Robyn S. Klein, M.D., Ph.D.
Pathology and Immunology
How do inflammatory cells enter the central nervous system (CNS) during normal and diseases states and how does their presence affect neuronal function? My laboratory studies the pathogenesis of neuroinflammatory diseases of the central nervous system (CNS). We have focused on two components of CNS inflammatory states: the mechanism of leukocyte recruitment into the CNS and the direct effects of inflammatory mediators on resdient neural cells. Common to both of these is the action of chemokines, which both recruit leukocytes into the CNS and signal through chemokine receptors present on neural cells, affecting their function and survival. Our experimental approach involves the development of in vitro and in vivo models of CNS mononuclear cell recruitment and neural cell chemokine receptor signaling responses. Our studies over the past few years have led us to focus on the roles of cytokines and chemokines in the regulation of blood-brain barrier permeability to protective versus pathogenic leukocytes, and to West Nile virus (WNV), a positive strand flavivirus that may enter the CNS and cause encephalitis. These inflammatory cues also regulate CNS repair by neural stem cells (NSCs) in mice with viral infection or demyelinating diseases. Aspects related to NSC-mediated repair include defining the localizing, proliferative and differentiation cues that lead to successful repair of damaged neurons and myelin.
Klein, R.S., Garber, C., Howard, N. (2017) Infectious immunity in the central nervous system and brain function. Nat. Immunology, in press
Daniels, B.P., Jujjavarapu, H., Durrant, D.M., Williams, J.L., Green, R.R., White, J.P., Lazear, H.M., Gale, M., Diamond, M.S., Klein, R.S. (2017) Regionally distinct astrocyte interferon signaling promotes blood-brain barrier integrity and limits immunopathology during neurotropic viral infection. J. Clin. Invest, in press
Vasek, M.V., Garber, C., Dorsey, D., Durrant, D.M., Bollman, B., Soung, A., Yu, J., Perez-Torres, C., Frouin, A., Wilton, D.K., Funk, K., DeMasters, B.K., Jiang, X., Bown, J.R., Mennerick, S., Robinson, J.K., Garbow, J.R., Tyler, K.L., Suthar, M.S., Schmidt, R.E., Stevens, B., Klein, R.S. (2016). A complement-microglial axis is required for synaptic loss during virus-induced memory impairment. Nature 534(7608):538-43
Miner, J.J., Daniels, B.P., Shrestha, B., Proenca-Modena, J.L., Lew, E.D., Lazear, H.M., Gorman, M.J., Lemke, G., Klein, R.S., Diamond, M.S. (2015) The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity. Nat. Med. Nov 2. doi: 10.1038/nm.3974.
Lazear HM, Daniels BP, Pinto AK, Huang AC, Vick SC, Doyle SE, Gale M Jr, Klein RS, Diamond MS. Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier. Sci Transl Med. 2015 Apr 22;7(284):284ra59.
Daniels, B.P., Klein, R.S. (2015) Knocking on closed doors: Encephalitic arboviruses and the Blood-Brain Barrier. PLoS Pathog. 2015 Sep 17;11(9):e1005096.
Daniels BP, Holman DW, Cruz-Orengo L, Jujjavarapu H, Durrant DM, Klein RS. (2014) Viral pathogen-associated molecular patterns regulate blood-brain barrier integrity via competing innate cytokine signals.MBio 5
Williams, J.L., Patel, J.R., Klein, R.S. (2014) Targeting CXCR7/ACKR3 as a therapeutic strategy to promote remyelination in the adult central nervous system. J. Exp. Med. 5;211(5):791-9. MBio. 2014 Aug 26;5(5):e01476-14.
Cruz-Orengo, L., Daniels, B.P., Dorsey, D., Basak, S.A., Grajales-Reyes, J.G., McCandless, E.E., Piccio, L., Cross, A.H., Crosby, S., and Klein R.S. (2014) Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility. J. Clin. Invest. 2014 124(6):2571-84.
Durrant, D.M., Daniels, B.P., Klein, R.S. (2014) IL-1R1 Signaling Regulates CXCL12-Mediated T Cell Localization and Fate within the Central Nervous System during West Nile Virus Encephalitis. J Immunol. 193(8):4095-106.
Durrant DM, Robinette ML, Klein RS. IL-1R1 is required for dendritic cell-mediated T cell reactivation within the CNS during West Nile virus encephalitis. J Exp Med. 2013 Mar 11;210(3):503-16
Patel JR, Williams JL, Muccigrosso MM, Liu L, Sun T, Rubin JB, Klein RS. Astrocyte TNFR2 is required for CXCL12-mediated regulation of oligodendrocyte progenitor proliferation and differentiation within the adult CNS. Acta Neuropathol. 2012 Dec;124(6):847-60.
Szretter KJ, Daniels BP, Cho H, Gainey MD, Yokoyama WM, Gale M Jr, Virgin HW, Klein RS, Sen GC, Diamond MS. 2`-O methylation of the viral mRNA cap by West Nile virus evades ifit1-dependent and -independent mechanisms of host restriction in vivo. PLoS Pathog. 2012;8(5):e1002698.
Cruz-Orengo L, Holman DW, Dorsey D, Zhou L, Zhang P, Wright M, McCandless EE, Patel JR, Luker GD, Littman DR, Russell JH, Klein RS. CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity. J. Exp. Med. 2011 208(2): 327-39.
Patel JR, McCandless EE, Dorsey D, Klein RS. CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination. Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):11062-7.
McCandless EE, Budde M, Lees JR, Dorsey D, Lyng E, Klein RS. IL-1R signaling within the central nervous system regulates CXCL12 expression at the blood-brain barrier and disease severity during experimental autoimmune encephalomyelitis. J Immunol. 2009 Jul 1;183(1):613-20.
McCandless EE, Zhang B, Diamond MS, Klein RS. CXCR4 antagonism increases T cell trafficking in the central nervous system and improves survival from West Nile virus encephalitis. Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11270-5.
Zhang B, Chan YK, Lu B, Diamond MS, Klein RS. CXCR3 mediates region-specific antiviral T cell trafficking within the central nervous system during West Nile virus encephalitis. J Immunol. 2008 Feb 15;180(4):2641-9.
Last Updated: 1/5/2017 1:55:37 PM
CXCL12 internalization at the blood-brain barrier