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* Unité d’Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie and Centre National de la Recherche Scientifique (CNRS) Unité de Recherche Associée 3015, Institut Pasteur, Paris, France;
Plateforme de Microscopie Electronique, Institut Pasteur, Paris, France;
Laboratoire de Neuropathologie, Hôpital de la Salpêtrière, Paris, France;
Institut National de la Santé et de la Recherche Médicale Unité 567, CNRS Unité Mixte de Recherche 8104, Département de Biologie Cellulaire, Institut Cochin, Paris, France;
¶ Department of Biological Sciences, The Open University, Milton Keynes, United Kingdom; and
|| Weill Medical College of Cornell University, New York, NY 10021
The blood-brain barrier (BBB), which constitutes the interface between blood and cerebral parenchyma, has been shown to be disrupted during retroviral associated neuromyelopathies. Human T cell leukemia virus (HTLV-1)-associated myelopathy/tropical spastic paraparesis is a slowly progressive neurodegenerative disease, in which evidence of BBB breakdown has been demonstrated by the presence of lymphocytic infiltrates in the CNS and plasma protein leakage through cerebral endothelium. Using an in vitro human BBB model, we investigated the cellular and molecular mechanisms involved in endothelial changes induced by HTLV-1-infected lymphocytes. We demonstrate that coculture with infected lymphocytes induces an increase in paracellular endothelial permeability and transcellular migration, via IL-1
and TNF- secretion. This disruption is associated with tight junction disorganization between endothelial cells, and alterations in the expression pattern of tight junction proteins such as zonula occludens 1. These changes could be prevented by inhibition of the NF-
B pathway or of myosin light chain kinase activity. Such disorganization was confirmed in histological sections of spinal cord from an HTLV-1-associated myelopathy/tropical spastic paraparesis patient. Based on this BBB model, the present data indicate that HTLV-1-infected lymphocytes can induce BBB breakdown and may be responsible for the CNS infiltration that occurs in the early steps of retroviral-associated neuromyelopathies.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a grant from the Association pour la Recherche sur la Sclérose en Plaques and Institut Pasteur (Programme Transversal de Recherche 190). P.V.A. is a grant recipient from the Ministère de la Recherche (France).
2 Address correspondence and reprint requests to Dr. Pierre-Emmanuel Ceccaldi, Institut Pasteur, 28 rue du Docteur Roux, 75015 Paris, France. E-mail address: ceccaldi{at}pasteur.fr
3 Abbreviations used in this paper: BBB, blood-brain barrier; TJ, tight junction; ZO-1, zonula occludens 1; HTLV, human T cell leukemia virus; HAM/TSP, human T cell leukemia virus-associated myelopathy/tropical spastic paraparesis; MLC, myosin light chain; MLCK, myosin light chain kinase; h, human; VEGF, vascular endothelial growth factor; IL-1-Ra, IL-1 receptor antagonist.
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