Case studies in immunology: a clinical companion: autoimmune lymphoproliferative syndrome (ALPS) PDF
Preview Case studies in immunology: a clinical companion: autoimmune lymphoproliferative syndrome (ALPS)
Autoimmune Lymphoproliferative Syndrome (ALPS) • Harvard Medical School This edition published in the Taylor & Francis e-Library, 2009. To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk. Vice President: Denise Schanck Senior Editor:Janet Foltin Text Editor:Eleanor Lawrence Assistant Editor:Sigrid Masson Editorial Assistant:Katherine Ghezzi Senior Production Editor:Simon Hill Copyeditor: Bruce Goatly Indexer:Merrall-Ross International Ltd. Illustration:Blink Studio Layout:Georgina Lucas © 2008 by Garland Science, Taylor & Francis Group, LLC This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. Every attempt has been made to source the figures accurately. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. All rights reserved. No part of this book covered by the copyright herein may be reproduced or used in any format in any form or by any means—graphic, electronic, or mechanical, including photocopying, recording, taping, or information storage and retrieval systems—without permission of the publisher. 10-digit ISBN 0-8153-4145-8 (paperback) 13-digit ISBN 978-0-8153-4145-1 (paperback) Library of Congress Cataloging-in-Publication Data Geha, Raif S. Case studies in immunology : a clinical companion / Raif Geha, Fred Rosen. -- 5th ed. p. ; cm. Rosen's name appears first on the earlier edition. Includes index. ISBN 978-0-8153-4145-1 1. Clinical immunology--Case studies. I. Rosen, Fred S. II. Title. [DNLM: 1. Immune System Diseases--Case Reports. 2. Allergy and Immunology-- Case Reports. 3. Immunity--genetics--Case Reports. WD 300 G311c 2007] RC582.R67 2007 616.07'9--dc22 2007002977 ISBN 0-203-85365-2 Master e-book ISBN Published by Garland Science, Taylor & Francis Group, LLC, an informa business 270 Madison Avenue, New York, NY 10016, USA, and 2 Park Square, Milton Park, Abingdon, OX14 4RN, UK. Taylor & Francis Group, an informa business Visit our web site at http://www.garlandscience.com iii Preface The science of immunology started as a case study. On May 15, 1796 Edward Jenner inoculated a neighbor’s son, James Phipps, with vaccinia (cowpox) virus. Six weeks later, on July 1, 1796, Jenner challenged the boy with live smallpox and found that he was protected against this infection. During its 208 year history the basic science of immunology has been closely related to clinical observations and has shed light on the pathogenesis of disease. The study of immunology provides a rare opportunity in medicine to relate the findings of basic scientific investigations to clinical problems. The case histories in this book are chosen for two purposes: to illustrate in a clinical context essen- tial points about the mechanisms of immunity; and to describe and explain some of the immunological problems often seen in the clinic. For this fifth edition, we have added five completely new cases that illustrate both recently discovered genetic immunodeficiencies and some more familiar and common diseases with interesting immunology. We have revised other cases to add newly acquired information about these diseases. Fundamental mechanisms of immunity are illustrated by cases of genetic defects in the immune system, immune complex diseases, immune mediated hypersensitivity reactions and autoimmune and alloimmune diseases. These cases describe real events from case histories, large- ly but not solely drawn from the records of the Boston Children’s Hospital and the Brigham and Women’s Hospital. Names, places, and time have been altered to obscure the identity of the patients described; all other details are faithfully repro- duced. The cases are intended to help medical students and pre-medical students to learn and understand the importance of basic immunological mechanisms, and particularly to serve as a review aid; but we hope and believe they will be use- ful and interesting to any student of immunology. Each case is presented in the same format. The case history is preceded by basic scientific facts that are needed to understand the case history. The case history is followed by a brief summary of the disease under study. Finally there are several questions and discussion points that highlight the lessons learned from the case. These are not intended to be a quiz but rather to shed further light on the details of the case. The Garland Science website (www.garlandscience.com) now provides instruc- tors who adopt Case Studieswith a link to Garland Science Classwire, where the textbook art can be found in a downloadable, web-ready format, as well as in PowerPoint-ready format. We are grateful to Dr. Peter Densen of the University of Iowa for C8 deficiency case material, Dr. Sanjiv Chopra of Harvard Medical School for the case on mixed essential cryoglobulinemia and Dr. Peter Schur of the Brigham and Women’s Hospital for the rheumatoid arthritis case. We also thank Dr. Jane Newburger of the Boston Children’s Hospital for the case on rheumatic fever and Dr. Eric Rosenberg of the Massachusetts General Hospital for the AIDS case. We are also greatly indebted to our colleagues Drs. David Dawson, Susan Berman, Lawrence Shulman and David Hafler of the Brigham and Women’s Hospital, to Dr. Razzaque Ahmed of the Harvard School of Dental Medicine, to Drs. Ernesto Gonzalez and Scott Snapper of the Massachusetts General Hospital and to Drs. Peter Newburger and Jamie Ferrara of the Departments of Pediatrics of the University of Massachusetts and the University of Michigan and Dr. Robertson Parkman of the Los Angeles Children’s Hospital as well as Henri de la Salle of the Centre régional de Transfusion sanguine in Strasbourg and Professor Michael iv Levin of St. Mary’s Hospital, London for supplying case materials. Our colleagues in the Immunology Division of the Children’s Hospital have provided invaluable service by extracting summaries of long and complicated case histories; we are particularly indebted to Drs. Lynda Schneider, Leonard Bacharier, Francisco Antonio Bonilla, Hans Oettgen, Jonathan Spergel, Rima Rachid, Scott Turvey, Jordan Orange, Eamanuela Castigli, Andrew McGinnitie, Marybeth Son, Melissa Hazen, Douglas McDonald and John Lee, and to Lilit Garibyan, third year medical student at Harvard Medical School, in constructing several case histories. In the course of developing these cases, we have been indebted for expert and pedagog- ic advice to Fred Alt, Mark Anderson, John Atkinson, Hugh Auchincloss, Stephen Baird, Zuhair K. Ballas, Leslie Berg, Corrado Betterle, Kurt Bloch, Jean-Laurent Casanova, John J. Cohen, Michael I. Colston, Anthony DeFranco, Peter Densen, Ten Feizi, Alain Fischer, Christopher Goodnow, Edward Kaplan, George Miller, Luigi Notarangelo, Peter Parham, Jaakko Perheentupa, Jennifer Puck, Westley Reeves, Patrick Revy, Peter Schur, Anthony Segal, Lisa Steiner, Stuart Tangye, Cox Terhorst, Emil Unanue, André Veillette, Jan Vilcek, Mark Walport, Fenella Woznarowska, and John Zabriskie. Eleanor Lawrence has spent many hours honing the prose as well as the content of the cases and we are grateful to her for this. We would also like to acknowledge the Garland Science team for their work on the fifth edition. A note to the reader The cases presented in this book have been ordered so that the main topics addressed in each case follow as far as possible the order in which these topics are presented in the seventh edition of Janeway’s Immunobiology by Kenneth Murphy, Paul Travers, and Mark Walport. However, inevitably many of the early cases raise important issues that are not addressed until the later chapters of Immunobiology. To indicate which sections of Immunobiologycontain material relevant to each case, we have listed on the first page of each case the topics cov- ered in it. The color code follows the code used for the five main sections of Immunobiology: yellow for the introductory chapter and innate immunity, blue for the section on recognition of antigen, red for the development of lympho- cytes, green for the adaptive immune response, purple for the response to infec- tion and clinical topics, and orange for methods. Dedication This fifth edition is dedicated to Fred Rosen (1935-2005). Fred dedicated his career of more than 50 years to the investigation and care of patients with prima- ry immunodeficiency disease. Above all, he loved to teach and he did so superbly, aided by an encyclopedic knowledge of immunology, an incisive intelligence, an incredible memory, and charisma combined with an aura of authority. Fred had an enormous influence on many generations of both basic and clinical immunol- ogists. This book is his brainchild and his contribution to it will be sorely missed. v CONTENTS Case 1 Congenital Asplenia Case 2 Chronic Granulomatous Disease Case 3 Leukocyte Adhesion Deficiency Case 4 Hereditary Angioneurotic Edema Case 5 Factor I Deficiency Case 6 Deficiency of the C8 Complement Component Case 7 Hereditary Periodic Fever Syndromes Case 8 Interleukin 1 Receptor-associated Kinase 4 Deficiency Case 9 X-linked Hypohydrotic Ectodermal Dysplasia and Immunodeficiency Case 10 X-linked Agammaglobulinemia Case 11 X-linked Hyper IgM Syndrome Case 12 Activation-induced Cytidine Deaminase (AID) Deficiency Case 13 Common Variable Immunodeficiency Case 14 X-linked Severe Combined Immunodeficiency Case 15 Adenosine Deaminase Deficiency Case 16 Omenn Syndrome Case 17 MHC Class I Deficiency Case 18 MHC Class II Deficiency Case 19 Multiple Myeloma Case 20 T-Cell Lymphoma Case 21 Interferon-gReceptor Deficiency Case 22 Wiskott-Aldrich Syndrome Case 23 X-linked Lymphoproliferative Syndrome Case 24 Autoimmune Lymphoproliferative Syndrome (ALPS) Case 25 Immune Dysregulation, Polyendocrinopathy, Enteropathy X-linked Disease Case 26 Toxic Shock Syndrome Case 27 Acute Infectious Mononucleosis Case 28 Mixed Essential Cryoglobulinemia Case 29 Rheumatic Fever Case 30 Lepromatous Leprosy Case 31 Acquired Immune Deficiency Syndrome (AIDS) vi Case 32 Acute Systemic Anaphylaxis Case 33 Allergic Asthma Case 34 Atopic Dermatitis Case 35 Drug-Induced Serum Sickness Case 36 Celiac Disease Case 37 Contact Sensitivity to Poison Ivy Case 38 Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Case 39 Autoimmune Hemolytic Anemia Case 40 Myasthenia Gravis Case 41 Pemphigus Vulgaris Case 42 Rheumatoid Arthritis Case 43 Systemic Lupus Erythematosus Case 44 Multiple Sclerosis Case 45 Hemolytic Disease of the Newborn Case 46 A Kidney Graft for Complications of Autoimmune Insulin-Dependent Diabetes Mellitus Case 47 Graft-Versus-Host Disease 1 Autoimmune Lymphoproliferative Syndrome (ALPS) Increased survival of lymphocytes as a result of a mutation in Fas. When antigen-specific lymphocytes are activated through their antigen receptors, they undergo blast transformation and then begin to increase their numbers exponentially by cell division. This clonal expansion can continue for up to 7 or 8 days, so that lymphocytes specific for the infecting antigen increase vastly in number and can come to predominate in the population. In the response to certain viruses, 50% or more of the CD8 T cells at the peak of the response are specific for a single virus-derived peptide:MHC class I complex. After clonal expansion, the activated lymphocytes undergo their final differentiation into effector cells; these remove the pathogen from the body and so terminate the antigenic stimulus. When an infection has been overcome, activated effector T cells are no longer needed, and cessation of the antigenic stimulus prompts them to undergo programmed cell death, or apoptosis (Fig. 24.1). Apoptosis is widespread in Topics bearing on the immune system and can be induced by several mechanisms; for example, this case: the granule proteins released by cytotoxic T cells kill their target cells by inducing apoptosis.Another well defined apoptotic pathway is that triggered Apoptosis by the interaction of the receptor molecule Fas with its ligand, called Fas ligand Fas–Fas ligand (FasL) (Fig. 24.2), which induces apoptosis in the Fas-bearing cell. FasL is a interactions member of the tumor necrosis factor (TNF) family of membrane-associated cytokines, and Fas is a member of the TNF receptor (TNFR) family. Both Fas TUNEL staining and FasL are normally induced on lymphocytes and other cell types during Autoimmune disease the course of an adaptive immune response. Apoptosis induced by cytotoxic T cells bearing FasL is a minor mechanism of cytotoxicity, whereas apoptosis Lymphocyte activation in lymphocytes themselves, induced through Fas, appears to be an important Lymphocyte survival mechanism of lymphocyte homeostasis, as this case shows. 2 Autoimmune Lymphoproliferative Syndrome (ALPS) a b c Fig. 24.1 Apoptosis.Apoptosis is a form of induced ‘cell suicide’ in retained, in contrast to the necrotic cell in the upper part of the same which the cell undergoes chromatin compaction and DNA fragmentation, field. In late stages of apoptosis (panel c), the cell nucleus (middle followed by cell shrinkage and internal degradation. Panel (a) shows a cell) is very condensed, no mitochondria are visible, and the cell has healthy cell with a normal nucleus. Early in apoptosis (panel b), the lost much of its cytoplasm and membrane through the shedding of chromatin in the nucleus becomes condensed (red) and, although the vesicles. Photographs (¥3500) courtesy of R. Windsor and E. Hirst. cell sheds membrane vesicles, the integrity of the cell membrane is The case of Ellen O’Hara: uncontrolled lymphocyte proliferation in the absence of infection or malignancy. Ellen O’Hara was born after a normal and uncomplicated pregnancy, was breast 1e8n-lmarognetdh -spollede ngi.r Ol,rder fmaendo e,n nathnlasdr goreleddc, e sdivpuelreidne gnh ea(rs rprooleuunttiionnmee ecimghaemlcyuk)n -auinzpad bt ieyox nhtsee nrw spiitvehedo iueanttr laiacnrigya neam,d svehenert s woefa rhse eafroc ultyinomdnp sth.o A nhtoa 1dv8ees blood tests. (lymphadenopathy) (Fig. 24.3). According to her parents, she had had no unusual infections and appeared to be growing and developing normally. Fig. 24.2 Binding of FasL to Fas initiates Activated caspase 3 cleaves the process of apoptosis in the Fas- Binding of FasL to Fas causes The adaptor proteins recruit and I-CAD, the inhibitor of CAD, binding of death domain- activate caspase 8, which bearingcell.Binding of trimeric FasL to containing adaptor proteins cleaves caspase 3 which is released to enter the nucleus and cleave DNA trimeric Fas brings the death domains in the Fas cytoplasmic tails together. A number of adaptor proteins containing death domains bind to the death domains of Fas, in particular the protein FADD, which in turn interacts through a second death domain with the protease caspase-8. Clustered caspase-8 can transactivate, cleaving caspase-8 itself to release an active caspase domain that in turn can activate other caspases. The ensuing caspase cascade culminates in the death FADD activation of the caspase-activatable DNase domains active (CAD), which is present in all cells in an caspase 8 inactive cytoplasmic form bound to an inhibitory protein called I-CAD. When I-CAD pro- caspase is broken down by caspases, CAD can enter 8 active caspase 3 the nucleus where it cleaves DNA into the 200 base pair fragments that are pro- caspase 3 CAD I-CAD characteristicof apoptosis. Autoimmune Lymphoproliferative Syndrome (ALPS) 3 Fig. 24.3 Lymphadenopathy in ALPS. Young girl with ALPS with very enlarged lymph nodes in her neck. Photograph courtesy of Jennifer Puck. Laboratory tests revealed that Ellen’s white blood cell count was 12,500 mml–1, of ww40he–ric2eh0 a0 9l)l 1 ae7nl5ed vw aIgeteAred, :1l yI6gm6G0p, h m4o0gc0 y0dt lem–s1.g (F ndlool–rw1m (canylo t3rom0m0a0el –t5r7y25 00a–0n1)a5. l0yH0se)ir;s sIogefMr uh, me4r0 il0my mmmpguh ndoolc–g1yl t(oenbsourlminasl Innucrmeabseerd o Bf D ceNll sT, lcaerllgse. revealed that 29% were CD19-positive B cells (normal 5–15%; CD19 is a component of the B-cell co-receptor complex) and 65% were CD3-positive T cells (normal 61–84%; CD3 is a component of the T-cell receptor complex). Of the CD3-positive T cells, 14% carried the co-receptor protein CD4 and 18% the co-receptor CD8. She thus had many CD3+4–8–T cells—so-called double-negative (DN) T cells (normally, DN T cells are either absent or less than 2% of circulating T cells). A biopsy of a lymph node from Ellen’s neck showed extensive enlargement of the follicles (hyperplasia) and a marked increase in the numbers of immunoblasts and plasma cells in the paracortical area. No infectious agents were cultured from the lymph node, despite the fact that the observed changes resembled those caused by a viral infection. Although more than 50% of the T cells in the lymph node were double negatives, no chromosomal abnormality was found on karyotyping, and there was no evidence of oligoclonality of the T-cell receptor, thus ruling out a mIlynma tlhpigehn oaapbnrscoeylnif(ceserea eoti fvC eeav sdideis e2en0ac)s.ee owf ains fdeciatgionno soer dm aanlidg nEallnetn d riesceeaisvee,d a tuhteo iamnmti-uinnfelammatory Noro mevaidliegnncaen ocfy .i nAfLecPtSio?n steroid prednisone and the immunosuppressant drug cyclosporin A. Her lymph nodes rapidly reduced in size following this therapy but enlarged again when therapy was discontinued. Ellen continued to grow and develop normally, and when she reached adolescence the size of her lymph nodes spontaneously decreased. At 18 years of age, repeat blood counts revealed that her platelet count was 75,000 mml–1 (normal 150,000–250,000). An autoantibody to platelets was found in her serum. A diagnosis of idiopathic thrombocytopenic purpura (low platelet numbers accompanied by red or purplish-red spotty skin discoloration due to local hemorrhages) was made. She was treated with the steroid dexamethasone, and the condition resolved. At age 32, Ellen’s blood neutrophil count fell to <1000 mml–1 (normal 2500–5000). She was found to have developed an autoantibody against granulocytes.
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