Multiple Sclerosis Proteins


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 Multiple Sclerosis Proteins Background

Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease with underlying neurodegeneration of the human central nervous system, which affects over 2.3 million individuals worldwide and currently has no cure. This disease affects 2 times more females than males and is the major cause of non-traumatic neurological disability in young adults, with onset occurring often in the third decade of life (average age 25-33, although pediatric multiple sclerosis also occurs in those 18 years old and younger). Creative Biomart provides kinds of multiple sclerosis related proteins as molecular tools for research applications.

The etiology of multiple sclerosis involves a complex relationship between environment and genetic susceptibility. The environmental factors that have been proposed to play a role in multiple sclerosis etiology and risk range from (A) sunlight exposure which is also highly connected to vitamin D status, with an increased prevalence of MS for individuals residing further from the equator; (B) smoking; and (C) infections from viruses like Epstein-Barr virus and human endogenous retrovirus-W.

Genetics also play a role in susceptibility to this disease, as demonstrated by the fact that the risk of developing MS increases in those individuals with a family history of the disease, particularly in immediate family members. Twin studies have demonstrated an increased concordance rate of 31% in monozygotic twins, compared to 5% for dizygotic twins. A specific allele has been identified as carrying a risk of 16-60% chance of developing MS. This gene is for the Human Leucocyte Antigen (HLA) Class II locus, which is part of the major histocompatibility complex located on chromosome 6p21 and has been shown to have a dose effect of increasing disease risk. MS patients that were homozygous for the HLA-DR2 allele were more likely to have a severe disease outcome than any other haplotype. The HLA-DR2 gene plays a role in antigen presentation on immune cells, and therefore is presenting fragments of myelin proteins to T lymphocytes and controlling their reactivity to myelin. This finding provides strong evidence that MS is an autoimmune disease.

Although demyelinating white matter lesions are the pathological hallmark of MS, and MS is generally considered to be a disease of the white matter, the cerebral gray matter, spinal cord and brainstem can also become demyelinated and contribute to the neurological disability of MS patients. Cortical demyelination has been estimated to develop in over 90% of MS patients, and has been shown to begin developing early in the disease course. Cortical demyelination can even exceed white matter lesion loads in the cerebrum in some patients. Cognitive deficits and some of the neurological disabilities which accumulate over the course of the disease may be a result of cortical and/or hippocampal demyelination frequently observed in individuals with MS. It is unknown, how cortical lesions arise, as well as how much secondary degeneration of axonal fiber tracts within cerebral white matter lesions contributes to the formation of cortical lesions. Parsing the mechanisms of cortical and white matter lesions would require examining individuals with compartmentalized demyelination to determine the relationship between these two lesions types without the influence of other pathologies. Case reports of patients in which pathology was limited to the spinal cord and others with only cerebral white matter demyelination, but no gray matter lesions, can provide insight into the mechanism of cortical demyelination in MS patients. Some MS patients exhibit strictly spinal cord demyelination, supporting the possibility that spinal cord and cerebral white matter demyelination occur through different mechanisms. Furthermore, if cases of MS patients can develop white matter demyelination in the absence of demyelination of gray matter, would suggest different pathological mechanisms.

 

Multiple Sclerosis Pathology

The pathology relating to MS can be observed throughout the central nervous system, however the white matter demyelinating lesions are the pathological hallmark of this disease and must disseminate in time and space before the diagnosis of MS is pronounced. The white matter pathology for all subtypes of MS has been studied for centuries and what we presently know is that the most common regions of the brain to be affected by demyelination are the periventricular white matter, the corpus callosum, the juxtacortical white matter, the spinal cord, optic nerve, and the brainstem. However, “no region is immune from the occurrence of plaques,” within the central nervous system. Lesions can be visualized on MRI scans as well as seen macroscopically in postmortem tissue by the discoloration of the tissue in the area of the lesion due to the loss of the iridescent myelin which gives the tissue its white coloring. Through the postmortem histological analysis of white matter lesions a chronological classification was established based upon myelin integrity and the activated inflammatory infiltrating cells; therefore by examining the microglial activation through immunohistochemical techniques, the “age” of the white matter lesion can be estimated. White matter lesions commence in the acute active stage with breakdown of the blood-brain barrier, extensive infiltration of peripheral inflammatory cells (mostly monocytes to phagocytize the myelin), demyelination of the axons, activation of the nearby microglia (the resident immune cells of the central nervous system), astrogliosis and axonal injury. The breakdown of the blood-brain barrier can be visualized by immunohistochemical stains for serum proteins such as IgG, albumin or fibrinogen. These acute lesions can be differentiated from chronic lesions by MRI scans following the infusion of gadolinium-DTPA (discussed in greater detail later in this chapter). The gadolinium enhancing lesions are most often observed in RRMS; however they are occasionally present in the SPMS stage. After a few months, the acute active white matter lesions will eventually develop into a chronic active lesion where activated microglia and macrophages are present at the borders of the lesion following the evacuation of the phagocytes from the interior of the white matter lesions. While the microglia and macrophages are continuing to remove myelin, axonal transection and neuronal loss also continue to transpire as described by Trapp and colleagues due to the damaging environment within the white matter lesion core. Chronic active lesions can be seen on T2-Weighted MRI scans as hyperintensities (bright spots) within the cerebral white matter which delineates where pathology is present. Finally, after several years, white matter lesions advance to chronic inactive lesions, where only activated microglia is present at the border of the lesion with continued ongoing neuronal and axonal damage. These lesions have been in the brain the longest and no longer have inflammatory infiltration causing breakdown of the blood-brain barrier.