| 1. |
- Bereczky-Veress, Biborka, et al.
(författare)
-
Host strain-dependent difference in susceptibility in a rat model of herpes simplex type 1 encephalitis.
- 2008
-
Ingår i: Journal of neurovirology. - : Springer Science and Business Media LLC. - 1538-2443 .- 1355-0284. ; 14:2, s. 102-18
-
Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex encephalitis (HSE) is characterized by severe focal brain inflammation leading to substantial loss of nervous tissue. The authors established a model of Herpes simplex virus type 1 (HSV)-1-induced acute encephalitis in the rat by injecting into the whiskers' area a virus strain isolated from a fatal human HSE case. The model might resemble natural propagation of HSV-1 in humans; spreading from the mouth and lips via the trigeminal nerve to trigeminal ganglia and subsequently entering the central nervous system (CNS). HSV-1 infected Dark Agouti (DA) rats developed a well-synchronized disease and died 5 days after inoculation. HSV-1 detection by quantitative polymerase chain reaction (qPCR), virus isolation and immunohistochemistry, magnetic resonance imaging, and histopathological examination verified dramatic encephalitis mainly in the brainstem, but also in the olfactory bulb and other segments of the brain of diseased rats. In contrast, Piebald Virol Glaxo (PVG) rats were completely resistant to disease, displaying a more rapid clearance of peripheral infection and no evidence of virus entering into neither the trigeminal ganglia nor the CNS. These results suggest a regulation of susceptibility to HSV-1-induced encephalitis at the level of peripheral infection and subsequent neuronal uptake/transport of the virus. This provides a basis for future positioning of genetic polymorphisms regulating HSE and for dissection of important pathogenetic mechanisms of this severe human disease.
|
|
| 2. |
|
|
| 3. |
- Diez, Margarita, et al.
(författare)
-
Identification of gene regions regulating inflammatory microglial response in the rat CNS after nerve injury
- 2009
-
Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 212:1-2, s. 82-92
-
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.
|
|
| 4. |
- Diez, Margarita
(författare)
-
Neuropeptide expression in mouse disease models
- 2003
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The role of neuropeptides and the significance of peptidergic mechanisms in neurodegenerative diseases are still relatively unexplored. In the periphery, nerve injury results in dramatic changes in the expression of neuropeptides (and other molecules). An interesting question is to what extent similar changes occur, and similar mechanisms operate, after lesions and/or degeneration in the brain. The purpose of this work is to study neuropeptides and other neuroactive molecules and their receptors in some mouse models for neurodegeneration using histochemical techniques. PRION DISEASE MODELS. Mice intracerebrally inoculated with prions were studied at different time points. A decreased binding to NPY Y2 and NMDA receptors was seen in certain regions of the hippocampal formation, as well as an aberrant induction Of NPY mRNA in the CA3 pyramidal neurons, all changes from 110 days and onwards after prion inoculation. This is before behavioural symptoms appear. There were also increased levels of the inhibitory peptide galanin, npy and dynorphin in mossy fibers, whereas the excitatory CCK peptide was decreased. ALZHEIMERS DISEASE MODELS. PDAPP and APP23 mice both overexpress human APP but with different mutations, leading to amyloid deposition. Pronounced changes were observed in the PDAPP and the APP23 mouse with regard to neuropeptides in the hippocampal formation and the ventral cortex, whereas the dorsolateral neocortex was comparatively less affected. Dystrophic and varicose peptide fibers containing galanin, NPY, CCK and/or enkephalin were commonly seen in close proximity to amyloid plaques. in addition generalised changes were observed in both models, such as increases of enkephalin and CCK in stratum lacunosum moleculare and Of NPY, enkephalin and dynorphin in mossy fibers/granule cells. in contrast CCK was decreased in mossy fibers in both types of mice. However, also differences were encountered between the two mouse models, in particular with regard to galanin. THE MEGENCEPHALY MOUSE. The megencephaly mouse carries a spontaneous mutation in a potassium channel causing brain enlargement. The total brain volume, ventral cortex, hippocampal formation and cerebral cortex length were enlarged at eight weeks and onwards in the megencephaly mouse. Distinct disturbances in the expression Of BDNF, IGFBP 6 and several neuropeptides such as NPY, galanin and enkephalin were seen already at two weeks of age, that is before an obvious behavioral phenotype has been reported. The normal mouse brain appeared to grow for a longer period than hitherto assumed, that is up to eight weeks of age. The results obtained in this thesis work show that neuropeptides are modulated, often in a similar way, in the brain of mouse models for Alzheimers disease and prion disease as well as in the megencephaly mouse. These changes are also reminiscent of the marked regulations of neuroactive molecules seen in peripheral neurons after nerve injury, suggesting that neurodegenerative disorders in the CNS may have some mechanisms in common with peripheral nerve injury. The significance of these alterations is not well understood, but it may reflect attempts to counteract degeneration by initiating protective and/or regenerative processes, as well as to attenuate excitation.
|
|
| 5. |
- Dominguez, Cecilia A, et al.
(författare)
-
Genetic analysis of neuropathic pain-like behavior following peripheral nerve injury suggests a role of the major histocompatibility complex in development of allodynia
- 2008
-
Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 1872-6623 .- 0304-3959. ; 136:3, s. 313-319
-
Tidskriftsartikel (refereegranskat)abstract
- Neuropathic pain is a common consequence of damage to the nervous system. We here report a genetic analysis of development of neuropathic pain-like behaviors after unilateral photochemically-induced ischemic sciatic nerve injury in a panel of inbred rat strains known to display different susceptibility to autoimmune neuroinflammation. Pain behavior was initially characterized in Dark-Agouti (DA; RT1(avl)), Piebald Virol Glaxo (PVG; RT1(c)), and in the major histocompatibility complex (MHC)-congenic strain PVG-RT1(avl). All strains developed mechanical hypersensitivity (allodynia) following nerve injury. However, the extent and duration of allodynia varied significantly among the strains, with PVG displaying more severe allodynia compared to DA rats. Interestingly, the response of PVG-RT1(avR1) was similar to that of DA, suggesting regulation by the MHC locus. This notion was subsequently confirmed in an F2 cohort derived from crossing of the PVG and PVG-RT1(avl) strains, where allodynia was reduced in homozygous or heterozygous carriers of the RT1(avl) allele in comparison to rats homozygous for the RT1(c) allele. These results indicate that certain allelic variants of the MHC could influence susceptibility to develop and maintain neuropathic pain-like behavior following peripheral nerve injury in rats.
|
|
| 6. |
- Harnesk, Karin, et al.
(författare)
-
Differential nerve injury-induced expression of MHC class II in the mouse correlates to genetic variability in the type I promoter of C2ta
- 2009
-
Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 212:1-2, s. 44-52
-
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.
|
|
| 7. |
- Harnesk, Karin, et al.
(författare)
-
Vra4 Congenic Rats with Allelic Differences in the Class II Transactivator Gene Display Altered Susceptibility to Experimental Autoimmune Encephalomyelitis
- 2008
-
Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 180:5, s. 3289-96
-
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.
|
|
| 8. |
- Laj, Paolo, et al.
(författare)
-
A global analysis of climate-relevant aerosol properties retrieved from the network of Global Atmosphere Watch (GAW) near-surface observatories
- 2020
-
Ingår i: Atmospheric Measurement Techniques. - : Copernicus GmbH. - 1867-1381 .- 1867-8548. ; 13:8, s. 4353-4392
-
Tidskriftsartikel (refereegranskat)abstract
- Aerosol particles are essential constituents of the Earth's atmosphere, impacting the earth radiation balance directly by scattering and absorbing solar radiation, and indirectly by acting as cloud condensation nuclei. In contrast to most greenhouse gases, aerosol particles have short atmospheric residence times, resulting in a highly heterogeneous distribution in space and time. There is a clear need to document this variability at regional scale through observations involving, in particular, the in situ near-surface segment of the atmospheric observation system. This paper will provide the widest effort so far to document variability of climate-relevant in situ aerosol properties (namely wavelength dependent particle light scattering and absorption coefficients, particle number concentration and particle number size distribution) from all sites connected to the Global Atmosphere Watch network. High-quality data from almost 90 stations worldwide have been collected and controlled for quality and are reported for a reference year in 2017, providing a very extended and robust view of the variability of these variables worldwide. The range of variability observed worldwide for light scattering and absorption coefficients, single-scattering albedo, and particle number concentration are presented together with preliminary information on their long-term trends and comparison with model simulation for the different stations. The scope of the present paper is also to provide the necessary suite of information, including data provision procedures, quality control and analysis, data policy, and usage of the ground-based aerosol measurement network. It delivers to users of the World Data Centre on Aerosol, the required confidence in data products in the form of a fully characterized value chain, including uncertainty estimation and requirements for contributing to the global climate monitoring system.
|
|
| 9. |
- Lindblom, Rickard P. F., et al.
(författare)
-
Complement receptor 2 is up regulated in the spinal cord following nerve root injury and modulates the spinal cord response
- 2015
-
Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094 .- 1742-2094. ; 12
-
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.
|
|
| 10. |
- Lindblom, Rickard P F, et al.
(författare)
-
Genetic variability in the rat Aplec C-type lectin gene cluster regulates lymphocyte trafficking and motor neuron survival after traumatic nerve root injury.
- 2013
-
Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094 .- 1742-2094. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: C-type lectin (CLEC) receptors are important for initiating and shaping immune responses; however, their role in inflammatory reactions in the central nervous system after traumatic injuries is not known. The antigen-presenting lectin-like receptor gene complex (Aplec) contains a few CLEC genes, which differ genetically among inbred rat strains. It was originally thought to be a region that regulates susceptibility to autoimmune arthritis, autoimmune neuroinflammation and infection.METHODS: The inbred rat strains DA and PVG differ substantially in degree of spinal cord motor neuron death following ventral root avulsion (VRA), which is a reproducible model of localized nerve root injury. A large F2 (DAxPVG) intercross was bred and genotyped after which global expressional profiling was performed on spinal cords from F2 rats subjected to VRA. A congenic strain, Aplec, created by transferring a small PVG segment containing only seven genes, all C-type lectins, ontoDA background, was used for further experiments together with the parental strains.RESULTS: Global expressional profiling of F2 (DAxPVG) spinal cords after VRA and genome-wide eQTL mapping identified a strong cis-regulated difference in the expression of Clec4a3 (Dcir3), a C-type lectin gene that is a part of the Aplec cluster. Second, we demonstrate significantly improved motor neuron survival and also increased T-cell infiltration into the spinal cord of congenic rats carrying Aplec from PVG on DA background compared to the parental DA strain. In vitro studies demonstrate that the Aplec genes are expressed on microglia and upregulated upon inflammatory stimuli. However, there were no differences in expression of general microglial activation markers between Aplec and parental DA rats, suggesting that the Aplec genes are involved in the signaling events rather than the primary activation of microglia occurring upon nerve root injury.CONCLUSIONS: In summary, we demonstrate that a genetic variation in Aplec occurring among inbred strains regulates both survival of axotomized motor neurons and the degree of lymphocyte infiltration. These results demonstrate a hitherto unknown role for CLECs for intercellular communication that occurs after damage to the nervous system, which is relevant for neuronal survival.
|
|
