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CNS-irrelevant T-cells enter the brain, cause blood–brain barrier disruption but no glial pathology

Authors

  • Alina Smorodchenko,

    1. Cecilie-Vogt-Clinic for Molecular Neurology, Charité-Universitaetsmedizin Berlin and Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
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    • *

      A.S., J.W and E.P. contributed equally to this work.

  • Jens Wuerfel,

    1. Cecilie-Vogt-Clinic for Molecular Neurology, Charité-Universitaetsmedizin Berlin and Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
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    • *

      A.S., J.W and E.P. contributed equally to this work.

  • Elena E. Pohl,

    1. Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité-Universitaetsmedizin Berlin, Germany
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    • *

      A.S., J.W and E.P. contributed equally to this work.

  • Johannes Vogt,

    1. Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité-Universitaetsmedizin Berlin, Germany
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  • Eva Tysiak,

    1. Cecilie-Vogt-Clinic for Molecular Neurology, Charité-Universitaetsmedizin Berlin and Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
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  • Robert Glumm,

    1. Cecilie-Vogt-Clinic for Molecular Neurology, Charité-Universitaetsmedizin Berlin and Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
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  • Sven Hendrix,

    1. Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité-Universitaetsmedizin Berlin, Germany
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  • Robert Nitsch,

    1. Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité-Universitaetsmedizin Berlin, Germany
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  • Frauke Zipp,

    1. Cecilie-Vogt-Clinic for Molecular Neurology, Charité-Universitaetsmedizin Berlin and Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
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    • C.I.-D. and F.Z. contributed as senior authors to this work.

  • Carmen Infante-Duarte

    1. Cecilie-Vogt-Clinic for Molecular Neurology, Charité-Universitaetsmedizin Berlin and Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
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    • C.I.-D. and F.Z. contributed as senior authors to this work.


Professor Frauke Zipp, as above.
E-mail: frauke.zipp@charite.de

Abstract

Invasion of autoreactive T-cells and alterations of the blood–brain barrier (BBB) represent early pathological manifestations of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Non-CNS-specific T-cells are also capable of entering the CNS. However, studies investigating the spatial pattern of BBB alterations as well as the exact localization and neuropathological consequences of transferred non-CNS-specific cells have been thus far lacking. Here, we used magnetic resonance imaging and multiphoton microscopy, as well as histochemical and high-precision unbiased stereological analyses to compare T-cell transmigration, localization, persistence, relation to BBB disruption and subsequent effects on CNS tissue in a model of T-cell transfer of ovalbumin (OVA)- and proteolipid protein (PLP)-specific T-cells. BBB alterations were present in both EAE-mice and mice transferred with OVA-specific T-cells. In the latter case, BBB alterations were less pronounced, but the pattern of initial cell migration into the CNS was similar for both PLP- and OVA-specific cells [mean (SEM), 95 × 103 (7.6 × 103) and 88 × 103 (18 × 103), respectively]. Increased microglial cell density, astrogliosis and demyelination were, however, observed exclusively in the brain of EAE-mice. While mice transferred with non-neural-specific cells showed similar levels of rhodamine-dextran extravasation in susceptible brain regions, EAE-mice presented huge BBB disruption in brainstem and moderate leakage in cerebellum. This suggests that antigen specificity and not the absolute number of infiltrating cells determine the magnitude of BBB disruption and glial pathology.

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