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

Harnesk, Karin; Swanberg, Maria; Öckinger, Johan; Diez, Margarita; Lidman, Olle; Wallström, Erik; Lobell, Anna; Olsson, Tomas; Piehl, Fredrik

doi:10.4049/jimmunol.180.5.3289

Cited by 21 publications

(21 citation statements)

References 44 publications

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“…Variants of genes exerting control over the inflammatory response, like polymorphisms of the Ciita (alternative symbol: Mhc2ta) have been reported to be associated with both lower expression of MHC class II-associated genes and with an increased neurodestruction in animal models of root avulsion injury [94,95]. ApoE4 increases the inflammatory tone following neurotrauma with a significant surge of Il6, Tnf and nitric oxide in the injured tissue [96].…”

Section: Introductionmentioning

confidence: 99%

Spinal cord trauma and the molecular point of no return

Yip

Malaspina

2012

Mol Neurodegeneration

123

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A mechanical trauma to the spinal cord can be followed by the development of irreversible and progressive neurodegeneration, as opposed to a temporary or partially reversible neurological damage. An increasing body of experimental and clinical evidence from humans and animal models indicates that spinal cord injury may set in motion the development of disabling and at times fatal neuromuscular disorders, whose occurrence is not normally associated with any major environmental event. This outcome appears to be dependent on the co-occurrence of a particular form of mechanical stress and of a genetically-determined vulnerability. This increased vulnerability to spinal cord injury may depend on a change of the nature and of the timing of activation of a number of neuroprotective and neurodestructive molecular signals in the injured cord. Among the main determinants, we could mention an altered homeostasis of lipids and neurofilaments, an earlier inflammatory response and the failure of the damaged tissue to rein in oxidative damage and apoptotic cell death. These changes could force injured tissue beyond a point of no return and precipitate an irreversible neurodegenerative process. A better knowledge of the molecular signals activated in a state of increased vulnerability to trauma can inform future treatment strategies and the prediction of the neurological outcome after spinal cord injury.

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Section: Introductionmentioning

confidence: 99%

Spinal cord trauma and the molecular point of no return

Yip

Malaspina

2012

Mol Neurodegeneration

123

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“…Interestingly, an association has been uncovered between MHC II genes and CNS neurodegeneration. Strain-dependent differences in susceptibility to experimental allergic encephalomyelitis (EAE), 16 ventral root avulsion, 17 and axonal injury-induced neuropathic pain 18 have all been linked to differential expression of the RT1B chain of MHC II. Furthermore, mouse MHC II knockout models demonstrate reduced axonal injury in EAE 19 and globoid cell leukodystrophy, 20 and minimal dopaminergic neuron loss in a model of Parkinson disease.…”

mentioning

confidence: 99%

Evidence Supporting an Association Between Expression of Major Histocompatibility Complex II by Microglia and Optic Nerve Degeneration During Experimental Glaucoma

Chidlow

Ebneter

Wood

et al. 2016

Journal of Glaucoma

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Aim: We acquired age-matched and sex-matched Sprague-Dawley rats from 2 independent breeding establishments. Serendipitously, we observed that constitutive, and bacterial toxin-induced, expression of major histocompatibility complex (MHC) class II RT1B chain in the uveal tract was much lower in one of the cohorts. Activated microglia are known to upregulate MHC II RT1B expression during optic nerve (ON) degeneration induced by raised intraocular pressure (IOP). We investigated whether, in a model of experimental glaucoma, microglial upregulation of MHC II RT1B was less efficacious and ON degeneration correspondingly less severe in the cohort of rats with low MHC II RT1B expression.Methods: Experimental glaucoma was induced by lasering the trabecular meshwork using a standard protocol. After 2 weeks of elevated IOP, retinal ganglion cells (RGC) survival, ON degeneration, and microglial responses were determined in both cohorts of rats.Results: Raised IOP-induced expression of MHC II RT1B by microglia was muted in the "Low" cohort compared with the "High" cohort. Axonal degeneration, RGC loss, and microgliosis were all significantly lower in the cohort of rats with low basal and induced expression of MHC II RT1B, despite both cohorts displaying IOP responses that were indistinguishable in terms of peak IOP and IOP exposure.Conclusions: Expression of MHC II RT1B by activated microglia in the ON during experimental glaucoma was associated with more severe RGC degeneration. Further studies are needed to elucidate the role of MHC II during experimental glaucoma.

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“…C2ta congenic and B6Q wt mice by immunization of either MOG 1–125 protein or MOG 79–96 peptide, both known to induce EAE in H‐2 q mice . In contrast to the findings in the Vra4 congenic rats, there was no difference in both the disease score and weight change between the B6Q. C2ta congenic and B6Q wt mice in both MOG 1–125 protein‐induced EAE (Fig.…”

Section: Resultsmentioning

confidence: 72%

“…We investigated whether MHC‐II expression difference on macrophages and dendritic cells and the subsequent increase in antigen presentation regulate susceptibility to autoimmune neuroinflammation. This is interesting especially since naturally occurring allelic differences in C2ta have been shown to regulate susceptibility to EAE in rats …”

Section: Resultsmentioning

confidence: 99%

Effects of C2ta genetic polymorphisms on MHC class II expression and autoimmune diseases

et al. 2016

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Antigen presentation by the MHC-II to CD4 T cells is important in adaptive immune responses. The class II transactivator (CIITA in human and C2TA in mouse) is the master regulator of MHC-II gene expression. It coordinates the transcription factors necessary for the transcription of MHC-II molecules. In humans, genetic variations in CIITA have been associated with differential expression of MHC-II and susceptibility to autoimmune diseases. Here we made use of a C2ta congenic mouse strain (expressing MHC-II haplotype H-2 ) to investigate the effect of the natural genetic polymorphisms in type I promoter of C2ta on MHC-II expression and function. We demonstrate that an allelic variant in the type I promoter of C2ta resulted in an increased expression of MHC-II on macrophages (72-151% higher mean florescence intensity) and conventional dendritic cells (13-65% higher mean florescence intensity) in both spleen and peripheral blood. The increase in MHC-II expression resulted in an increase in antigen presentation to T cells in vitro and increased T-cell activation. The differential MHC-II expression in B6Q.C2ta, however, did not alter the disease development in models of rheumatoid arthritis (collagen-induced arthritis and human glucose-6-phosphate-isomerase -peptide-induced arthritis), or multiple sclerosis (MOG protein-induced and MOG peptide-induced experimental autoimmune encephalomyelitis). This is the first study to address the role of an allelic variant in type I promoter of C2ta in MHC-II expression and autoimmune diseases; and shows that C2ta polymorphisms regulate MHC-II expression and T-cell responses but do not necessarily have a strong impact on autoimmune diseases.

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

Cited by 21 publications

References 44 publications

Spinal cord trauma and the molecular point of no return

Spinal cord trauma and the molecular point of no return

Evidence Supporting an Association Between Expression of Major Histocompatibility Complex II by Microglia and Optic Nerve Degeneration During Experimental Glaucoma

Effects of C2ta genetic polymorphisms on MHC class II expression and autoimmune diseases

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