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

详细信息    查看全文

• 作者：Holly L Johnson (15) (16) (17)
  Lisa M Hanson (16)
  Yi Chen (18)
  Allan J Bieber (15)
  Russell J Buono (19)
  Thomas N Ferraro (20)
  Istvan Pirko (15)
  Aaron J Johnson (15) (16)
  
• 关键词：Quantitative 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
• 刊名：BMC Genomics
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：14
• 期：1
• 全文大小：269 KB
• 参考文献：1. Brown H, Hien TT, Day N, Mai NT, Chuong LV, Chau TT, Loc PP, Phu NH, Bethell D, Farrar J, / et al.: Evidence of blood–brain barrier dysfunction in human cerebral malaria. / Neuropathol Appl Neurobiol 1999, 25:331-40. CrossRef
  2. Huber JD, Egleton RD, Davis TP: Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier. / Trends Parasitol 2001, 24:719-25.
  3. Lacerda-Queiroz N, Rodrigues DH, Vilela MC, Rachid MA, Soriani FM, Sousa LP, Campos RDL, Quesniaux VFJ, Teixeira MM, Teixeira AL: Platelet-activating factor receptor is essential for the development of experimental cerebral malaria. / Am J Pathol 2012, 180:246-55. CrossRef
  4. Medana IM, Turner GD: Human cerebral malaria and the blood–brain barrier. / Int J Parasitol 2006, 36:555-68. CrossRef
  5. Minagar A, Alexander JS: Blood–brain barrier disruption in multiple sclerosis. / Mult Scler 2003, 9:540-49. CrossRef
  6. Nacer A, Movila A, Baer K, Mikolajczak SA, Kappe SH, Frevert U: Neuroimmunological blood brain barrier opening in experimental cerebral malaria. / PLoS Pathog 2012, 8:e1002982. CrossRef
  7. Pirko I, Suidan GL, Rodriguez M, Johnson AJ: Acute hemorrhagic demyelination in a murine model of multiple sclerosis. / J Neuroinflammation 2008, 5:31. CrossRef
  8. Talavera D, Castillo AM, Dominguez MC, Gutierrez AE, Meza I: IL8 release, tight junction and cytoskeleton dynamic reorganization conducive to permeability increase are induced by dengue virus infection of microvascular endothelial monolayers. / J Gen Virol 2004, 85:1801-813. CrossRef
  9. Johnson AJ, Njenga MK, Hansen MJ, Kuhns ST, Chen L, Rodriguez M, Pease LR: Prevalent class I-restricted T-cell response to the Theiler’s virus epitope Db:VP2121-30 in the absence of endogenous CD4 help, tumor necrosis factor alpha, gamma interferon, perforin, or costimulation through CD28. / J Virol 1999, 73:3702-708.
  10. Johnson HL, Chen Y, Jin F, Hanson LM, Gamez JD, Pirko I, Johnson AJ: CD8 T cell-initiated blood–brain barrier disruption is independent of neutrophil support. / J Immunol 2012, 189:1937-945. CrossRef
  11. Njenga MK, Asakura K, Hunter SF, Wettstein P, Pease LR, Rodriguez M: The immune system preferentially clears Theiler’s virus from the gray matter of the central nervous system. / J Virol 1997, 71:8592-601.
  12. Rodriguez M, David CS: Demyelination induced by Theiler’s virus: influence of the H-2 haplotype. / J Immunol 1985, 135:2145-148.
  13. Rodriguez M, Pease LR, David CS: Immune-mediated injury of virus-infected oligodendrocytes - a model of multiple-sclerosis. / Immunol Today 1986, 7:359-63. CrossRef
  14. Johnson HL, Chen Y, Suidan GL, McDole JR, Lohrey AK, Hanson LM, Jin F, Pirko I, Johnson AJ: A hematopoietic contribution to microhemorrhage formation during antiviral CD8 T cell-initiated blood–brain barrier disruption. / J Neuroinflammation 2012, 9:60. CrossRef
  15. Johnson AJ, Mendez-Fernandez Y, Moyer AM, Sloma CR, Pirko I, Block MS, Rodriguez M, Pease LR: Antigen-specific CD8+ T cells mediate a peptide-induced fatal syndrome. / J Immunol 2005, 174:6854-862.
  16. Jiang C, Zeng ZB: Mapping quantitative trait loci with dominant and missing markers in various crosses from two inbred lines. / Genetica 1997, 101:47-8. CrossRef
  17. Suidan GL, Dickerson JW, Chen Y, McDole JR, Tripathi P, Pirko I, Seroogy KB, Johnson AJ: CD8 T cell-initiated vascular endothelial growth factor expression promotes central nervous system vascular permeability under neuroinflammatory conditions. / J Immunol 2010, 184:1031-040. CrossRef
  18. Suidan GL, McDole JR, Chen Y, Pirko I, Johnson AJ: Induction of blood brain barrier tight junction protein alterations by CD8 T cells. / PloS one 2008, 3:e3037. CrossRef
  19. Moore KJ, Nagle DL: Complex trait analysis in the mouse: the strengths, the limitations and the promise yet to come. / Annu Rev Genet 2000, 34:653-86. CrossRef
  20. Brodnicki TC, Quirk F, Morahan G: A susceptibility allele from a non-diabetes-prone mouse strain accelerates diabetes in NOD congenic mice. / Diabetes 2003, 52:218-22. CrossRef
  21. Roper RJ, Weis JJ, McCracken BA, Green CB, Ma Y, Weber KS, Fairbairn D, Butterfield RJ, Potter MR, Zachary JF, / et al.: Genetic control of susceptibility to experimental Lyme arthritis is polygenic and exhibits consistent linkage to multiple loci on chromosome 5 in four independent mouse crosses. / Genes Immun 2001, 2:388-97. CrossRef
  22. Baranzini SE, Wang J, Gibson RA, Galwey N, Naegelin Y, Barkhof F, Radue EW, Lindberg RL, Uitdehaag BM, Johnson MR, / et al.: Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. / Hum Mol Genet 2009, 18:767-78. CrossRef
  23. Ferraro TN, Golden GT, Smith GG, Martin JF, Schwebel CL, Doyle GA, Buono RJ, Berrettini WH: Confirmation of a major QTL influencing oral morphine intake in C57 and DBA mice using reciprocal congenic strains. / Neuropsychopharmacology 2005, 30:742-46.
  24. Ferraro TN, Smith GG, Schwebel CL, Lohoff FW, Furlong P, Berrettini WH, Buono RJ: Quantitative trait locus for seizure susceptibility on mouse chromosome 5 confirmed with reciprocal congenic strains. / Physiol Genomics 2007, 31:458-62. CrossRef
  25. Ferraro TN, Golden GT, Dahl JP, Smith GG, Schwebel CL, MacDonald R, Lohoff FW, Berrettini WH, Buono RJ: Analysis of a quantitative trait locus for seizure susceptibility in mice using bacterial artificial chromosome-mediated gene transfer. / Epilepsia 2007, 48:1667-677. CrossRef
  26. Shifman S, Bell JT, Copley RR, Taylor MS, Williams RW, Mott R, Flint J: A high-resolution single nucleotide polymorphism genetic map of the mouse genome. / PLoS Biol 2006, 4:e395. CrossRef
  27. Silva Lda C, Wang S, Zeng ZB: Composite interval mapping and multiple interval mapping: procedures and guidelines for using windows QTL cartographer. / Methods Mol Biol 2012, 871:75-19. CrossRef
  
• 作者单位：Holly L Johnson (15) (16) (17)
  Lisa M Hanson (16)
  Yi Chen (18)
  Allan J Bieber (15)
  Russell J Buono (19)
  Thomas N Ferraro (20)
  Istvan Pirko (15)
  Aaron J Johnson (15) (16)
  
  15. Department of Neurology, Mayo Clinic, Rochester, MN, USA
  16. Department of Immunology, Mayo Clinic, Rochester, MN, USA
  17. Neurobiology of Disease Graduate Program, Mayo Graduate School, Rochester, MN, USA
  18. Department of Neurology, University of Cincinnati, Cincinnati, OH, USA
  19. Department of Neuroscience, Cooper Medical School of Rowan University, Camden, NJ, USA
  20. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
  
• ISSN：1471-2164

文摘

Background 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. Results 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). 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--.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.