Discrete Gene Loci Regulate Neurodegeneration, Lymphocyte Infiltration, and Major Histocompatibility Complex Class II Expression in the CNS

Lidman, Olle; Swanberg, Maria; Horvath, Linn; Broman, Karl W.; Olsson, Tomas; Piehl, Fredrik

doi:10.1523/jneurosci.23-30-09817.2003

Cited by 39 publications

(44 citation statements)

References 61 publications

(68 reference statements)

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“…These findings corroborate and complement the mapping of differences in MHC II expression to the Vra4 locus obtained in previous intercross experiments (12,16). By using congenics, that is, isolating Vra4 from a donor strain on a recipient background, we obtained the tools to study the effects in a well-controlled and reproducible model.…”

Section: Discussionsupporting

confidence: 86%

“…Possible explanations could be effects from the PVG av1 genome acting upstream of Mhc2ta transcription or an interactive effect of the DA Mhc2ta allele with other gene regions present in the PVG av1 background. In the original genome-wide scan of differences in MHC II expression in an F 2 DA ϫ PVG intercross, the Vra4 locus was the only region displaying genome-wide significance (16). However, after correction for genotype at the Vra4 locus, linkage to the MHC complex on chromosome 20 is also evident (O. Lidman, M. Swanberg, T. Olsson, and F. Piehl, unpublished observation).…”

Section: Discussionmentioning

confidence: 99%

“…Initial studies identified differential expression of MHC II as a genetically regulated phenotype segregating a panel of inbred rat strains into high and low responders (14,15). A full genome scan in an F 2 intercross between a high (DA) and low (PVG) responder strain subsequently identified the Vra4 locus as regulating MHC II in the CNS after mechanical nerve injury (16). Finally, the Vra4 locus was fine-mapped in the G8 and G10 generations of an advanced intercross line and Mhc2ta identified as the candidate gene, with differential expression of MHC II segregating with a haplotype spanning the promoter regions of the gene (12).…”

Section: Presentation Of Ag Bound To Mhc Class II (Mhc Ii) Molecules mentioning

confidence: 99%

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Vra4 Congenic Rats with Allelic Differences in the Class II Transactivator Gene Display Altered Susceptibility to Experimental Autoimmune Encephalomyelitis

Harnesk

Swanberg

Öckinger

et al. 2008

The Journal of Immunology

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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-γ 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-γ. 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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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Presentation Of Ag Bound To Mhc Class II (Mhc Ii) Molecules mentioning

confidence: 99%

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Vra4 Congenic Rats with Allelic Differences in the Class II Transactivator Gene Display Altered Susceptibility to Experimental Autoimmune Encephalomyelitis

Harnesk

Swanberg

Öckinger

et al. 2008

The Journal of Immunology

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“…Thereby, influencing both inflammatory as well as lymphocyte regulatory T-cells to spread the range of inflammation throughout systemic and CNS regions [104][105][106]. Alteration of CD4+ and CD8+ T-cells are detected in subjects suffering from neurodegenerative disorders suggesting involvement of T-cells in such diseases apart from posing a persistent antigenic contest [10,[107][108][109]. Presence of antibodies alongside neuronal antigen confirms role of immunity in neurodegenerative disorders [110].…”

Section: Neuroinflammation and Neurodegeneration: A Tale Of Promise Amentioning

confidence: 94%

Effect and Disease Indicative Role of Inflammation in Neurodegenerative Pathology: A Mechanistic Crosstalk of Promise and Dilemma

Choudhury¹,

Chakraborty²,

Banerjee³

et al. 2018

Neuropsychiatry

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The pathobiology of neuronal cell loss due to various endogenous or exogenous influences is clinically termed as neurodegeneration. Neurodegeneration has been reported to be the major contributor to aging and central nervous system diseases. Apart from aging and endogenous involvement, neurodegeneration also has been reported from viral infection and prion diseases. Studies have shown that, chronic degeneration of neuronal cells initiate the pathology of Alzheimer's disease-the most prevalent neurodegenerative disorder in the world. Similar neurodegenerative pathology is also evident in Parkinson's disease, multiple sclerosis, and Amyotrophic Lateral Sclerosis. Neurodegeneration negatively affects the mental and physical functioning of the patient. Intriguingly, the involvement of inflammation has been linked as the most crucial entity in the mechanistic progress of neurodegeneration. Moreover, recent data also have shown that inflammatory biomarkers can prognosticate the silent progress of neurodegeneration through low-cost diagnostic approach. Mainly, Th17 and MDSCs are the particular immune cells, which have been reported to assist adequately to get a detailed insight into the underlying pathological process in neurodegeneration. Similarly, depression and dementia are also having a crucial association with pro-inflammatory cytokines, which in chronic spectrum indicates the degenerative pathology. Together, available literatures are depicting a direct association between neuroinflammation and neurodegeneration. In the present review, we have summed up all the neuropathologies in light of inflammation and emphasized the possible diagnostic measures by using inflammatory cells and mediators as biomarkers for neurodegenerative diseases.

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“…All animals except for naive controls were subjected to a unilateral avulsion of the left L3-L5 ventral roots, as previously described (15), at an age of 9-12 wk. In short, a dorsal laminectomy was performed at the level of the L2-L3 vertebrae.…”

Section: Animals and Surgerymentioning

confidence: 99%

Unbiased Expression Mapping Identifies a Link between the Complement and Cholinergic Systems in the Rat Central Nervous System

Lindblom

Ström

Heinig

et al. 2014

The Journal of Immunology

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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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Discrete Gene Loci Regulate Neurodegeneration, Lymphocyte Infiltration, and Major Histocompatibility Complex Class II Expression in the CNS

Cited by 39 publications

References 61 publications

Vra4 Congenic Rats with Allelic Differences in the Class II Transactivator Gene Display Altered Susceptibility to Experimental Autoimmune Encephalomyelitis

Vra4 Congenic Rats with Allelic Differences in the Class II Transactivator Gene Display Altered Susceptibility to Experimental Autoimmune Encephalomyelitis

Effect and Disease Indicative Role of Inflammation in Neurodegenerative Pathology: A Mechanistic Crosstalk of Promise and Dilemma

Unbiased Expression Mapping Identifies a Link between the Complement and Cholinergic Systems in the Rat Central Nervous System

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