Quantitative trait loci analysis reveals candidate genes implicated in regulating functional deficit and CNS vascular permeability in CD8 T cell-initiated blood–brain barrier disruptionReport as inadecuate




Quantitative trait loci analysis reveals candidate genes implicated in regulating functional deficit and CNS vascular permeability in CD8 T cell-initiated blood–brain barrier disruption - Download this document for free, or read online. Document in PDF available to download.

BMC Genomics

, 14:678

Human and rodent genomics

Abstract

BackgroundBlood–brain barrier BBB disruption is an integral feature of numerous neurological disorders. However, there is a relative lack of knowledge regarding the underlying molecular mechanisms of immune-mediated BBB disruption. We have previously shown that CD8 T cells and perforin play critical roles in initiating altered permeability of the BBB in the peptide-induced fatal syndrome PIFS model developed by our laboratory. Additionally, despite having indistinguishable CD8 T cell responses, C57BL-6J B6 mice are highly susceptible to PIFS, exhibiting functional motor deficits, increased astrocyte activation, and severe CNS vascular permeability, while 129S1-SvImJ 129S1 mice remain resistant. Therefore, to investigate the potential role of genetic factors, we performed a comprehensive genetic analysis of B6 x 129S1 F2 progeny to define quantitative trait loci QTL linked to the phenotypic characteristics stated above that mediate CD8 T cell-initiated BBB disruption.

ResultsUsing single nucleotide polymorphism SNP markers and a 95% confidence interval, we identified one QTL PIFS1 on chromosome 12 linked to deficits in motor function SNP markers rs6292954, rs13481303, rs3655057, and rs13481324, LOD score = 3.3. In addition we identified a second QTL PIFS2 on chromosome 17 linked to changes in CNS vascular permeability SNP markers rs6196216 and rs3672065, LOD score = 3.7.

ConclusionsThe QTL critical intervals discovered have allowed for compilation of a list of candidate genes implicated in regulating functional deficit and CNS vascular permeability. These genes encode for factors that may be potential targets for therapeutic approaches to treat disorders characterized by CD8 T cell-mediated BBB disruption.

KeywordsQuantitative trait loci QTL Single nucleotide polymorphism SNP Blood–brain barrier BBB Theiler’s murine encephalomyelitis virus TMEV Peptide-induced fatal syndrome PIFS CD8 T cell CNS vascular permeability AbbreviationsBBBBlood–brain barrier

TMEVTheiler’s murine encephalomyelitis virus

PIFSPeptide-induced fatal syndrome

QTLQuantitative trait loci

SNPSingle nucleotide polymorphism

FITCFluorescein isothiocyanate

GFAPGlial fibrillary acidic protein.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2164-14-678 contains supplementary material, which is available to authorized users.

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Author: Holly L Johnson - Lisa M Hanson - Yi Chen - Allan J Bieber - Russell J Buono - Thomas N Ferraro - Istvan Pirko - Aaron

Source: https://link.springer.com/







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