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Originally published online as doi:10.2353/ajpath.2008.080001 on August 7, 2008

Published online before print August 7, 2008
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(American Journal of Pathology. 2008;173:892-900.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080001

Von-Willebrand Factor Influences Blood Brain Barrier Permeability and Brain Inflammation in Experimental Allergic Encephalomyelitis

Rajkumar Noubade*, Roxana del Rio*, Benjamin McElvany*, James F. Zachary{dagger}, Jason M. Millward{ddagger}, Denisa D. Wagner§, Halina Offner, Elizabeth P. Blankenhorn|| and Cory Teuscher*,**

From the Department of Medicine,* University of Vermont, Burlington, VT; Department of Pathobiology,{dagger} University of Illinois at Urbana-Champaign, Urbana, IL; Montreal Neurological Institute,{ddagger} McGill University, Montreal; The Immune Disease Institute and Department of Pathology,§ Harvard Medical School; Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR; Department of Microbiology and Immunology,|| Drexel University College of Medicine, Philadelphia, PA; and Department of Pathology,** University of Vermont, Burlington, VT

Weibel-Palade bodies within endothelial cells are secretory granules known to release von Willebrand Factor (VWF), P-selectin, chemokines, and other stored molecules following histamine exposure. Mice with a disrupted VWF gene (VWFKO) have endothelial cells that are deficient in Weibel-Palade bodies. These mice were used to evaluate the role of VWF and/or Weibel-Palade bodies in Bordetella pertussis toxin-induced hypersensitivity to histamine, a subphenotype of experimental allergic encephalomyelitis, the principal autoimmune model of multiple sclerosis. No significant differences in susceptibility to histamine between wild-type and VWFKO mice were detected after 3 days; however, histamine sensitivity persisted significantly longer in VWFKO mice. Correspondingly, encephalomyelitis onset was earlier, disease was more severe, and blood brain barrier (BBB) permeability was significantly increased in VWFKO mice, as compared with wild-type mice. Moreover, inflammation was selectively increased in the brains, but not spinal cords, of VWFKO mice as compared with wild-type mice. Early increases in BBB permeability in VWFKO mice were not due to increased encephalitogenic T-cell activity since BBB permeability did not differ in adjuvant-treated VWFKO mice as compared with littermates immunized with encephalitogenic peptide plus adjuvant. Taken together, these data indicate that VWF and/or Weibel-Palade bodies negatively regulate BBB permeability changes and autoimmune inflammatory lesion formation within the brain elicited by peripheral inflammatory stimuli.






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Copyright © 2008 by the American Society for Investigative Pathology.