| 1. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 2. |
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| 4. |
- Beecham, Ashley H, et al.
(författare)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Tidskriftsartikel (refereegranskat)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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| 5. |
- Delli, Ahmed, et al.
(författare)
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Autoimmune type 1 diabetes.
- 2010
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Ingår i: Textbook of Diabetes. - : Wiley. - 9781405191814 ; , s. 141-152
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Bokkapitel (refereegranskat)abstract
- The pathophysiologic mechanisms in type 1 diabetes (T1DM) involve loss of islet β-cell secretory function caused by selective killing of these cells primarily by aggressive autoimmune responses involving both cellular and humoral immune pathways. Inflammatory cells heavily infiltrate pancreatic islets leading to insulitis where CD8+ T lymphocytes are thought to be responsible for selective and specific killing of β-cells. The complex etiology of T1DM involves a strong genetic predisposition, mainly human leukocyte antigen class II genes, and several putative environmental factors, which are thought to trigger autoimmunity or progression to clinical T1DM. A preclinical prodrome in T1DM may vary in duration in which one or more islet autoantibodies may precede insulitis and predict the disease at the early stages of pathologic insult. In genetically susceptible individuals with islet autoantibodies, metabolic indicators such as insulin release abnormalities and insulin resistance may best predict T1DM especially near clinical onset. Based on the improving understanding of the etiopathogenesis of T1DM, several clinical trials have been launched aiming at halting the autoimmunity responses, retarding disease progression or preserving remaining β-cell function after clinical onset.
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| 6. |
- Fatima, Nowshir, et al.
(författare)
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Adsorption of ATF additives on wet clutch friction interfaces under water contaminated lubricant conditions
- 2014
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Konferensbidrag (refereegranskat)abstract
- Stable friction and positive slope of friction-speed is the typical criterion for a good clutch performance. Lubricated friction interfaces used for wet clutches produces different friction behavior depending on the lubricant conditions. Usually the lubricant conditions vary for different automatic transmission fluid (ATF) formulations implying e.g. water contamination and these conditions might influence the deterioration of the clutch plates. The aim of this paper is to verify additive adsorption on friction interfaces and ageing of the friction material in wet clutch system for a water contaminated commercial ATF (DEXRON® VI). Standard clutch plates are employed in an automated wet clutch test rig to evaluate the friction characteristics of the tested lubricant. For controlled test conditions (speed, contact pressure, oil temperature) and specific number of test cycles, the mean friction coefficient and the friction vs. speed relations are monitored during sliding test. The resultant tribofilms on the tested friction interface surfaces are characterized by means of Scanning Electron Microscopy-Energy Dispersive X-ray spectroscopy (SEM- EDS), Attenuated Total Reflectance -Fourier Transform Infrared Spectroscopy (ATR-FTIR) and X-ray Photoelectron Spectroscopy (XPS analysis). The spectroscopic techniques were used to analyse adsorbed additives on friction interfaces and made it possible to correlate measured data to the specific friction behavior obtained after water contamination of the ATF.
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| 8. |
- Koeck, Thomas, et al.
(författare)
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A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes.
- 2011
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 13:1, s. 80-91
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) evolves when insulin secretion fails. Insulin release from the pancreatic β cell is controlled by mitochondrial metabolism, which translates fluctuations in blood glucose into metabolic coupling signals. We identified a common variant (rs950994) in the human transcription factor B1 mitochondrial (TFB1M) gene associated with reduced insulin secretion, elevated postprandial glucose levels, and future risk of T2D. Because islet TFB1M mRNA levels were lower in carriers of the risk allele and correlated with insulin secretion, we examined mice heterozygous for Tfb1m deficiency. These mice displayed lower expression of TFB1M in islets and impaired mitochondrial function and released less insulin in response to glucose in vivo and in vitro. Reducing TFB1M mRNA and protein in clonal β cells by RNA interference impaired complexes of the mitochondrial oxidative phosphorylation system. Consequently, nutrient-stimulated ATP generation was reduced, leading to perturbed insulin secretion. We conclude that a deficiency in TFB1M and impaired mitochondrial function contribute to the pathogenesis of T2D.
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| 10. |
- Larsson, Helena, et al.
(författare)
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Future drug treatment of Type 1 diabetes
- 2010
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Ingår i: Textbook of Diabetes. - : Wiley. - 9781405191814 ; , s. 1001-1016
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Bokkapitel (refereegranskat)abstract
- Insulin replacement therapy is considered the only effective and feasible treatment for type 1 diabetes mellitus (T1DM) as only insulin is capable of reversing the metabolic disturbances and restoring a near - normal quality of life in patients with T1DM. Despite rigorous measures and major advances in health care provided for patients with T1DM, increased morbidity and mortality are still common from complications, which commonly develop within 10 – 12 years after clinical onset. Advances in the understanding of the natural history of T1DM and increased abilities to predict the disease have made it possible to design and implement prevention and intervention clinical trials. Clinical trials are aimed at: (a) preventing the initiation of islet autoimmunity (primary prevention);(b)reducing autoimmune β-cell killing and progression to clinical diabetes (secondary prevention); or(c)suppressing or modulating the immune response in order to halt β-cell killing and enhance β-cell regeneration (tertiary prevention or intervention). Several trials were implemented or are currently ongoing with dietary manipulation, parenteral or oral insulin or immune-suppressing or immune-modulating agents with the aim of preventing the disease or retarding its progression. The search for safe, effective and feasible drugs to prevent or cure T1DM is still ongoing. So far, immune modulation with alum - formulated GAD65 has been shown to be the most promising intervention to reduce the loss of β-cells. Anti-CD3 monocloncal autoantibodies also showed some benefits in patients with newly diagnosed T1DM.
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