User:Wellschitt/sandbox

Multiple Sclerosis
To be added onto Neurodegeneration article

To do: Define Multiple Sclerosis, what is it? What is it caused by? Current Treatments/incidence/

Multiple Sclerosis is a chronic debilitating disease of the central nervous system, caused by an autoimmune attack resulting in the progressive loss of myelin sheath on neuronal axons. The resultant decrease in the speed of signal transaction leads to a loss of functionality that includes both cognitive and motor impairment depending on the location of the lesion. The progression of MS occurs due to episodes of increasing inflammation, which is proposed to be due to the release of antigens such as myelin oligodendrocyte glycoprotein, myelin basic protein, and proteolipid protein, causing an autoimmune response. This sets of a cascade of signaling molecules that result in T cells, B cells, and Macrophages to cross the blood-brain barrier and attack myelin on neuronal axons leading to inflammation. Further release of antigens drives subsequent degeneration causing increased inflammation. Multiple sclerosis presents itself as a spectrum based on the degree of inflammation, a majority of patients suffer from early relapsing and remitting episodes of neuronal deterioration following a period of recovery. Some of these individuals may transition to a more linear progression of the disease, while about 15% of others begin with a progressive course on the onset of Multiple sclerosis. The inflammatory response contributes to the loss of the grey matter, and as a result current literature devotes itself to combatting the auto-inflammatory aspect of the disease. While there are several proposed causal linked between EBV and the HLA-DRB1*15:01 allele to the onset of Multiple Sclerosis they may contribute to the degree of autoimmune attack and the resultant inflammation it does not determine the onset of Multiple Sclerosis.

The pathogenesis of multiple sclerosis includes severe loss of myelin, and axon degeneration due to prominent plaque formation that results in reduced cognitive and motor impairment. The etiology of Multiple sclerosis remains unclear, the subsequent immune response is thought to occur due to auto-reactive T cells crossing the Blood brain barrier along with Macrophages and B cells as a response to the release of cytokines that target myelin on neuronal axons.

"MS is distinguishable from most other chronic neurological disorders by its unique fluctuating course; the majority of patients with MS present with early relapsing and remitting episodes of neurological and radiological worsening followed by varying degrees of recovery (relapsing-remitting MS, or RRMS) 1. In most patients, this initial relapsing remitting phase is followed years later by a more chronic progressive phase (secondary progressive MS, or SPMS), whereas a minority (≈15%) of patients begin with a progressive course from onset (primary progressive MS, or PPMS) for unknown reasons."

There is a causal link between the onset of Multiple Sclerosis and the presence of EPV within patients. "it plays a key role in MS pathogenesis"

"Epidemiological evidence supporting the important role of this virus includes observations that patients with a history of symptomatic EBV infection carry a higher risk of developing MS"

Genetic interactions, link to HLA-DR2 and higher prevalence in females.

Vitamin D deficiency explains why there is a higher prevalence in the northern versus the southern hemisphere

There are different types of Multiple sclerosis including Relapsing Remitting MS - periods of immune cell attack which result in the progressive loss of ability. Secondary progressive which starts in shorts bouts of attack and then becomes constant leading to linear increase in disability. primary progressive - steady attack leading to a loss of functionality. Progressive relapsing Multiple sclerosis- Constant attack on Myelin - the fastest loss of functionality due to a steady loss of myelin coupled with periods of attack. The symptoms vary in each individual and are largely based on the location of the plaques. It affects individuals between the ages 20-40 years, and the period of attack can last for weeks leading to deterioration symptoms that persist for months.

"Epidemiologic studies have shown the powerful effect of environmental factors. In general, the prevalence of MS varies with the distance from the equator. One of the most impressive groups of studies consistently found a relatively high incidence of MS among people born and raised in cool climates."

"Although MS acts primarily as a CNS demyelinating disorder, its pathology includes prominent axon degeneration. In contrast to demyelination associated with plaques, axon degeneration regularly produces permanent mental and physical disabilities. The illness’ mean age of onset is 33 years, with 70% of cases developing between 21 and 40 years."

"Traditionally, the etiology of MS was based on an “outside-in” autoimmune hypothesis whereby dysregulated auto-reactive T cells in the periphery cross into the central nervous system (CNS) parenchyma and, together with macrophages and B cells, proceed to attack various CNS elements, where myelin is a prominent target.

"This traditional model is being challenged by a competing theory proposing that the initial malfunction occurs within the CNS, as suspected for other neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases 3– 7. This alternative “inside-out” hypothesis argues that MS is a primary degenerative disease and is accompanied by varying degrees of inflammation, leading to the release of antigenic cell components such as myelin oligodendrocyte glycoprotein, myelin basic protein, and proteolipid protein 8, 9. This chronic shedding of auto-antigens secondarily promotes an autoimmune inflammatory response in the predisposed host, in turn driving additional degeneration in a vicious cycle. The extent of inflammatory activity, which varies by patient and over time within the same individual, determines the spectrum of MS phenotypes"

"Instead, a large number of susceptibility loci, the vast majority of which are related to immune function, have been found through genome-wide association studies (GWASs) 20– 27"

"The HLA-DRB1*15:01 allele is one of the most intensively studied 31, 32, exhibiting a consistent association with a lower age of onset, greater white matter lesion volume, and faster brain atrophy in RRMS 33. In addition, a recent report suggested that the high-risk HLA genotype (two predisposing haplotypes) associates with significant reduction in whole brain and grey matter volumes compared with medium- or low-risk genotypes (one or no predisposing haplotypes) 34. Many loci outside the major histocompatibility complex (MHC) have also been correlated with MS risk and involve other immune pathways, including B-cell activation, cytokine release, and activation of immune cells both in the periphery and within the CNS 27. However, none of these has a strong association with progressive MS, suggesting that these immune-related factors are unlikely to be causative but instead might determine the intensity of autoimmune reactivity to a degenerating brain."

Compiled Bibliography to look into
https://n.neurology.org/content/92/10/e1029

https://www.ninds.nih.gov/Disorders/All-Disorders/Multiple-Sclerosis-Information-Page

https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Multiple-Sclerosis-Hope-Through-Research

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915812/