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| 3. |
- Diez, Margarita, et al.
(författare)
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Identification of gene regions regulating inflammatory microglial response in the rat CNS after nerve injury
- 2009
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 212:1-2, s. 82-92
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Tidskriftsartikel (refereegranskat)abstract
- Local CNS inflammation takes place in many neurological disorders and is important for autoimmune neuroinflammation. Microglial activation is strain-dependent in rats and differential MHC class II expression is influenced by variations in the Mhc2ta gene. Despite sharing Mhc2ta and MHC class II alleles, BN and LEW.1N rats differ in MHC class II expression after ventral root avulsion (VRA). We studied MHC class II expression and glial activation markers in BN rats after VRA. Our results demonstrate that MHC class II expression originates from a subpopulation of IBA1(+), ED1(-), and ED2(-) microglia. We subsequently performed a genome-wide linkage scan in an F2(BNxLEW.1N) population, to investigate gene regions regulating this inflammatory response. Alongside MHC class II, we studied the expression of MHC class 1, costimulatory molecules, complement components, microglial markers and Il1b. MHC class II and other transcripts were commonly regulated by gene regions on chromosomes 1 and 7. Furthermore, a common region on chromosome 10 regulated expression of complement and co-stimulatory molecules, while a region on chromosome II regulated MHC class I. We also detected epistatic interactions in the regulation of the inflammatory process. These results reveal the complex regulation of CNS inflammation by several gene regions, which may have relevance for disease. (C) 2009 Elsevier B.V. All rights reserved.
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| 4. |
- Harnesk, Karin, et al.
(författare)
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Differential nerve injury-induced expression of MHC class II in the mouse correlates to genetic variability in the type I promoter of C2ta
- 2009
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 212:1-2, s. 44-52
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Tidskriftsartikel (refereegranskat)abstract
- Major histocompatibility complex (MHC) class II is of critical importance for the induction of immune responses. Levels of MHC class II in the nervous system are normally low, but expression is up-regulated in many disease conditions. In rat and human, variation in the MHC class II transactivator gene (Uta) is associated with differential expression of MHC class II and susceptibility to autoimmune disease. Here we have characterized the response to facial nerve transection in 7 inbred mouse strains (C57BL/6J, DBA/2J, 129X1/SvJ, BALB/cJ, SJL/J, CBA/J, and NOD). The results demonstrate differences in expression of C2ta and markers for MHC class I and II expression, glial activation. and T cell infiltration. Expression levels of C2ta and Cd74 followed similar patterns, in contrast to MHC class I and markers of glial activation. The regulatory region of the C2ta gene was subsequently sequenced in the four strains (C57BL/6/J, DBA/2J, SJL/J and 129X1/SvJ) that represented the phenotypical extremes with regard to C2ta/Cd74 expression. We found 3 single nucleotide polymorphisms in the type I (pI) and type III (pIII) promoters of C2ta, respectively. Higher expression of pI in 129X1/SvJ correlated with the pI haplotype specific for this strain. Furthermore, congenic strains carrying the 129X1/SvJ C2ta allele on B6 background displayed significantly higher C2ta and Cd74 expression compared to parental controls. We conclude that genetic polymorphisms in the type I promoter of C2ta regulates differential expression of MHC class II, but not MHC class I, Cd3 and other markers of glial activation. (C) 2009 Elsevier B.V. All rights reserved.
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| 5. |
- Harnesk, Karin
(författare)
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Genetic dissection of models for neuroinflammation and neurodegeneration
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Many central nervous system (CNS) diseases are characterized by inflammation and nerve cell loss, but the exact relationship between these phenomena is not known. The complex etiology of CNS disorders includes a genetic component. MHC class II molecules are key mediators of immune activation and variations in MHC class II genes are the main genetic determinant of several complex autoimmune disorders. Gene regions regulating complex phenotypes can be mapped in experimental animal crosses. In this thesis, the genetic regulation of the response to mechanical nerve injury and experimental autoimmune encephalomyelitis (EAE) was investigated in populations of intercrossed mice and rats. The effect of a previously identified gene region, Vra4, on MHC class II expression was characterized in DA.PVG1av1-Vra4 and PVG1av1DA-Vra4 congenic rat strains after ventral root avulsion (VRA). Vra4 contains the class II transactivator gene, Mhc2ta, which is a transcription factor for MHC class II. The influence of the same region was tested in EAE. The results show that Vra4 regulates MHC class II on microglia after VRA, as well as risk and severity of EAE. In addition, IFN-g inducible class II expression on antigen presenting cells (APCs) is dependent on the Vra4 region. Similar results were obtained in a study of inbred mouse strains, where differential MHC class II expression was observed in the facial nucleus after axotomy of the facial nerve. Congenic strain experiments and sequencing of C2ta strongly indicate that polymorphisms in the regulatory region of the pI promoter are regulating this trait. Vra4/C2ta had no effect on expression of microglial markers, co-stimulatory molecules or MHC class I, nor T cell infiltration. Additional genetic influence on MHC class II expression was mapped to chromosomes 1 and 7 in a F2 cross between BN and LEW.1N rats, two strains which share Mhc2ta haplotype but display differential MHC class II expression after VRA. Analysis of other inflammatory markers in this cross revealed common regulation of several immune related molecules by the same gene region, which may suggest upstream effects. Finally, the genetic impact on nerve cell death following VRA by two gene regions previously detected in a F2(DAxPVGc) cross, Vra1 and Vra2, was fine mapped in 2 generations of an advanced intercross line (AIL) between DA and PVG1av1 rats, as well as in a panel of Vra1 congenic strains. The effect of Vra1 on neurodegeneration was reproduced in both AIL populations. Increased support was given by the congenic strains, where PVG alleles in the Vra1 region on DA background resulted in significantly reduced neuronal loss. These studies also narrowed down the Vra1 region from 54 to 9 Mb. Vra2 displayed suggestive linkage to neurodegeneration only in one AIL cohort, but showed an additive effect on the phenotype together with Vra1. To conclude, these results show that neuroinflammation and neurodegeneration are influenced by genetic factors. Identification of genes and pathways will increase our understanding of the molecular pathways of human complex disease.
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| 6. |
- Harnesk, Karin, et al.
(författare)
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Vra4 Congenic Rats with Allelic Differences in the Class II Transactivator Gene Display Altered Susceptibility to Experimental Autoimmune Encephalomyelitis
- 2008
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 180:5, s. 3289-96
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Tidskriftsartikel (refereegranskat)abstract
- Presentation of Ag bound to MHC class II (MHC II) molecules to CD4+ T cells is a key event in adaptive immune responses. Genetic differences in MHC II expression in the rat CNS were recently positioned to allelic variability in the CIITA gene (Mhc2ta), located within the Vra4 locus on rat chromosome 10. In this study, we have examined reciprocal Vra4-congenic strains on the DA and PVGav1 backgrounds, respectively. After experimental nerve injury the strain-specific MHC II expression on microglia was reversed in the congenic strains. Similar findings were obtained after intraparenchymal injection of IFN-gamma in the brain. Expression of MHC class II was also lower on B cells and dendritic cells from the DA.PVGav1-Vra4- congenic strain compared with DA rats after in vitro stimulation with IFN-gamma. We next explored whether Vra4 may affect the outcome of experimental autoimmune disease. In experimental autoimmune encephalomyelitis induced by immunization with myelin oligodendrocyte glycoprotein, DA.PVGav1-Vra4 rats displayed a lower disease incidence and milder disease course compared with DA, whereas both PVGav1 and PVGav1.DA-Vra4 rats were completely protected. These results demonstrate that naturally occurring allelic differences in Mhc2ta have profound effects on the quantity of MHC II expression in the CNS and on immune cells and that this genetic variability also modulates susceptibility to autoimmune neuroinflammation.
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| 7. |
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| 8. |
- Harnesk, Roland, et al.
(författare)
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How successful Swedish organisations achieve sustaniable health
- 2005
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Ingår i: International Journal of Management Practice. - 1477-9064 .- 1741-8143. ; 1:3, s. 233-250
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Tidskriftsartikel (refereegranskat)abstract
- The costs connected to the rapidly increasing sick leaves have risen to alarming levels in Sweden and, for instance, Norway and the Netherlands. To find out how to handle the situation on an organizational level, a case study of two organizations has been carried out, which are recognized and have been awarded for their excellence in methodologies for decreasing the number of sick leaves. One is a small manufacturing company and the other one is a large public health care organization. Both organizations are non-hierarchical with responsibility and authority delegated to different groups. The data collection has mainly been carried out through brainstorming in groups, structured in tree diagrams, complemented by interviews. Important working methods for mangers are low-prestige, visibility and functioning as coaches with activities aimed at building relations. On the basis of the result of this study, suggestions are presented which are considered possible for others to adopt.
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| 9. |
- Lindblom, Rickard P. F., et al.
(författare)
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Complement receptor 2 is up regulated in the spinal cord following nerve root injury and modulates the spinal cord response
- 2015
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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Activation of the complement system has been implicated in both acute and chronic states of neurodegeneration. However, a detailed understanding of this complex network of interacting components is still lacking. Methods: Large-scale global expression profiling in a rat F2(DAxPVG) intercross identified a strong cis-regulatory influence on the local expression of complement receptor 2 (Cr2) in the spinal cord after ventral root avulsion (VRA). Expression of Cr2 in the spinal cord was studied in a separate cohort of DA and PVG rats at different time-points after VRA, and also following sciatic nerve transection (SNT) in the same strains. Consequently, Cr2(-/-) mice and Wt controls were used to further explore the role of Cr2 in the spinal cord following SNT. The in vivo experiments were complemented by astrocyte and microglia cell cultures. Results: Expression of Cr2 in naive spinal cord was low but strongly up regulated at 5-7 days after both VRA and SNT. Levels of Cr2 expression, as well as astrocyte activation, was higher in PVG rats than DA rats following both VRA and SNT. Subsequent in vitro studies proposed astrocytes as the main source of Cr2 expression. A functional role for Cr2 is suggested by the finding that transgenic mice lacking Cr2 displayed increased loss of synaptic nerve terminals following nerve injury. We also detected increased levels of soluble CR2 (sCR2) in the cerebrospinal fluid of rats following VRA. Conclusions: These results demonstrate that local expression of Cr2 in the central nervous system is part of the axotomy reaction and is suggested to modulate subsequent complement mediated effects.
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| 10. |
- Lindblom, Rickard P. F., et al.
(författare)
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Unbiased expression mapping identifies a link between the complement and cholinergic systems in the rat central nervous system
- 2014
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 192:3, s. 1138-1153
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Tidskriftsartikel (refereegranskat)abstract
- The complement system is activated in a wide spectrum of CNS diseases and is suggested to play a role in degenerative phenomena such as elimination of synaptic terminals. Still, little is known of mechanisms regulating complement activation in the CNS. Loss of synaptic terminals in the spinal cord after an experimental nerve injury is increased in the inbred DA strain compared with the PVG strain and is associated with expression of the upstream complement components C1q and C3, in the absence of membrane attack complex activation and neutrophil infiltration. To further dissect pathways regulating complement expression, we performed genome-wide expression profiling and linkage analysis in a large F2(DA × PVG) intercross, which identified quantitative trait loci regulating expression of C1qa, C1qb, C3, and C9. Unlike C1qa, C1qb, and C9, which all displayed distinct coregulation with different cis-regulated C-type lectins, C3 was regulated in a coexpression network immediately downstream of butyrylcholinesterase. Butyrylcholinesterase hydrolyses acetylcholine, which exerts immunoregulatory effects partly through TNF-α pathways. Accordingly, increased C3, but not C1q, expression was demonstrated in rat and mouse glia following TNF-α stimulation, which was abrogated in a dose-dependent manner by acetylcholine. These findings demonstrate new pathways regulating CNS complement expression using unbiased mapping in an experimental in vivo system. A direct link between cholinergic activity and complement activation is supported by in vitro experiments. The identification of distinct pathways subjected to regulation by naturally occurring genetic variability is of relevance for the understanding of disease mechanisms in neurologic conditions characterized by neuronal injury and complement activation.
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