The Journal of Immunology, 2002,
Laura Piccio*, Barbara Rossi*, Elio Scarpini, Carlo Laudanna*, Cinzia Giagulli*, Andrew C. Issekutz, Dietmar Vestweber, Eugene C. Butcher ¶ and Gabriela Constantin *
* Department of Pathology, University of Verona, Verona, Italy; Department of Neurological Sciences, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Maggiore Policlinico, and "Dino Ferrari" Center, Milan, Italy; Department of Pediatrics, Pathology, and Microbiology-Immunology, Dalhousie University, Halifax, Nova Scotia, Canada; Institute of Cell Biology, Center for Molecular Biology of Inflammation, University of Muenster, and Max-Planck-Institut, Muenster, Germany; and
¶ Department of Pathology, Stanford University, Stanford, CA 94305
Lymphocyte recruitment into the brain is a critical event in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis.
We developed a novel intravital microscopy model to directly analyze through the skull the interactions between lymphocytes and the endothelium in cerebral venules of mice.
No adhesive interactions were observed between lymphocytes and the nonactivated endothelium in the cerebral microcirculation.
When brain venules were activated by pretreating mice with TNF-a or LPS, proteolipid protein 139–151 autoreactive T lymphocytes rolled and arrested; notably, only a few peripheral lymph node cells rolled and firmly adhered.
Abs anti-P-selectin glycoprotein ligand-1 and anti-E- and P-selectin blocked tethering and rolling of autoreactive lymphocytes, suggesting that P-selectin glycoprotein ligand-1/endothelial selectins are critical in the recruitment of lymphocytes in inflamed brain venules.
E- and P-selectin were expressed on cerebral vessels upon in vivo activation and had a patchy distribution during the preclinical phase of active and passive experimental autoimmune encephalomyelitis.
LFA-1/ICAM-1 and 4 integrins/VCAM-1 supported rolling, but were not relevant to rolling velocity.
Firm arrest was mainly mediated by LFA-1 and ICAM-1.
Pretreatment of autoreactive lymphocytes with pertussis toxin blocked integrin-dependent arrest, implicating a requirement for Gi protein-dependent signaling in vessels from nonlymphoid districts.
In conclusion, our data unveils the
molecular mechanisms controlling the recruitment of autoreactive lymphocytes
in inflamed cerebral vessels and suggest new insights into the pathogenesis
of autoimmune inflammatory diseases of the CNS.
Copyright © 2002 by The American Association of Immunologists