Principles of Molecular Rheumatology

cur r en t

MOLECULAR MEDICINE

Principles of Molecular Rheumatology, edited by George C. Tsokos, MD, 2000

series editor: J. Larry Jameson, MD, phD

Current Molecular Med cine

Principles of

Molecular Rheumatology

Edited by

George C. Tsokos, MD

Walter Reed Army Institute of Research, Silver Spring, MO

Uniformed Services University of the Health Sciences, Bethesda, MO

Springer Science+Business Media, LLC "

© 2000 Springer Science+Business Media New York Originally published by Humana Press lnc. in 2000 Softcover reprint of the hardcover l st edition 2000

To Sophia and Christos ToMaria

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Library of Congress Cataloging-in-Publication Data Principles of molecular rheumatology / edited by George C. Tsokos.

p. ; cm. -- (Current molecular medicine) Includes bibliographical references and index.

ISBN 978-1-61737-182-0 ISBN 978-1-59259-018-6 (eBook) DOI 10.1007/978-1-59259-018-6

1. Rheumatism--Molecular aspects. 2. Arthritis--Molecular aspects. 3. Rheumatism--Pathophysiology. 4. Arthritis--Pathophysiology. 1. Tsokos, George C. [1. Serics.

[DNLM: l. Rheumatic Diseases--genetics. 2. Rheumatic diseases--physiopathology. 3. Rheumatic Diseases--therapy. WE 544 P9567 2000] RC927 .P676 2000 6 [6. 7'23'07--dc2 [ 00-24930

Preface

" ... we simply do not know enough, we are still a largely ignorant profession, faced by an array of illnesses which we do not really understand, unable to do much beyond trying to make the right diagnosis, shoring things up whenever we can by one halfway technology or another ... "

Lewis Thomas, The Fragile Species, TOUCHSTONE, New York, 1992

Principles of Molecular Rheumatology has been organized to help Rheumatology Fellows, House Officers, and Rheumatologists better understand the molecular and cel­lular aspects of Rheumatic Diseases. The ambition of the editor and the authors is to present and discuss the pathogenesis of rheumatic diseases in a concise manner. We hope that Principles of Molecular Rheumatology will facilitate the introduction of clini­cal trainees to the science of Rheumatology and will serve as a helpful accessory in reviewing basic and clinical articles with reference to basic science issues. Further­more, it is our intention to help those students of human disease who do not have a formal medical training gain an informed perspective on rheumatic diseases.

The first section of Principles of Molecular Rheumatology discusses the molecular mechanisms that are central to many rheumatic diseases. Established authors pre­sent the biochemical mechanisms by which apoptosis, cell signaling, complement, lipids, and viruses contribute to disease expression. The second section reviews immune and nonimmune cell function as it relates to rheumatic diseases. The function oflymphocytes, monocytes, neutrophils, synoviocytes, chondrocytes, and bone cells is discussed. The third section takes a synthetic approach to disease. The authors present integrated discussions of the cellular, biochemical, and molecular biological mecha­nisms that are directly important to disease pathogenesis. Major diseases are reviewed and concepts are formulated. In the final section, the molecular aspects of those thera­peutics that are routinely used in rheumatic diseases are discussed. The emphasis on mechanisms rather than clinical pharmacology aims at familiarizing the reader with what is being accomplished at the molecular and cellular levels following the adminis­tration of each medication.

Principles of Molecular Rheumatology does not replace any of the classic textbooks in Rheumatology. Rather, it adopts a fresh perspective designed to enhance the under­standing of Rheumatology by emphasizing the importance of knowledge of molecular and cellular pathophysiology to the mastery of rheumatic diseases.

v

vi Preface

I am grateful to the authors for many exciting discussions on the format and content of the book and for their enthusiasm and support, which provided me with the stamina to see the project to its completion. I learned so much from my interactions with my esteemed colleagues, authors of Principles of Molecular Rheumatology, that I do not seek reward. My only hope is that Principles of Molecular Rheumatology will help our fellow Rheumatologists better serve the patients who suffer from rheumatic diseases. The unwavering support of Paul Dolgert is once more appreciated. Craig Adams and Elyse O'Grady are responsible for all the good things in this book, whereas I am responsible for its shortcomings

George C. Tsokos, MD

Contents

Preface ............................................................................................................................ v

Contributors .................................................................................................................. . xi

PART I. MOLECULAR MECHANISMS IN RHEUMATIC DISEASES

1 Genetics Peter K. Gregersen ............................................................................................... 3

2 Viruses Andras Perl ......................................................................................................... 15

3 Apoptosis John D. Mountz, Hui-Chen Hsu, Huang-Ge Zhang, and Tong Zhou .....•..... 35

4 Humoral Response Gary S. Gilkeson ................................................................................................. 59

5 T -Cell Signaling Gary A. Koretzky and Erik J. Peterson ............................................................. 75

6 Adhesion and Costimulatory Molecules Vassiliki A. Boussiotis, Gordon J. Freeman, and Lee M. Nadler •••................ 87

7 Transcription Factors Henry K. Wong ................................................................................................. l' 09

8 Immune Complexes Mark H. Wener .............•......•..............•............................................................. 127

9 Complement V. Michael Holers ............................................................................................. 145

10 Eicosanoids and Other Bioactive Lipids Leslie J. Crofford .............................................................................................. 161

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viii Contents

11 Collagens Sergio A. Jimenez ............................................................................................. 175

PART II. CELLULAR MECHANISMS IN RHEUMATIC DISEASES

12 T-Lymphocytes Ni/amadhab Mishra and Gary M. Kammer .................................................... 199

13 B-Lymphocytes Robert F. Ashman ....................................•....................................................... 213

14 Monocytes and Macrophages James M. K. Chan and Sharon M. Wahl ........................................................ 225

15 Polymorphonuclear Cells Michael H. Pi/linger, Pamela B. Rosenthal, and Bruce N. Cronstein .....•... 243

16 Synoviocytes David E. Yocum ..................................•........•.........•..................•....................... 259

17 Chondrocytes Tariq M. Haqqi, Donald D. Anthony, and Charles J. Malemud ................... 267

18 Osteoblasts and Osteoclasts Stavros C. Manolagas ...................................................................................... 279

19 Animal Models Thomas J. Lang and Charles S. Via ............................................................... 293

PART III. PATHOGENESIS OF RHEUMATIC DISEASES

20 Systemic Lupus Erythematosus Stamatis-Nick C. Liossis and George C. Tsokos ............................................ 311

21 Rheumatoid Arthritis Richard M. Pope and Harris Perlman ............................................................ 325

22 Inflammatory Myopathies Norbert Goebels and Reinhard Hohlfeld ........................................................ 363

23 Systemic Sclerosis Timothy M. Wright ........................................................................................... 375

24 Vasculitis Jorg J. Goronzy and Cornelia M. Weyand ..................................................... 385

Contents ix

25 Osteoarthritis A. Robin Poole and Ginette Webb ................................................................... 401

26 Osteoporosis Stavros C. Manolagas ...................................................................................... 413

27 Heritable Disorders of Connective Tissue Petros Tsipouras ............................................................................................... 423

PART IV. MOLECULAR ASPECTS OF TREATMENT OF RHEUMATIC DISEASES

28 Corticosteroids Henry K. Wong and George C. Tsokos ........................................................... 439

29 Cytotoxic Drugs David A. Fox and W. Joseph McCune ............................................................ 451

30 Complement Inhibitors Savvas C. Makrides .......................................................................................... 465

31 Cytokine Response Modifiers Richard E. Jones and Larry W. Moreland ..................................................... 477

32 Restoration of Immune Tolerance Woodruff Em len ............................................................................................... 487

33 Metalloproteases and Their Modulation as Treatment in Osteoarthritis Johanne Martel-Pelletier, Ginette Tardif, Julio Fernandes, and Jean-Pierre Pelletier ................................................................................. 499

34 Gene Therapy Robert P. Kimberly ........................................................................................... 515

Index ........................................................................................................................... 525

Contributors

DONALD D. ANTHONY, MD, PHD· Division of Rheumatic Diseases, Department of Medicine, Case Western Reserve University, Cleveland, OH

ROBERT F. ASHMAN, MD • Division of Rheumatology, Department of Medicine, University of Iowa College of Medicine and Department of Veterans Affairs Medical Center, Iowa City, IA

V ASSILIKI A. BOUSSIOTIS, MD • Department of Adult Oncology, Dana Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA

JAMES M. K. CHAN, PHD • Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institute of Health, Bethesda, MD

LESLIE J. CROFFORD, MD • Division of Rheumatology Internal Medicine, University of Michigan, Ann Arbor, MI

BRUCE N. CRONSTEIN, MD • Bellevue Hospital Center, and Division of Rheumatology, Departments of Medicine and Pathology, New York University School of Medicine, New York, NY

WOODRUFF EMLEN, MD· Exploratory Medicine, Connetics Corporation, Palo Alto, CA JULIO C. FERNANDES, MD, MSc • Osteoarthritis Research Unit, Centre Hospitalier de

l'Universite de Montreal, Hopital Notre-Dame, Montreal, Canada DAVID A. Fox, MD • Division of Rheumatology, University of Michigan Multipurpose

Arthritis and Musculoskeletal Diseases Center, University of Michigan Medical Center, Ann Arbor, MI

GORDON J. FREEMAN· Department of Adult Oncology, Dana Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA

GARY S. GILKESON, MD • Division of Rheumatology, Medical University of South Carolina, Charleston, SC

NORBERT GOEBELS, MD • Department of Neurology and Institute for Clinical Neuroimmunology, Klinikum Grosshadern, Ludwig Maximilians-University of Munich, Munich, Germany

JORG J. GORONZY, MD • Division of Rheumatology, Department of Medicine, Mayo Clinic and Foundation, Rochester, MN

PETER K. GREGERSEN, MD· Departments of Medicine and Pathology, New York University School of Medicine and Chief Division of Biology and Human Genetics, North Shore University Hospital, Manhasset, NY

TARIQ M. HAQQI, PHD • Division of Rheumatic Diseases, Department of Medicine, Case Western Reserve University, Cleveland, OH

REINHARD HOHLFELD, MD • Department of Neurology and Institute for Clinical Neuroimmunology, Klinikum Grosshadern, Ludwig Maximilians-University of Munich, Munich, Germany

V. MICHAEL HOLERS, MD • Divison of Rheumatology, Departments of Medicine and Immunology, University of Colorado Health Sciences Center, Denver, CO

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xii Contributors

HUI-CHEN Hsu, PHD • Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, and the Birmingham Veterans Administration Medical Center, Birmingham, AL

SERGIO A. JIMENEZ, MD • Division of Rheumatology, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA

RICHARD E. JONES, MD, PHD • Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL

GARY M. KAMMER, MD • Section on Rheumatology and Clinical Immunology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC

ROBERT P. KIMBERLY, MD· Division of Clinical Immunology and Rheumatology, and University of Alabama at Birmingham Arthritis and Musculoskeletal Center, Birmingham, AL

GARY A. KORETZKY, MD, PHD • Leonard and Madlyn Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA

THOMAS 1. LANG, MD, PHD • Division of Rheumatology, Department of Medicine, University of Maryland School of Medicine, Baltimore Veterans Affairs Medical Center, Baltimore, MD

STAMATIS-NICK C. LIOSSIS, MD· Division of Rheumatology and Immunology, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD

SAVVAS C. MAKRIDES, PHD • EIC Laboratories Inc, Norwood, MA CHARLES J. MALEMUD, PHD· Division of Rheumatic Diseases, Department of Medicine,

Case Western Reserve University, Cleveland, OH STAVROS C. MANOLAGAS, MD, PHD· Center for Osteoporosis and Metabolic Bone

Diseases, Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, and the Central Arkansas Veterans Healthcare System, Little Rock, AR

JOHANNE MARTEL-PELLETIER, PHD· Osteoarthritis Research Unit, Centre Hospitalier de l'Universite de Montreal, Hopital Notre-Dame, Montreal, Canada

W. JOSEPH MCCUNE, MD • Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI

NILAMADHAB MISHRA, MD • Section on Rheumatology and Clinical Immunology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC

LARRY W. MORELAND, MD· Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL

JOHN D. MOUNTZ, MD, PHD· Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham and the Birmingham Veterans Administration Medical Center, Birmingham, AL

LEE M. NADLER· Department of Adult Oncology, Dana Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA

JEAN-PIERRE PELLETIER, MD • Rheumatic Disease Unit, Universite de Montreal, and Osteoarthritis Research Unit, Centre Hospitalier de l'Universite de Montreal, Hopital Notre-Dame, Montreal, Canada

ANDRAS PERL, MD, PHD • Section of Rheumatology, Department of Medicine, State University of New York Health Science Center, College of Medicine, Syracuse, NY

Contributors

HARRIS PERLMAN • Division of Rheumatology, Northwestern University Medical School, Chicago, IL

xiii

ERIK J. PETERSON, MD • Division of Rheumatology, Department of Medicine, University of Pennsylvania and the Abramson Family Cancer Research Institute, Philadelphia, PA

MICHAEL H. PILLINGER, MD· Division of Rheumatology, Department of Medicine, New York University School of Medicine, Department of Rheumatology, The Hospital for Joint Diseases, and Department of Rheumatology, Manhattan VA Hospital, New York, NY

RICHARD M. POPE, MD • Division of Rheumatology, Northwestern Multipurpose Arthritis and Musculoskeletal Diseases Center, Northwestern University Medical School, Chicago, IL

A. ROBIN POOLE, PHD, DSc • Departments of Surgery and Medicine, McGill University and Shriners Hospitals for Children, Montreal, Canada

PAMELA B. ROSENTHAL, MD • Divison of Rheumatology, Department of Medicine, New York University School of Medicine, and Department of Rheumatology, The Hospital for Joint Diseases, New York, NY

GINETTE TARDIF, PHD • Osteoarthritis Research Unit, Centre Hospitalier de l'Universite de Montreal, Hopital Notre-Dame, Montreal, Canada

PETROS TSIPOURAS, MD • Department of Pediatrics, University of Connecticut Health Center, Farmington, CT

GEORGE C. TSOKOS, MD· Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, and Division of Rheumatology and Immunology, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD

CHARLES S. VIA, MD • Division of Rheumatology, Department of Medicine, University of Maryland School of Medicine, and Baltimore Veterans Affairs Medical Center, Baltimore, MD

SHARON M. WAHL, PHD • Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institute of Health, Bethesda, MD

GINETTE WEBB, PHD • Joint Diseases Laboratory, Shriners Hospitals for Children and Department of Surgery, McGill University, Montreal, Canada

MARK H. WENER, MD • Immunology Division, Department of Laboratory Medicine, and Rheumatology Division, Department of Medicine, University of Washington, Seattle, WA

CORNELIA M. WEYAND, MD • Division of Rheumatology, Department of Medicine, Mayo Clinic and Foundation, Rochester, MN

HENRY K. WONG, MD • Department of Dermatology, and Division of Rheumatology and Immunology, Department of Medicine, Uniformed Services University for the Health Sciences, Bethesda, MD, and Department of Cellular Injury, Walter Reed Army Institute of Research, Washington, DC

TIMOTHY M. WRIGHT, MD • Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh Arthritis Institute, University of Pittsburgh, Pittsburgh, PA

DAVID E. YOCUM, MD· Arizona Arthritis Center, University of Arizona, Tucson, AZ HUANG-GE ZHANG, PHD, DVM • Division of Clinical Immunology and Rheumatology,

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL TONG ZHOU, MD· Division of Clinical Immunology and Rheumatology, Department of

Medicine, University of Alabama at Birmingham, Birmingham, AL