MS Disease Biology

Research Paper Summaries

This page contains summaries of research papers reviewed and discussed during the course.

The Genetics of Multiple Sclerosis

In this paper, Didonna and Oksenberg review the historical advances in MS genetic research and understanding the genetics of MS from multiple areas of research. For instance, one aspect of MS is that it is influenced by genetic risk factors as well as regional differences in the heritability of the disease. Specifically, siblings have a higher risk of developing MS by 10 to 20 fold with twins having an even greater risk. Moreover, MS is prevalent in northern Europe and North America compared to other regions and ethnic groups, suggesting a factor of MS-resistant or low-incidence ancestral groups that influence an individual’s risk of developing MS. Additionally, The MHC complex which includes about 160 linked genes (immune system regulators and HLA genes) have a strong genetic impact on MS. The paper also reviews how GWAS studies and a custom high-density genotyping array called ImmunoChip became highly useful technologies in deconstructing the genes of MS. Furthermore, the discussion of how such genes can contribute to phenotypic variations and how the genetics of MS can be studied through use of animal models is reviewed later in the chapter.

Didonna A, Oksenberg RJ. Multiple Sclerosis: Perspectives in Treatment and Pathogenesis. Ian S. Zagon and Patricia J. McLaughlin (Editors), Codon Publications, Brisbane, Australia. ISBN: 978-0-9944381-3-3. http://dx.doi.org/10.15586/codon.multiplesclerosis.2017

The Nature of Genetic and Environmental Susceptibility to Multiple Sclerosis

Goodin et al. (2021), the main focus of this MS research seeks to understand the susceptibility of MS based on genetic and environmental factors. Specifically, the paper determines whether the two categorical factors coincide or not.

From the genetic aspect, more than 233 loci are MS related, including those within the major histocompatibility complex (MHC). The MHC is a group of polymorphic genes that code for immune system proteins, therefore suggesting its role in the pathogenesis of MS. Additionally, MS has an association with the with the HLA-DTB1* 15:01-HLA-DQB1*06:02-a1 haplotype. Using a genome-wide association screen (GWAS), the paper identified the loci/polymorphisms by finding the relation between genetic variations and MS, otherwise known as the polygenic risk score. Techniques employed include epidemiological parameters and statistical analysis to determine influences of genetic susceptibility to MS. These parameters were abbreviations and subsets for the analysis, for example, the use of “(G)” for genetically-susceptible subset and “(G-)” for non-susceptible subset. Such abbreviations were overall used for simplicity and efficiency since based on the relationships between the terms, the researchers could use the pre-existing population parameters to infer a non-observable parameter.

The results found that 7.3% or less of the population is genetically susceptible to MS and the remaining percentage of the population has no chance of getting the disease regardless of environmental factors. Moreover, environmental factors have greater influence on women, but women are less likely to get MS than men. Therefore, the conclusions extrapolated from the results are that MS needs influence from both genetic and environmental factors to develop, and the haplotype is not a risk-factor unless combined with other genetic factors. Future directions for the research can include the use of more GWAS studies to research whether behavioral differences in patients with MS have a population level effect similar to physiological differences.

Goodin DS, Khankhanian P, Gourraud P- A, Vince N (2021) The nature of genetic and environmental susceptibility to multiple sclerosis. PLoS ONE 16(3): e0246157. https://doi.org/10.1371/journal.pone.0246157

The Potential Impact of Digital Biomarkers in Multiple Sclerosis in The Netherlands: An Early Health Technology Assessment of MS Sherpa

Health interventions are becoming more integrated in patient care as they can enhance the efficiency and quality of managing patients and developing the most effective course of treatment. The research paper, Cloosterman et al. (2021), tests the benefits of adding MS Sherpa for MS patient care. MS Sherpa is a medical device/ eHealth intervention system that monitors MS patients using digital biomarkers. Specifically, the 2 digital biomarkers include one for indicating cognitive processing speed and one for walking speed (2 related symptoms of MS). MS Sherpa can monitor the symptoms of MS patients on a frequent basis as a form of decentralized care that can even be done at home, rather than at a hospital. Since MS readout varies each day and is specific to each individual, treatment is aimed at preventing relapses and slowing disease progression.

This research utilized Health Technology Assessments (with an MS model) to estimate the costs and benefits of using/ not using MS Sherpa. Specifically, the paper used eHTA analysis from the societal and health care perspective. The societal perspective is as follows: all relevant MS costs and benefits must be included in the analysis no matter who is affected by the benefits or costs. Conversely, the healthcare perspective is that costs outside healthcare are not included. Functions of MS Sherpa also included a daily questionnaire for answers regarding the impact of MS on the patient (ex: stress, fatigue, etc.).

The results were that there was 90% adherence to the scheduled tasks of the MS Sherpa app compared to other eHealth interventions. Moreover, both digital biomarkers showed reliability and validity to cause a reduction in MS disease progression and relapse rates, for instance, patients developed severe disability later than seen without MS Sherpa. Thus, it could be concluded that with MS Sherpa, there was more available information on MS sooner, therefore, patients could switch to the next treatment earlier (cost-effective and can prevent MS relapses and progression). Thus, future directions for research can include more clinical trials for MS Sherpa regarding earlier detection of the disease.

Cloosterman,S.;Wijnands, I.; Huygens, S.; Wester, V.; Lam, K.-H.; Strijbis, E.; den Teuling, B.; Versteegh, M. The Potential Impact of Digital Biomarkers in Multiple Sclerosis in The Netherlands: An Early Health Technology Assessment of MS Sherpa. BrainSci.2021,11,1305. https://doi.org/10.3390/brainsci11101305

Illumination of Molecular Pathways in Multiple Sclerosis Lesions and the Immune Mechanism of Matrine Treatment in EAE, a Mouse Model of MS

In this research paper, Dou et al. set out to investigate the pathogenesis and potential targets for MS treatment. This was done by defining target genes of matrine, an alkaloid derived from a specific root that was shown to inhibit inflammation and suppress autoimmune encephalomyelitis (EAE) in an animal model of MS. In humans, Acute Disseminated Encephalomyelitis (ADEM) is an isolated event of inflammation in the central nervous system (CNS) that causes damage to myelin as a possible precursor to MS. Therefore, models of experimental autoimmune encephalomyelitis try to replicate features of MS. Additionally, the investigation of MS pathogenesis was specific to immune cells since an increased number of IFN-y or IL17+ CD4+T cells were found in the CNS lesion tissues in patients with MS, and microglial cells were activated before the onset of EAE. Thus, an overall cross-analysis between DEGs (genes that help identify biological differences of individuals without MS and with MS) in MS patients and further validated target genes of matrine in EAE mice was done.

This paper used a multitude of methods: a gene expression data set from GEO Datasets was chosen which included chronic active MS lesions followed by the use of microarrays and high throughput sequencing technologies, Xcell, KEGG (kyoto encyclopedia of genes and genomes), and STRING to identify the 20 key genes involved in MS. Then, the animal models with EAE were treated with matrine followed by various techniques such as H&E staining to find the levels of inflammatory cell infiltration, L&B staining to find the levels of demyelination, and PCR to identify the primer sequences of the matrine target genes.

The results were that the MS group had decreased scores of specific immune cells and increased scores of other immune cells. By screening the GSE108000 data set, Dou et al. found 637 DEGs involved in immune response (ex: DEGs associated w/ MHC protein complex). Furthermore, the results state that key DEGs including HLA genes might lead to MS disease progression by influencing immune cells and mediating key pathways of the immune cells (based on KEGG analysis which assessed signaling pathways). Moreover, the results for the animal model found 199 overlapping target genes between 2 main components of matrine. Overall, by analyzing the crossover between matrine target genes and previously found DEGs from MS lesions, Dou et al. found 12 key genes that could be target genes for matrine treatment in EAE and possibly MS. Thus, such results could be used to develop therapeutic approaches that may target these genes in MS patients.

Dou M, Zhou X, Li L, Zhang M, Wang W, Wang M, Jing Y, Ma R, Zhao J and Zhu L (2021) Illumination of Molecular Pathways in Multiple Sclerosis Lesions and the Immune Mechanism of Matrine Treatment in EAE, a Mouse Model of MS. Front. Immunol. 12:640778. https://doi.org/10.3389/fimmu.2021.640778

Animal Models of Multiple Sclerosis

No animal model is perfect since it can not completely replicate all the complexities of MS, such as its disease courses. MS has 3 disease courses that are all difficult to replicate in just one animal model: Relapsing-remitting, seen most commonly in MS patients and is characterized by attacks or flare ups and periods of stability, Secondary Progressive, and Primary Progressive. However, animal models help test therapeutic approaches for MS and can give insight into the pathogenesis of the disease. Specifically, this paper reviewed several types of animal models including EAE for the autoimmune origin of MS, viral induced models such as TMEV and chronic demyelination, and toxin-induced models such as cuprizone and lyso-lethin (induce demyelination).

Claudio Procaccini, Veronica De Rosa, Valentina Pucino, Luigi Formisano, Giuseppe Matarese (2015) Animal models of Multiple Sclerosis. European Journal of Pharmacology. Volume 759. Pages 182-191. https://doi.org/10.1016/j.ejphar.2015.03.042

Diagnosis and Treatment of Multiple Sclerosis

MS is prevalent in 20-30 year old young adults and affects about 900,000 people in the U.S. The clinical presentation of MS can be seen through symptoms such as optic neuritis, partial myelitis, brainstem syndrome, etc. MRI scans can be used to identify lesions throughout the central nervous system, and these imaging technologies along with clinical findings and lab data from diagnostic criteria allow for diagnosis of MS. The treatment for MS involves the use of DMTs, which are disease modifying treatments that are still under research for efficacy and safety. Thus, the future directions for research include testing DMTs on treating MS, stem cell based therapies, and remyelination therapies.

McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and Treatment of Multiple Sclerosis: A Review. JAMA. 2021;325(8):765–779. https://doi.org/10.1001/jama.2020.26858

Molecular Biomarkers in Multiple Sclerosis

To assist diagnosis and assessment of treatments for MS, molecular biomarkers are needed. Molecular biomarkers are easily quantifiable and can coincide with MRI screening and clinical presentation of MS. In this review Ziemssen et al. discusses what the characteristics of a MS biomarker should have and the challenges identifying them. A biomarker is defined in the paper as a “objectively measured and evaluated and serves as an indicator of normal biological processes, pathological processes or pharmacological reactions to therapy.” A molecular biomarker should be safe, easily detectable, accurate, and reproducible (ex: for use in animal models). There are also imaging biomarkers such as lesions from MRI scans and molecular biomarkers for MS that consist mainly of proteins such as antibodies.

The challenges of establishing new biomarkers include sensitivity and specificity factors as well as the biomarkers’ positive and negative predictive values. Thus, due to the difficulty in having similar results between small investigative groups and large populations/groups, the detection method for a biomarker must be through and validated appropriately to be applicable to large populations.

The molecular biomarkers for MS diagnosis

oligoclonal bands
IgG index
measles/rubella/varicella-zoster reaction
anti-aquaporin-4 antibodies
anti-MOG antibodies & antinuclear antibodies

The molecular biomarkers for MS prognosis

oligoclonal bands
Chitinase-3-like-1
neurofilaments

Ziemssen, T., Akgün, K. & Brück, W. Molecular biomarkers in multiple sclerosis. J Neuroinflammation 16, 272 (2019). https://doi.org/10.1186/s12974-019-1674-2

The molecular biomarkers for monitoring therapy response

neutralizing antibodies against interferon- β,
neutralizing antibodies against natalizumab
neurofilament light chain
C-X-C motif chemokine-13

The molecular biomarkers for therapeutic side effects

anti-varicella zoster virus antibodies
anti-John Cunningham virus antibodies
L-selectin expression.

Longitudinal Analysis Reveals High Prevalence of Epstein-Barr Virus Associated with Multiple Sclerosis

Currently, in the research of MS, the causes of the disease are unknown, but the demyelination in MS has been linked to being possibly triggered by a viral infection. The research paper, Bjornevik et al. (2022), tests whether MS is caused by Epstein-Barr Virus (EBV), a human herpesvirus that infects about 95% of adults and persists throughout the host’s life in B lymphocytes even after infection(produce antibodies to provide defense against pathogens). Through a longitudinal investigation, MS incidence was tested in a group of EBV-negative individuals. The results found were that there was a high seroconversion rate among the individuals. Thus, the paper concluded that MS risk increased after infection with EBV.

*Further details provided in the research poster*

Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, Elledge SJ, Niebuhr DW, Scher AI, Munger KL, et al. (2022) Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 375(6578). https://doi.org/10.1126/science.abj8222

EBV–specific T cell Therapy for Progressive Multiple Sclerosis

In this research, Pender et al. tested EBV-specific T cell therapy for treating progressive MS patients. The therapy targeted EBV nuclear antigen 1, latent membrane protein 1 (LMP1), and LMP2A. A clinical trial was conducted to test the therapy on thirteen MS patients and the following aspects of the results were discussed: Adoptive T cell therapy characterization and clinical safety, clinical outcomes following the therapy, and relation between the therapy and response. The results were that most patients showed improvements from a clinical standpoint and the patients’ response to the therapy varied depending on the reactivity of the T cells to EBV.

*Further details provided in the research poster*

Pender MP, Csurhes PA, Smith C, Douglas NL, Neller MA, Matthews KK, Beagley L, Rehan S, Crooks P, Hopkins TJ, et al. (2018) Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI insight. 3(22):e124714. https://doi.org/10.1172/jci.insight.124714

Mechanisms of Neurobehavioral Abnormalities in Multiple Sclerosis: Contributions from Neural and Immune Components

MS can cause neurobehavioral abnormalities (NBAs) and cognitive impairment. Both the inflammatory demyelination with episodes of relapses and the progression of the disease occur concurrently. The main NBAs in MS patients include fatigue, depression, anxiety, cognitive decline, decreased processing speed, and altered attention. Moreover, the main clinical factors of MS are altered including an (The Expanded Disability Status Scale

score of more than 4.0 (indicating higher disability), altered vocabulary, gray matter degeneration, the presence of cortical lesions, increased width of the third ventricle, and low premorbid intelligence. In this paper, Lazo-Gomez et al. demonstrates that there are various mechanisms that have been shown to cause NBAs, including immunopathological components of MS and neuropathological mechanisms that can cause NBAs, but may not be specific to MS.

The immunopathological component of MS that may lead to NBAs is the autoimmune response to antigens by immune cells, such as T lymphocytes, self-reactive immunoglobulins produced by B cells, and chemokine CXCL13 (cytokine that induces action by lymphocytes). The neuropathological mechanisms to the NBAs include glutamate-mediated excitotoxicity that induce neuronal death through excessive activation of glutamate receptors, lower levels of GABA, and the alteration of serotonin and dopamine. Additionally, oxidative stress (imbalance between formation of reactive oxygen species and antioxidants) can induce axonal degeneration, and synaptic pruning (elimination of extra synapses) by microglial cells can cause NBAs as well. However, further research can conclude whether these mechanisms are consistent in causing the development of NBAs in MS patients.

Rafael Lazo-Gomez, Gloria de Lourdes Llamosa-García Velázquez, Diego Mireles-Jacobo, Marco Antonio Sotomayor-Sobrino (2019) Mechanisms of neurobehavioral abnormalities in multiple sclerosis: Contributions from neural and immune components. Clinical Neurophysiology Practice. Volume 4. Pages 39-46. https://doi.org/10.1016/j.cnp.2019.01.004.

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