Inflammatory Disorders of the Nervous System: Pathogenesis, Immunology, and Clinical Management (Current Clinical Neurology)

Inflammatory Disorders of the Nervous System Pathogenesis, Immunology, and Clinical Management Edited by

Alireza Minagar, MD J. Steven Alexander, PhD

Inflammatory Disorders of the Nervous System

CURRENT CLINICAL NEUROLOGY Daniel Tarsy, MD, SERIES EDITORS Inflammatory Disorders of the Nervous System: Pathogenesis, Immunology, and Clinical Management, edited by Alireza Minagar and J. Steven Alexander, 2005 Psychiatry for Neurologists, edited by Dilip V. Jeste and Joseph H. Friedman, 2005 Status Epilepticus: A Clinical Perspective, edited by Frank W. Drislane, 2005 Thrombolytic Therapy for Acute Stroke, Second Edition, edited by Patrick D. Lyden, 2005 Neurological and Psychiatric Disorders: From Bench to Bedside, edited by Frank I. Tarazi and John A. Schetz, 2005 Movement Disorder Emergencies: Diagnosis and Treatment, edited by Steven J. Frucht and Stanley Fahn, 2005 Multiple Sclerosis: Etiology, Diagnosis, and New Treatment Strategies, edited by Michael J. Olek, 2005 Parkinson’s Disease and Nonmotor Dysfunction, edited by Ronald F. Pfeiffer and Ivan Bodis-Wollner, 2005 Seizures in Critical Care: A Guide to Diagnosis and Therapeutics, edited by Panayiotis N. Varelas, 2005 Vascular Dementia: Cerebrovascular Mechanisms and Clinical Management, edited by Robert H. Paul, Ronald Cohen, Brian R. Ott, Stephen Salloway, 2005 Atypical Parkinsonian Disorders, edited by Irene Litvan, 2005 Handbook of Neurocritical Care, edited by Anish Bhardwaj, Marek A. Mirski, and John A. Ulatowski, 2004 Handbook of Stroke Prevention in Clinical Practice, edited by Karen L. Furie and Peter J. Kelly, 2004 Clinical Handbook of Insomnia, edited by Hrayr P. Attarian, 2004 Critical Care Neurology and Neurosurgery, edited by Jose I. Suarez, 2004 Alzheimer’s Disease: A Physician’s Guide to Practical Management, edited by Ralph W. Richter and Brigitte Zoeller Richter, 2004 Field of Vision: A Manual and Atlas of Perimetry, edited by Jason J. S. Barton and Michael Benatar, 2003 Surgical Treatment of Parkinson’s Disease and Other Movement Disorders, edited by Daniel Tarsy, Jerrold L. Vitek, and Andres M. Lozano, 2003 Myasthenia Gravis and Related Disorders, edited by Henry J. Kaminski, 2003 Seizures: Medical Causes and Management, edited by Norman Delanty, 2002 Clinical Evaluation and Management of Spasticity, edited by David A. Gelber and Douglas R. Jeffery, 2002 Early Diagnosis of Alzheimer's Disease, edited by Leonard F. M. Scinto and Kirk R. Daffner, 2000 Sexual and Reproductive Neurorehabilitation, edited by Mindy Aisen, 1997

Inflammatory Disorders of the Nervous System Pathogenesis, Immunology, and Clinical Management

Edited by

Alireza Minagar, MD J. Steven Alexander, PhD Louisiana State University Health Science Center Shreveport, LA

© 2005 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 humanapress.com All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. All papers, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher.

Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the information published and to describe generally accepted practices. The contributors herein have carefully checked to ensure that the drug selections and dosages set forth in this text are accurate and in accord with the standards accepted at the time of publication. Notwithstanding, as new research, changes in government regulations, and knowledge from clinical experience relating to drug therapy and drug reactions constantly occurs, the reader is advised to check the product information provided by the manufacturer of each drug for any change in dosages or for additional warnings and contraindications. This is of utmost importance when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the treating physician to determine dosages and treatment strategies for individual patients. Further it is the responsibility of the health care provider to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences from the application of the information presented in this book and make no warranty, express or implied, with respect to the contents in this publication. This publication is printed on acid-free paper. ∞ ANSI Z39.48-1984 (American Standards Institute) Permanence of Paper for Printed Library Materials. Production Editor: Robin B. Weisberg Cover design by Patricia F. Cleary Cover illustration: Cerebral endothelial cells. Photograph by Dr. J. Steven Alexander. For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel.: 973-256-1699; Fax: 973-256-8341; E-mail: [email protected]; or visit our Website: www.humanapress.com Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press Inc., provided that the base fee of US $30.00 per copy is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press Inc. The fee code for users of the Transactional Reporting Service is: [1-58829-424-2/05 $30.00]. Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1 eISBN: 1-59259-905-2 Library of Congress Cataloging-in-Publication Data Inflammatory disorders of the nervous system : pathogenesis, immunology, and clinical management / edited by Alireza Minagar, J. Steven Alexander. p. ; cm. -- (Current clinical neurology) Includes bibliographical references and index. ISBN 1-58829-424-2 (alk. paper) 1. Neuritis. 2. Nervous system--Pathophysiology. 3. Inflammation. [DNLM: 1. Inflammation. 2. Nervous System Diseases. WL 140 I43 2005] I. Minagar, Alireza. II. Alexander, J. Steven. III. Series. RC416.I546 2005 616.8'56--dc22 2004020033

Series Editor’s Introduction The critical role of the inflammatory response in the pathophysiology of certain nervous system disorders has been appreciated for quite some time. Currently, rapidly accelerating knowledge of new molecular mechanisms known to be involved in systemic inflammatory disorders has extended to the investigation of a number of peripheral and central neurological disorders. Many of those discussed in this volume have been the usual suspects for immunemediated, inflammatory neurological disorders such as, for example, multiple sclerosis, acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, central nervous system (CNS) vasculitis, and neuropsychiatric systemic lupus erythematosis. Importantly, possible inflammatory mechanisms are now also undergoing scrutiny in chronic neurological diseases traditionally classified as neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. In Inflammatory Disorders of the Nervous System, Drs. Minagar and Alexander have gathered an impressive group of investigators who review the basic principles of neuroinflammation and their emerging role in the more common inflammatory disorders of the nervous system. The first group of chapters review new and emerging research in neuroinflammation, while the rest explore the diseases cited above as well as other disorders where the role of the immune system and inflammation is currently less well understood, such as neurosarcoidois, HIVassociated dementia, and HTLV-associated neurological disorders. As the authors of these chapters point out, the central nervous and immune systems have a known special relationship, disturbances in which may account for some aspects of neuroinflammation. The role of microglia in inflammatory CNS disease has never been fully understood and now comes under scrutiny as possibly mediating maladaptive inflammatory responses. On the other hand, a balance appears to exist between the useful and protective vs possibly damaging effects of various neuroinflammatory mechanisms. The extent to which neuroinflammation is either a primary, etiological cause or a more passive, associated bystander in the pathophysiology of neurological disorders probably varies considerably among various conditions. Sorting all of this out remains for future research that should be ably assisted by this outstanding overview of the current state of knowledge in this area. Daniel Tarsy, MD Department of Neurology Beth Israel Deaconess Medical Center Harvard Medical School Boston, MA

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Preface The last decade witnessed vast scientific advances in our understanding of molecular mechanisms of the inflammatory cascade involved in pathogenesis of diverse neurological disorders. Endothelial cells, activated leukocytes, resident immune cells within the central nervous system (CNS), and many classes of inflammatory mediators, especially chemokines and cytokines, are the major components of this complex and largely unsolved pathological puzzle. Through innumerable experiments, we have learned more about the role of each one of these players in the course of the inflammatory response, and have become able to apply some of our knowledge toward the development of more effective treatments with fewer adverse effects. The objective of Inflammatory Disorders of the Nervous System: Pathogenesis, Immunology, and Clinical Management is to provide readers with a highly detailed review of the basic principles of neuroinflammation and extensive updates on the latest findings on common neuroinflammatory disorders. Emerging concepts in the field of inflammation such as “endothelial and leukocyte microparticles” and “gene microarray technology” are introduced and provide important links between CNS and general inflammation processes. Our book should be of interest to a broad range of both basic research and clinical scientists with a core interest in neuroinflammation. It is our impression that neuroinflammation is among the most rapidly growing fields in inflammation research, and our knowledge of new developments in this field will enable scientists and clinicians around the globe to better diagnose and treat some of these untreatable and exigent neurological conditions. We are greatly indebted to the contributors, who made Inflammatory Disorders of the Nervous System: Pathogenesis, Immunology, and Clinical Management a reality by providing their superior knowledge and expertise in this rapidly developing field. We are also grateful to Richard Lansing, Robin Weisberg, and Damien DeFrances of Humana Press who provided their invaluable editorial expertise and technical advice for the publication of this book. We hope that our scientist colleagues find this book a useful resource in their unrelenting research into the mechanisms of inflammation. Alireza Minagar J. Steven Alexander

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Contents Series Editor’s Introduction ............................................................................................................. v Preface ................................................................................................................................................ vii Contributors ....................................................................................................................................... xi Continuing Medical Education .................................................................................................... xiii 1. Endothelial Cell–Leukocyte Interactions During CNS Inflammation .......................... 1 J. Steven Alexander and Alireza Minagar 2. Multiple Sclerosis: A Disease of Miscommunication Between the Immune and Central Nervous Systems? ........................................................................................... 17 Monica J. Carson, Crystal S. Anglen, and Corinne Ploix 3. Cytokines and Brain: Health and Disease ........................................................................... 41 Tammy Kielian and Paul D. Drew 4. Chemokines and Central Nervous System Disorders .................................................... 81 William J. Karpus 5. Circulating Cell-Derived Microparticles in Thrombotic and Inflammatory Disorders ............................................................................................................................. 91 Wenche Jy, Lawrence L. Horstman, Joaquin J. Jimenez, Alireza Minagar, and Yeon S. Ahn 6. Multiple Sclerosis: Clinical Features, Immunopathogenesis, and Clinical Management ....................................................................................................................... 103 William A. Sheremata 7. Neuroprotective Effects of Interferon-β in Multiple Sclerosis .................................... 133 Fabrizio Giuliani, Rana Zabad, and V. Wee Yong 8. Acute Disseminated Encephalomyelitis ......................................................................... 147 Sean J. Pittock and Dean M. Wingerchuk 9. Ingested Type I Interferon in Experimental Autoimmune Encephalomyelitis ........................................................................................................... 163 Staley A. Brod 10. Neuromyelitis Optica ......................................................................................................... 203 Dean M. Wingerchuk 11. Transverse Myelitis: Clinical Manifestations, Pathogenesis, and Management ............. 217 Chitra Krishnan, Adam I. Kaplin, Deepa M. Deshpande, Carlos A. Pardo, and Douglas A. Kerr 12. Optic Neuritis: Pathogenesis, Immunology, Diagnosis, and Clinical Management ........ 237 Robert Zivadinov and Rohit Bakshi 13. Central Nervous System Vasculitis: Pathogenesis, Immunology, and Clinical Management .................................................................................................. 257 Shariq Mumtaz, Marjorie R. Fowler, Eduardo Gonzales-Toledo, and Roger E. Kelley

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Contents 14. Neurosarcoidosis: Pathogenesis, Immunology, and Clinical Management ..................... 269 Dakshinamurty Gullapalli and Lawrence H. Phillips, II 15. Neuropsychiatric SLE: Pathogenesis, Immunology, and Clinical Management ............ 291 Deborah Aleman-Hoey and Robin L. Brey 16. Gene Expression in HIV-Associated Dementia ............................................................ 305 Paul Shapshak, Alireza Minagar, Elda M. Duran, Fabiana Ziegler, Wade Davis, Raman Seth, and Toni Kazic 17. Human T-Lymphotropic Virus-Associated Neurological Disorders: Pathogenesis, Immunology, and Clinical Management ................................................... 319 Michael D. Lairmore, Bindhu Michael, Lee Silverman, and Amrithraj Nair 18. West Nile Virus Infection of the Nervous System: Pathogenesis, Immunology, and Clinical Management .......................................................................... 337 Douglas J. Lanska

Index ................................................................................................................................................. 349

Contributors YEON S. AHN, MD • Wallace H. Coulter Platelet Laboratory, Department of Medicine, University of Miami School of Medicine, Miami, FL DEBORAH ALEMAN-HOEY, MD • Division of Neurology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX J. STEVEN ALEXANDER, PhD • Department of Cellular and Molecular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA CRYSTAL S. ANGLEN, PhD • Department of Cellular and Molecular Physiology, The Scripps Research Institute, La Jolla, CA ROHIT BAKSHI, MD • Center for Neurological Imaging, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA ROBIN L. BREY, MD • Division of Neurology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX STALEY A. BROD, MD • Department of Neurology, University of Texas Health Science Center at Houston, Houston, TX MONICA J. CARSON, PhD • Division of Biomedical Sciences, University of California, Riverside, CA WADE DAVIS, PhD • Department of Statistics, Baylor University, Waco, TX DEEPA M. DESHPANDE • Transverse Myelitis Center, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD PAUL D. DREW, PhD • Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR ELDA M. DURAN, MS •Departments of Psychiatry and Behavioral Sciences, University of Miami School of Medicine, Miami, FL MARJORIE R. FOWLER, MD • Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA FABRIZIO GIULIANI, MD • Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada EDUARDO GONZALES-TOLEDO, MD, PhD • Department of Radiology, Louisiana State University Health Sciences Center, Shreveport, LA DAKSHINAMURTY GULLAPALLI, MD • Veterans Administrations Hospital, Salem, VA LAWRENCE L. HORSTMAN, BS • Wallace H. Coulter Platelet Laboratory, Department of Medicine, University of Miami School of Medicine, Miami, FL JOAQUIN J. JIMENEZ, MD • Wallace H. Coulter Platelet Laboratory, Department of Medicine, University of Miami School of Medicine, Miami, FL WENCHE JY, PhD • Wallace H. Coulter Platelet Laboratory, Department of Medicine, University of Miami School of Medicine, Miami, FL ADAM I. KAPLIN, MD, PhD • Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD WILLIAM J. KARPUS, PhD • Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL TONI KAZIC, PhD • Departments of Computer Science and Health Management Informatics, University of Missouri, Columbia, MO ROGER E. KELLEY, MD • Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA

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DOUGLAS A. KERR, MD, PhD • Transverse Myelitis Center, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD TAMMY KIELIAN, PhD • Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR CHITRA KRISHNAN, MHS • Transverse Myelitis Center, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD MICHAEL D. LAIRMORE, DVM, PhD • Center for Retrovirus Research and Department of Veterinary Biosciences; Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Arthur G. James Cancer Hospital and Solove Research Institute, Ohio State University, Columbus, OH DOUGLAS J. LANSKA, MD • Veterans Affairs Medical Center, Tomah, WI and Department of Neurology, University of Wisconsin, Madison, WI BINDHU MICHAEL, BVSc & AH, MSc, MS, PhD • Center for Retrovirus Research and Department of Veterinary Biosciences, Ohio State University, Columbus OH ALIREZA MINAGAR, MD • Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA SHARIQ MUMTAZ, MD • Department of Neurology, Memorial University New Foundland, NL, Canada AMRITHRAJ NAIR, BVSc & AH • Center for Retrovirus Research and Department of Veterinary Biosciences, Ohio State University, Columbus OH CARLOS A. PARDO, MD • Transverse Myelitis Center, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD LAWRENCE H. PHILLIPS, II, MD • Department of Neurology, University of Virginia Health Sciences Center, Charlottesville, VA SEAN J. PITTOCK, MD • Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN CORINNE PLOIX, PharmD, PhD • Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA RAMAN SETH, MBBS, MS • Departments of Computer Science and Health Management Informatics, University of Missouri, Columbia, MO PAUL SHAPSHAK, PhD • Departments of Psychiatry and Behavioral Sciences, Neurology, Pathology, Comprehensive Drug Research Center, and Pediatrics McDonald Foundation Gene Team, University of Miami School of Medicine, Miami, FL WILLIAM A. SHEREMATA, MD • Multiple Sclerosis Center, University of Miami School of Medicine, Miami, FL LEE SILVERMAN, DVM • Center for Retrovirus Research and Department of Veterinary Biosciences, Ohio State University, Columbus OH DEAN M. WINGERCHUK, MD • Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, AZ V. WEE YONG, PhD • University of Calgary, Departments of Clinical Neurosciences and Oncology, Calgary, Alberta, Canada RANA ZABAD, MD • Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada FABIANA ZIEGLER, MD • Departments of Psychiatry and Behavioral Sciences, University of Miami School of Medicine, Miami, FL ROBERT ZIVADINOV, MD, PhD • Department of Neurology, State University of New York at Buffalo School of Medicine and Biomedical Sciences; Buffalo Neuroimaging Analysis Center, The Jacobs Neurological Institute, Buffalo, NY

Continuing Medical Education RELEASE DATE May 1, 2005 EXPIRATION DATE May 1, 2007 ESTIMATED TIME TO COMPLETE 5 hours ACCREDITATION This activity has been planned and implemented in accordance with the essential areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of The American Society of Contemporary Medicine and Surgery and Humana Press/eXtensia. The American Society of Contemporary Medicine and Surgery is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CREDIT DESIGNATION The American Society of Contemporary Medicine and Surgery designates this educational activity for a maximum of five category 1 credits toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity. METHOD OF PARTICIPATION AND FEE The American Society of Contemporary Medicine and Surgery is pleased to award category 1 credit(s) toward the AMA Physician’s Recognition Award for this activity. By reading the chapters and completing the CME questions, you are eligible for up to five category 1 credits toward the AMA/PRA. Following that, please complete the Answer Sheet and claim the credits. A minimum of 75% correct must be obtained for credit to be awarded. Finally, please complete the Activity Evaluation on the other side of the Answer Sheet. Please submit the Answer Sheet/Activity Evaluation according to the information printed on the top of that page. Your test will be scored within 4 weeks. You will then be notified of your score with a certificate of credit, or you will receive an additional chance to pass the posttest. Credit for the activity is available until May 1, 2007. There is no fee for this activity. FACULTY AND DISCLOSURE Faculty for CME activities are expected to disclose to the activity audience any real or apparent conflict(s) of interest related to the content of the material they present. The faculty for this activity report no conflicts of interests or relationships to disclose. PROVIDER DISCLOSURE The American Society of Contemporary Medicine and Surgery is an independent organization that does not endorse specific products of any pharmaceutical concern and therefore has nothing to disclose. Humana Press/ eXtensia are independent organizations that do not endorse specific products of any pharmaceutical concern and therefore have nothing to disclose.

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INTENDED AUDIENCE This activity is intended for neurologists and other physicians who treat inflammatory disorders of the nervous system. OVERALL GOAL The overall goal of this activity is to update the knowledge of clinicians on strategies and techniques needed to comprehensively manage patients with inflammatory disorders of the nervous system. LEARNING OBJECTIVES After completing this CME activity, participants should have improved their overall knowledge and attitudes in regard to inflammatory disorders of the nervous system. Specifically, participants should be able to: • Distinguish the pathogenesis of inflammation • Discuss the details of interactions among activated leukocytes, endothelial cells, and inflammatory mediators (i.e., cytokines, chemokines, adhesion molecules, etc.) in the context of inflammatory disorders of the central nervous system • Describe how the central nervous system and immune system communicate and interact during inflammation of the nervous system • Assess the modern concepts behind the phenomenon of inflammation, such as endothelial microparticles, gene microarray expression, and failure of endothelial barrier function • Understand the pathogenesis and clinical manifestations, as well as management, of some of the most common and least understood inflammatory disorders of the central nervous system, such as multiple sclerosis, neuro-sarcoidosis, HIV-associated-dementia, Devic’s disease, and West Nile virus encephalitis • Demonstrate assessment strategies for patients with a variety of inflammatory disorders of the central nervous system UNLABELED/ UNAPPROVED USE DISCLOSURE In accordance with ACCME standards for Commercial Support, the audience is advised that this CME activity may contain references to unlabeled or unapproved uses of drugs or devices.

1 Endothelial Cell–Leukocyte Interactions During CNS Inflammation J. Steven Alexander and Alireza Minagar 1. INTRODUCTION Inflammation is a reactive response to infection or injury that involves many complex interactions between formed blood elements, vascular and tissue cells, which is controlled by the release and synthesis of several classes of soluble mediators in response to tissue injury, bacterial, or viral products. Some mediators are stored within several cell types (e.g., histamine, 5hydroxytryptamine, proteases, and cationic proteins), whereas others are synthesized or induced cell-derived factors (e.g., prostanoids, leukotrienes, platelet-activating factor, and cytokine/chemokines), as well as products of proteolytic cascades in plasma (complement products, blood-coagulation cascade products, kinins). The extent, timing, and specificity of this response is related to the lability, metabolism, and scavenging/inactivation of these mediators. The recruitment of leukocytes to the sites of injury or infection is a central event in the inflammatory response, and often results in “bystander” tissue dysfunction and damage from leukocyte oxidants, proteases, and other mediators in several disease states. The steps in leukocyte recruitment include capture and rolling of activated leukocyte by the endothelium, leukocyte adhesion to the endothelial lining of the vessel wall, transendothelial migration of activated leukocytes to the inflammatory focus, and passage through the extracellular matrix. Endothelial cells are critical regulators and participants in this process and interact with leukocytes, particularly following exposure to inflammatory mediators. This chapter highlights recent advances in our understanding of the mechanisms of leukocyte–endothelial adhesive interactions at the level of cell-surface protein–protein binding events and in intracellular signal transduction pathways that regulate leukocyte egress out of the vascular space and into epithelial-lined tissues and their relevance to inflammation of the central nervous system (CNS).

2. VASCULAR LEAKAGE One of the earliest inflammatory responses to the release of several acutely acting mediators (e.g., histamine, kinins, prostanoids, etc.) is an acutely increased microvascular (usually postcapillary venular) permeability to water and plasma proteins. This leak is thought to reflect reorganization and/or contraction of endothelial adherens and tight junctions (1). Vascular endothelial (VE) cadherin (VE-cadherin) or cadherin-5 has been shown to be a major component of the endothelial adherens junction (2,3) with N- and P-cadherins (4,5), which maintain and regulate

From: Current Clinical Neurology: Inflammatory Disorders of the Nervous System: Pathogenesis, Immunology, and Clinical Management Edited by: A. Minagar and J. S. Alexander © Humana Press Inc., Totowa, NJ

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vascular permeability along with several components of tight junctions, which include junctional adhesion molecules (JAMs) (6), occludin (7), and members of the claudin family of proteins (8). It is still unclear how these proteins reorganize when the barrier is altered; however, endocytosis (9), or a similar form of cadherin internalization, has been demonstrated in endothelial cells exposed to several vasoactive mediators (10). Redistribution or contraction of junctional proteins (11) might also increase endothelial solute permeability by disintegrating the seal created by these proteins, or by changing the amount of proteins in cells or their expression at the cell surface. Additionally, active junction remodeling may play an important role in controlling how leukocytes pass across the endothelium into tissues during inflammation. Although leukocyte recruitment during inflammation is often associated with increased solute leakage, this probably reflects both the number of leukocytes recruited and migrated, and the extent of their activation, because leukocytes can often migrate across the endothelium without significant perturbation of this solute barrier (12). In the CNS, this increased endothelial solute leakage delivers plasma-borne inflammatory mediators to the CNS and presents a more serious problem. The interruption of the blood–brain barrier (BBB) even transiently can lead to extensive nervous system disturbances, including altered nerve conduction, irreversible damage to neurons, loss of myelin sheath, and loss of other CNS-resident cells. This increased vascular permeability in the BBB is now recognized as an underlying mechanism in many CNS disease processes. Mechanistically the increased solute leakage serves at least two purposes: first, to deliver opsonizing antibodies to sites of inflammation and second, the solute leakage from vessels may hemoconcentrate plasma to slow blood flow below the critical velocity, favoring a close approach of leukocytes to the underlying endothelium, an initial step in leukocyte recruitment. The actual tethering or capture events between leukocytes and activated endothelium are mediated by the selectin family of adhesion molecules and their sulfated, sialylated, and fucosylated, glycoprotein ligands (13,14).

2.1. Selectins Selectins are a group of calcium-dependent, type-I transmembrane glycoproteins that bind to sialylated carbohydrate moieties on target proteins. The selectin family consists of three structurally related molecules: L-selectin, E-selectin, and P-selectin (15–17). Genes encoding selectin adhesion molecules are located on chromosome 1. Each selectin molecule contains an amino-terminus C-type lectin domain, which plays a central role in adhesion of selectin to its ligand. C-type lectin domains recognize carbohydrate structures in a Ca2+-dependent manner. This region is followed by an epidermal growth factor (EGF)-like motif, which modulates selectin binding to its ligands by maintaining the lectin domain in a proper orientation for ligand binding (18,19). The EGF-like domain is followed by various numbers of consensus repeat (CR) domains. The selectin molecule is anchored in the membrane by a single transmembrane domain and contains a short cytoplasmic tail. The number of CR domains is the major structural difference between selectin molecules.

2.2.1. L-Selectin L-selectin (CD62L), which initially was identified as a lymphocyte homing receptor, is exclusively expressed by leukocytes (neutrophils, monocytes, some subgroups of natural killer[NK] cells, and naïve T and B lymphocytes). L-selectin supports rolling in vivo and in vitro (20) and is expressed at the tips of leukocyte microvilli, which mediate early capture of leukocytes. L-selectin mediates lymphocyte recruitment and attachment to the high endothelial venules of the lymphatic tissue. Additionally, L-selectin plays a major role in recruitment of leukocytes into the inflammatory foci (21). Upon activation of the leukocytes by fMet-Leu-Phe (fMLP) or interleukin (IL)-8, Lselectin is shed from leukocytes in what appears to be a metalloproteinase-dependent cleavage. 2.2.2. P-Selectin P-selectin (CD62P), which is synthesized and stored in endothelial Weibel-Palade and platelet α-granules, can be rapidly ( 95