title: Determinants of human B cell migration across brain endothelial cells.
abstract: Circulating B cells enter the CNS as part of normal immune surveillance and in pathologic states, including the common and disabling illness multiple sclerosis. However, little is known about the molecular mechanisms that mediate human B cell interaction with the specialized brain endothelial cells comprising the blood-brain barrier (BBB). We studied the molecular mechanisms that regulate the migration of normal human B cells purified ex vivo, across human adult brain-derived endothelial cells (HBECs). We found that B cells migrated across HBECs more efficiently than T cells from the same individuals. B cell migration was significantly inhibited by blocking Abs to the adhesion molecules ICAM-1 and VLA-4, but not VCAM-1, similar to the results previously reported for T cells. Blockade of the chemokines monocyte chemoattractant protein-1 and IL-8, but not RANTES or IFN-gamma-inducible protein-10, significantly inhibited B cell migration, and these results were correlated with the chemokine receptor expression of B cells measured by flow cytometry and by RNase protection assay. Tissue inhibitor of metalloproteinase-1, a natural inhibitor of matrix metalloproteinases, significantly decreased B cell migration across the HBECs. A comprehensive RT-PCR comparative analysis of all known matrix metalloproteinases and tissue inhibitors of metalloproteinases in human B and T cells revealed distinct profiles of expression of these molecules in the different cell subsets. Our results provide insights into the molecular mechanisms that underlie human B cell migration across the BBB. Furthermore, they identify potential common, and unique, therapeutic targets for limiting CNS B cell infiltration and predict how therapies currently developed to target T cell migration, such as anti-VLA-4 Abs, may impact on B cell trafficking.
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, Montreal, Quebec, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Alter
authors.forename: Martin
authors.initials: M
authors.lastname: Duddy
authors.forename: Sherry
authors.initials: S
authors.lastname: Hebert
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Biernacki
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
authors.forename: Jack P
authors.initials: JP
authors.lastname: Antel
authors.forename: Voon Wee
authors.initials: VW
authors.lastname: Yong
authors.forename: Robert K
authors.initials: RK
authors.lastname: Nuttall
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Pennington
authors.forename: Dylan R
authors.initials: DR
authors.lastname: Edwards
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000276:immunology*; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D002469:Cell Separation; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015194:Diffusion Chambers, Culture; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism / Q000502:physiology; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D023062:Receptors, Interleukin-8A / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C515334:CCR2 protein, human; D018932:Chemokine CCL2; D005353:Fibronectins; D039041:Integrin alpha4beta1; D016209:Interleukin-8; D061965:Matrix Metalloproteinase Inhibitors; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D019715:Tissue Inhibitor of Metalloproteinase-1; D019010:Vascular Cell Adhesion Molecule-1; D020782:Matrix Metalloproteinases