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

Blood-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.

The 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.

Using 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). Conclusions: The 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.