eginition Hospital, Athens, Greece
| | - Maria Anagnostouli
- Demyelinating Diseases Unit and Immunogenetics Laboratory, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios P Bogdanos
- Cellular Immunotherapy & Molecular Immunodiagnostics, Biomedical Section, Centre for Research and Technology-Hellas (CERTH), Institute for Research and Technology-Thessaly (IRETETH), Larissa, Greece
| | - Nikolaos Grigoriadis
- Laboratory of Experimental Neurology and Neuroimmunology, B' Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Georgios M Hadjigeorgiou
- Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, University of Thessaly, Larissa, Greece; Department of Neurology, Medical School, University of Cyprus, Nicosia, Cyprus
| | - Efthimios Dardiotis
- Department of Neurology, Laboratory of Neurogenetics, University Hospital of Larissa, University of Thessaly, Larissa, Greece.
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Deeba E, Koptides D, Lambrianides A, Pantzaris M, Krashias G, Christodoulou C. Complete sequence analysis of human toll-like receptor 3 gene in natural killer cells of multiple sclerosis patients. Mult Scler Relat Disord 2019; 33:100-106. [PMID: 31177052 DOI: 10.1016/j.msard.2019.05.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 05/20/2019] [Accepted: 05/29/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) where both environmental and genetic risk factors play a role. Among the environmental risk factors, EBV and HSV infections have been suggested as strong candidates contributing to MS pathology/progression. Viral recognition and control is largely tasked to the NK cells via TLR recognition and various cytotoxic and immunoregulatory functions. The present work aimed to characterize NK cells isolated from MS patients for genetic polymorphisms in the gene encoding for TLR3, as TLR3 in NK cells is important in herpesvirus recognition. METHODS Highly purified NK cells isolated from peripheral blood of MS patients (n = 27) and healthy controls (n = 30) were used to sequence all five exons of the TLR3 gene using sanger sequencing. Alignment of the obtained sequences with the wild-type TLR3 sequence was used to identify genetic polymorphisms within the TLR3 gene. RESULTS The alignment identified multiple substitution mutations across the five exons of the TLR3 gene (rs116729895, rs3775296, rs377529, rs3775290, rs3775291, rs376735334 and rs73873710). A significant difference was observed in the allele distribution of rs3775291 (Leu412Phe) between MS patients and HC, whereby the minor allele was detected in 38.9% of MS patients versus 11% of HC (Fisher's exact test, p = 0.021). CONCLUSION There appears to be a possible association between the TLR3 missense mutation rs3775291 and multiple sclerosis, which might be attributed to changes in the TLR3 functional properties.
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Affiliation(s)
- Elie Deeba
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Dana Koptides
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Anastasia Lambrianides
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; Neurology Clinic C, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Marios Pantzaris
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; Neurology Clinic C, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - George Krashias
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
| | - Christina Christodoulou
- Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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Uddin MS, Kabir MT, Jakaria M, Mamun AA, Niaz K, Amran MS, Barreto GE, Ashraf GM. Endothelial PPARγ Is Crucial for Averting Age-Related Vascular Dysfunction by Stalling Oxidative Stress and ROCK. Neurotox Res 2019; 36:583-601. [PMID: 31055770 DOI: 10.1007/s12640-019-00047-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 04/01/2019] [Accepted: 04/11/2019] [Indexed: 02/07/2023]
Abstract
Aging plays a significant role in the progression of vascular diseases and vascular dysfunction. Activation of the ADP-ribosylation factor 6 and small GTPases by inflammatory signals may cause vascular permeability and endothelial leakage. Pro-inflammatory molecules have a significant effect on smooth muscle cells (SMC). The migration and proliferation of SMC can be promoted by tumor necrosis factor alpha (TNF-α). TNF-α can also increase oxidative stress in SMCs, which has been identified to persuade DNA damage resulting in apoptosis and cellular senescence. Peroxisome proliferator-activated receptor (PPAR) acts as a ligand-dependent transcription factor and a member of the nuclear receptor superfamily. They play key roles in a wide range of biological processes, including cell differentiation and proliferation, bone formation, cell metabolism, tissue remodeling, insulin sensitivity, and eicosanoid signaling. The PPARγ activation regulates inflammatory responses, which can exert protective effects in the vasculature. In addition, loss of function of PPARγ enhances cardiovascular events and atherosclerosis in the vascular endothelium. This appraisal, therefore, discusses the critical linkage of PPARγ in the inflammatory process and highlights a crucial defensive role for endothelial PPARγ in vascular dysfunction and disease, as well as therapy for vascular aging.
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Affiliation(s)
- Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh.
| | | | - Md Jakaria
- Department of Applied Life Sciences, Graduate School, Konkuk University, Chungju, South Korea
| | | | - Kamal Niaz
- Department of Pharmacology and Toxicology, Faculty of Bio-Sciences, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan
| | - Md Shah Amran
- Department of Pharmaceutical Chemistry, University of Dhaka, Dhaka, Bangladesh
| | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, DC, Colombia.,Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia. .,Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
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Gregson A, Thompson K, Tsirka SE, Selwood DL. Emerging small-molecule treatments for multiple sclerosis: focus on B cells. F1000Res 2019; 8:F1000 Faculty Rev-245. [PMID: 30863536 PMCID: PMC6402079 DOI: 10.12688/f1000research.16495.1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/20/2019] [Indexed: 12/27/2022] Open
Abstract
Multiple sclerosis (MS) is a major cause of disability in young adults. Following an unknown trigger (or triggers), the immune system attacks the myelin sheath surrounding axons, leading to progressive nerve cell death. Antibodies and small-molecule drugs directed against B cells have demonstrated good efficacy in slowing progression of the disease. This review focusses on small-molecule drugs that can affect B-cell biology and may have utility in disease management. The risk genes for MS are examined from the drug target perspective. Existing small-molecule therapies for MS with B-cell actions together with new drugs in development are described. The potential for experimental molecules with B-cell effects is also considered. Small molecules can have diverse actions on B cells and be cytotoxic, anti-inflammatory and anti-viral. The current B cell-directed therapies often kill B-cell subsets, which can be effective but lead to side effects and toxicity. A deeper understanding of B-cell biology and the effect on MS disease should lead to new drugs with better selectivity, efficacy, and an improved safety profile. Small-molecule drugs, once the patent term has expired, provide a uniquely sustainable form of healthcare.
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Affiliation(s)
- Aaron Gregson
- The Wolfson Institute for Biomedical Research, University College London, Gower Street, London, WC1E 6BT, UK
| | - Kaitlyn Thompson
- Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, 11794, USA
| | - Stella E Tsirka
- Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, 11794, USA
| | - David L Selwood
- The Wolfson Institute for Biomedical Research, University College London, Gower Street, London, WC1E 6BT, UK
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