title: VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells.
abstract: The focus of this study is the characterization of human T cell blood-brain barrier migration and corresponding molecular trafficking signatures. We examined peripheral blood and cerebrospinal fluid immune cells from patients under long-term anti-very late antigen-4 (VLA-4)/natalizumab therapy (LTNT) and from CNS specimens. LTNT patients' cerebrospinal fluid T cells exhibited healthy central-/effector-memory ratios, but lacked CD49d and showed enhanced myeloma cell adhesion molecule (MCAM) expression. LTNT led to an increase of PSGL-1 expression on peripheral T cells. Although vascular cell adhesion molecule-1 (VLA-4 receptor) was expressed at all CNS barriers, P-selectin (PSGL-1-receptor) was mainly detected at the choroid plexus. Accordingly, in vitro experiments under physiological flow conditions using primary human endothelial cells and LTNT patients' T cells showed increased PSGL-1-mediated rolling and residual adhesion, even under VLA-4 blockade. Adhesion of MCAM(+)/TH17 cells was not affected by VLA-4 blocking alone, but was abrogated when both VLA-4 and MCAM were inhibited. Consistent with these data, MCAM(+) cells were detected in white matter lesions, and in gray matter of multiple sclerosis patients. Our data indicate that lymphocyte trafficking into the CNS under VLA-4 blockade can occur by using the alternative adhesion molecules, PSGL-1 and MCAM, the latter representing an exclusive pathway for TH17 cells to migrate over the blood-brain barrier.
authors.affiliation: Department of Neurology; Department of Anaesthesiology, Intensive Care and Pain Medicine; Institute for Medical Physics and Biophysics; Institute of Neuropathology; and Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Schneider-Hohendorf
authors.affiliation: Department of Neurology; Department of Anaesthesiology, Intensive Care and Pain Medicine; Institute for Medical Physics and Biophysics; Institute of Neuropathology; and Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Rossaint
authors.affiliation: Department of Neurology; Department of Anaesthesiology, Intensive Care and Pain Medicine; Institute for Medical Physics and Biophysics; Institute of Neuropathology; and Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany.
authors.forename: Hema
authors.initials: H
authors.lastname: Mohan
authors.affiliation: Department of Neurology; Department of Anaesthesiology, Intensive Care and Pain Medicine; Institute for Medical Physics and Biophysics; Institute of Neuropathology; and Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Böning
authors.affiliation: Department of Neurology; Department of Anaesthesiology, Intensive Care and Pain Medicine; Institute for Medical Physics and Biophysics; Institute of Neuropathology; and Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Breuer
authors.affiliation: Department of Neurology; Department of Anaesthesiology, Intensive Care and Pain Medicine; Institute for Medical Physics and Biophysics; Institute of Neuropathology; and Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Kuhlmann
authors.affiliation: Department of Neurology; Department of Anaesthesiology, Intensive Care and Pain Medicine; Institute for Medical Physics and Biophysics; Institute of Neuropathology; and Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany.
authors.forename: Catharina C
authors.initials: CC
authors.lastname: Gross
authors.affiliation: Prothena Corporation plc, South San Francisco, CA 94080.
authors.forename: Ken
authors.initials: K
authors.lastname: Flanagan
authors.affiliation: Department of Neurology; Department of Anaesthesiology, Intensive Care and Pain Medicine; Institute for Medical Physics and Biophysics; Institute of Neuropathology; and Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Sorokin
authors.affiliation: Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
authors.affiliation: Department of Neurology; Department of Anaesthesiology, Intensive Care and Pain Medicine; Institute for Medical Physics and Biophysics; Institute of Neuropathology; and Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
authors.affiliation: Department of Neurology; Department of Anaesthesiology, Intensive Care and Pain Medicine; Institute for Medical Physics and Biophysics; Institute of Neuropathology; and Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany heinz.wiendl@ukmuenster.de nicholas.schwab@ukmuenster.de.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Schwab
authors.affiliation: Department of Neurology; Department of Anaesthesiology, Intensive Care and Pain Medicine; Institute for Medical Physics and Biophysics; Institute of Neuropathology; and Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany heinz.wiendl@ukmuenster.de nicholas.schwab@ukmuenster.de.
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000276:immunology; D051929:CD146 Antigen / Q000276:immunology; D016022:Case-Control Studies; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology* / Q000276:immunology*; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D036904:Leukocyte Rolling / Q000276:immunology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000276:immunology*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000134:cerebrospinal fluid / Q000276:immunology / Q000628:therapy; D000069442:Natalizumab; D019007:P-Selectin / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D051929:CD146 Antigen; D039041:Integrin alpha4beta1; D008024:Ligands; C497902:MCAM protein, human; D008562:Membrane Glycoproteins; D000069442:Natalizumab; D019007:P-Selectin; C084882:P-selectin ligand protein; D019010:Vascular Cell Adhesion Molecule-1