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- Original Study: http://www.ncbi.nlm.nih.gov/pubmed/25694554
- Abstract: We identified a family in which five siblings were diagnosed with multiple sclerosis (MS) or clinically isolated syndrome. Several women in the maternal lineage have comorbidities typically associated with Peutz Jeghers Syndrome, a rare autosomal-dominant disease caused by mutations in the serine-threonine-kinase 11 (STK11) gene, which encodes liver kinase B1. Sequence analysis of DNA from one sibling identified a single-nucleotide polymorphism (SNP) within STK11 intron 5. This SNP (dbSNP ID: rs9282860) was identified by TaqMan polymerase chain reaction (PCR) assays in DNA samples available from two other siblings. Further screening was carried out in samples from 654 relapsing-remitting MS patients, 100 primary progressive MS patients, and 661 controls. The STK11-SNP has increased frequency in all female patients versus controls (odds ratio = 1.66, 95% CI = 1.05, 2.64, p = .032). The STK11-SNP was not associated with disease duration or onset; however, it was significantly associated with reduced severity (assessed by MS severity scores), with the lowest scores in patients who also harbored the HLA-DRB1*1501 allele. In vitro studies showed that peripheral blood mononuclear cells from members of the family were more sensitive to the mitochondrial inhibitor metformin than cells from MS patients with the major STK11 allele. The increased association of SNP rs9282860 in women with MS defines this variant as a genetic risk factor. The lower disease severity observed in the context of HLA-DRB1*1501 combined with limited in vitro studies raises the provocative possibility that cells harboring the STK11-SNP could be targeted by drugs which increase metabolic stress.
A closer look at how cells die in MS lesions suggests that a new drug might be useful for treating MS. Researchers showed that a substance that blocks certain enzymes stop the damage to the myelin in experiments using mice with MS and in culture experiments with human cells. Not only does this tell us more about disease mechanisms, but it also provides something new to target for MS therapy.
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- Abstract: Multiple sclerosis (MS), a common neurodegenerative disease of the CNS, is characterized by the loss of oligodendrocytes and demyelination. Tumor necrosis factor α (TNF-α), a proinflammatory cytokine implicated in MS, can activate necroptosis, a necrotic cell death pathway regulated by RIPK1 and RIPK3 under caspase-8-deficient conditions. Here, we demonstrate defective caspase-8 activation, as well as activation of RIPK1, RIPK3, and MLKL, the hallmark mediators of necroptosis, in the cortical lesions of human MS pathological samples. Furthermore, we show that MS pathological samples are characterized by an increased insoluble proteome in common with other neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Finally, we show that necroptosis mediates oligodendrocyte degeneration induced by TNF-α and that inhibition of RIPK1 protects against oligodendrocyte cell death in two animal models of MS and in culture. Our findings demonstrate that necroptosis is involved in MS and suggest that targeting RIPK1 may represent a therapeutic strategy for MS.
Big data in MS requires central database. One way to collect and store a lot of data from a lot of people is to build a structure to hold the data. This is called a database. Having a large database with information from a lot of people with MS, such as the imaging of their brains with MRI, will let researchers track data easily and over time. This will allow researchers to look for patterns and trends in the data. Early work in the eFolder project builds the framework for such a database that will be open to any person with MS and will allow researchers to be able to get to the data, and to look for relationships in the data.
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- Abstract: In the past, we have developed and displayed a multiple sclerosis eFolder system for patient data storage, image viewing, and automatic lesion quantification results stored in DICOM-SR format. The web-based system aims to be integrated in DICOM-compliant clinical and research environments to aid clinicians in patient treatments and disease tracking. This year, we have further developed the eFolder system to handle big data analysis and data mining in today’s medical imaging field. The database has been updated to allow data mining and data look-up from DICOM-SR lesion analysis contents. Longitudinal studies are tracked, and any changes in lesion volumes and brain parenchyma volumes are calculated and shown on the web-based user interface as graphical representations. Longitudinal lesion characteristic changes are compared with patients’ disease history, including treatments, symptom progressions, and any other changes in the disease profile. The image viewer is updated such that imaging studies can be viewed side-by-side to allow visual comparisons. We aim to use the web-based medical imaging informatics eFolder system to demonstrate big data analysis in medical imaging, and use the analysis results to predict MS disease trends and patterns in Hispanic and Caucasian populations in our pilot study. The discovery of disease patterns among the two ethnicities is a big data analysis result that will help lead to personalized patient care and treatment planning.
GM-CSF: traffic control cop of blood-brain barrier. The blood-brain barrier protects the central nervous system from cells that cause the inflammation in MS. One type of cell has been shown to be related to the cause of MS in many ways. This cell is called the granulocyte-macrophage colony-stimulating factor (GM-CSF). A study in the European Journal of Immunology has shown that GM-CSF makes it easier for monocytes, a kind of immune cell, to get across the blood-brain barrier.
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- Link to original study: http://onlinelibrary.wiley.com/doi/10.1002/eji.201444960/abstract
- Abstract: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Infiltration of monocytes into the CNS is crucial for disease onset and progression. Animal studies indicate that granulocyte-macrophage colony-stimulating factor (GM-CSF) may play an essential role in this process, possibly by acting on the migratory capacities of myeloid cells across the blood-brain barrier (BBB). This study describes the effect of GM-CSF on human monocytes, macrophages and microglia. Furthermore, the expression of GM-CSF and its receptor was investigated in the CNS under healthy and pathological conditions. We show that GM-CSF enhances monocyte migration across human BBB endothelial cells in vitro. Next, immunohistochemical analysis on human brain tissues revealed that GM-CSF is highly expressed by microglia and macrophages in MS lesions. The GM-CSF receptor is expressed by neurons in the rim of combined gray/white matter lesions and astrocytes. Finally, the effect of GM-CSF on human macrophages was determined, revealing an intermediate activation status, with a phenotype similar to that observed in active MS lesions. Together our data indicate that GM-CSF is a powerful stimulator of monocyte migration, and is abundantly present in the inflamed CNS where it may act as an activator of macrophages and microglia.