| 1. |
- Bereczky-Veress, Biborka, et al.
(författare)
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Host strain-dependent difference in susceptibility in a rat model of herpes simplex type 1 encephalitis.
- 2008
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Ingår i: Journal of neurovirology. - : Springer Science and Business Media LLC. - 1538-2443 .- 1355-0284. ; 14:2, s. 102-18
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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.
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| 2. |
- 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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| 3. |
- Dominguez, Cecilia A, et al.
(författare)
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Genetic analysis of neuropathic pain-like behavior following peripheral nerve injury suggests a role of the major histocompatibility complex in development of allodynia
- 2008
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Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 1872-6623 .- 0304-3959. ; 136:3, s. 313-319
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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.
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| 4. |
- Gielen, Alexander W., et al.
(författare)
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Expression of T cell immunoglobulin- and mucin-domain-containing molecules-1 and -3 (TIM-1 and -3) in the rat nervous and immune systems
- 2005
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728 .- 1872-8421. ; 164:1, s. 93-104
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Tidskriftsartikel (refereegranskat)abstract
- Expression of T cell immunoglobulin- and mucin-domain-containing molecules (TIMs) can be used as T helper (Th) differentiation markers in the human and mouse. We examined the expression of TIM-1 and -3 mRNAs in rat MBP(63-88)-induced experimental autoimmune encephalomyelitis (EAE). TIM-3 expression was upregulated in the spinal cord during EAE and following antigen restimulation of the encephalitogenic TCRBV8S2+ population. Interestingly, TIM-3 expression was also detected by in situ hybridization in resident cells of the nervous system. TIM-1 was expressed in B cells but not in resident CNS cells and TIM-1 mRNA levels in spinal cord were unchanged throughout the course of EAE. These results support the notion that TIM-3 can also be used as a Th1 differentiation marker in the rat. However, expression of TIM-1 and -3 is not restricted solely to T cells and the presence of TIM-3 in resident CNS cells may indicate a role for this molecule in the interaction between the nervous and immune systems.
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| 5. |
- 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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| 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. |
- Lidman, Olle
(författare)
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Genetics and inflammation in nerve injury-induced neurodegeneration
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neurodegeneration and inflammation are characteristic of many diseases of the central nervous system (CNS) and understanding the molecular networks that regulate these processes is of central importance for the development of effective therapies. Although the CNS has traditionally been regarded as an immuno privileged organ, immune reactions, including components of both local innate and systemic immunity, do occur in this tissue. Animal models can provide powerful tools for mimicking and dissecting certain aspects of human pathology. Accordingly, responses to nerve lesions have been investigated in various such animal models and certain key regulators identified. However, our knowledge of how these processes are regulated on a more global genomic level is extremely limited. In the present thesis models of nerve lesion and experimental autoimmune encephalomyelitis have been employed to probe certain fundamental questions regarding neuroinflammation. The three-fold findings can be summarized as follows: First, the pattern of expression and functional role of MHC class I in the changes in CNS neurons induced by axotomy were examined. Pronounced expression of non-classical MHC class I, RT1-U, was observed in several different neuronal populations in the CNS. Furthermore, lack of functional MHC class I was found to enhance synaptic detachment from axotomized motoneurons, as well as the astroglial reaction. This novel finding which indicates that MHC class I plays an important role in the synaptic plasticity in the adult animal. Secondly, genetic influences on experimentally induced neurodegeneration and CNS inflammation were examined. Using different rat strains (i.e., DA(RT1av1), PVG.1AV1, LEW.1AV1, LEW1.N, BN(RT1n), and E3(RT1u)) significant strain differences were observed in the responses to a standardized nerve trauma, ventral root avulsion (VRA), including glial activation, motoneuronal degeneration, and expression of MHC class II on microglia. There were also substantial strain differences in the glial response to facial nerve lesion in mice. Subsequently, utilizing a microsatellitebased genome scan in an F2 population established by crossing DA(RT1av1) and PVG(RT1c), several discrete QTLs involved in the regulation of VRA-induced phenotypes were identified. These QTLs are Vra1, located on rat chromosome 8 and significantly linked to neurodegeneration; Vra2, located on rat chromosome 5 and significantly linked to T cell infiltration and with suggestive linkage to neurodegeneration as well; Vra3, also located on rat chromosome 5 and suggestively linked to T cell infiltration; and, finally, Vra4, located on rat chromosome 10 and significantly linked to expression of MHC class II on microglia. Employing an advanced intercross line, the QTL regulating MHC class 11 expression by microglia was further mapped more precisely to a 3.7-megabase DNA fragment that contains the mhc2ta gene encoding the class II transactivator (CIITA). Expression studies and gene sequencing identify this gene as a strong candidate regulator of nerve lesion-induced MHC class II expression in the CNS. Finally, the potential neuroprotective roles of CNS-directed autoimmunity and the expression of neurotrophic factors by leukocyte populations infiltrating this tissue were explored. A combination of VRA and active induction of EAE resulted in increased survival of axotomized motoneurons, compared to rats subjected to VRA alone, suggesting that an autoantigen-specific immune response in the CNS plays a protective role. This survival was associated with increased expression of several neurotrophic factors in the CNS of EAE animals, as well as increased of infiltration of T and NK cells into the CNS. These findings shed new light on highly interesting aspects of the association between neurodegeneration and CNS inflammation. These new insights have implications for the understanding of chronic and acute human neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke and traumatic brain injury.
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| 8. |
- Swanberg, Maria, et al.
(författare)
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MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction
- 2005
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 37:5, s. 486-494
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Tidskriftsartikel (refereegranskat)abstract
- Antigen presentation to T cells by MHC molecules is essential for adaptive immune responses. To determine the exact position of a gene affecting expression of MHC molecules, we finely mapped a previously defined rat quantitative trait locus regulating MHC class II on microglia in an advanced intercross line. We identified a small interval including the gene MHC class II transactivator (Mhc2ta) and, using a map over six inbred strains combined with gene sequencing and expression analysis, two conserved Mhc2ta haplotypes segregating with MHC class II levels. In humans, a -168A --> G polymorphism in the type III promoter of the MHC class II transactivator (MHC2TA) was associated with increased susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction, as well as lower expression of MHC2TA after stimulation of leukocytes with interferon-gamma. We conclude that polymorphisms in Mhc2ta and MHC2TA result in differential MHC molecule expression and are associated with susceptibility to common complex diseases with inflammatory components.
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