Case Studies in Immunology: Acute Infectious Mononucleosis: a Clinical Companion

16 Pages·2010·1.172 MB·English

by  Geha, Raif, Rosen, FRED

Acute Infectious Mononucleosis
•
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 0-203-85368-7 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
Acute Infectious
Mononucleosis
Cytotoxic T cells terminate viral infection.
All viruses, and some bacteria, multiply inside infected cells; indeed, viruses
are highly sophisticated parasites that do not have a complete biosynthetic or
metabolic apparatus of their own and, in consequence, must replicate inside
a living cell. Once inside a cell, a pathogen is not accessible to antibodies and
has to be eliminated by other means.
Some intracellular bacteria live and multiply in membrane-bound phagosomes
within macrophages and are killed by antibacterial agents released into these
vacuoles after macrophage activation by CD4 T 1 cells (see for example Case
H
Topics bearing on
30). Viruses, in contrast, together with those bacteria that live in the cytosol,
this case:
can be eliminated only by destruction of the infected cell itself. This role in
host defense is fulfilled by the cytotoxic CD8 T cells of adaptive immunity and Activation of cytotoxic
the natural killer (NK) cellsof innate immunity. T cells
Cell killing by cytotoxic
CD8 cytotoxic T cells kill infected cells by recognizing foreign, pathogen- T cells
derived peptides that are transported to the cell surface bound to MHC
Processing and
class I molecules (see Fig. 17.1). The peptides carried by MHC class I mole-
presentation of
cules come from the degradation of proteins in the cytosol and so cytotoxic T
cytosolic antigens
cells act against pathogens whose proteins are found in the cytosol of the host
2 Acute Infectious Mononucleosis
Viral proteins synthesized Peptide fragments ofviralproteins Bound peptides transported by
Virus infects cell
in cytosol bound by MHCclass IinER MHC class I to the cell surface
Cytosol
Endoplasmic
Cytosol
reticulum
Nucleus
Fig. 27.1 MHC class I molecules present antigen derived from transported into the endoplasmic reticulum, where they are bound by
proteins in the cytosol. In cells infected with viruses, viral proteins MHC class I molecules, which then deliver the peptides to the cell
are synthesized in the cytosol. Peptide fragments of viral proteins are surface.
cell at some stage in their life-cycle (Fig. 27.1). The critical role of cytotoxic
CD8 T cells in host defense is seen in the increased susceptibility of animals
T cell recognizes infected cell
artificially depleted of cytotoxic T cells to many viral and intracytosolic bac-
terial infections. Mice and humans lacking the MHC class I molecules that
present antigen to CD8 cells are also more susceptible to such infections.
Cytotoxic T cells kill their infected targets with great precision and neatness,
by inducing apoptosis in the infected cell while sparing adjacent normal cells;
this strategy minimizes tissue damage (Fig. 27.2). CD8 cytotoxic T cells release
two types of preformed cytotoxin—the fragmentins or granzmes, which seem
able to induce apoptosis in any type of target cell, and the protein perforin,
which is thought to act as a translocator protein to enable granzymes to cross
the membrane of the target cell (Fig. 27.3). A membrane-bound molecule, the
Fas ligand, which is expressed on CD8 T cells as well as on some CD4 T cellscan
also induce apoptosis by binding to Fas on a limited range of target cells.
Infected cell is programmed for death
Together, these properties allow the cytotoxic T cell to attack and destroy
virtually any infected cell. Cytotoxic CD8 T cells also produce the cytokine
interferon (IFN)-g; this cytokine inhibits viral replication, induces MHC
class I expression, and also activates macrophages. As well as combating
infection by viruses and intracytosolic bacteria, CD8 T cells are important in
controllingsome protozoal infections; they are crucial, for example, in host
defense against Toxoplasma gondii, an intracellular protozoan.
The importance of cytotoxic T cells in the control of viral replication is
highlighted by many aspects of Epstein–Barr virus (EBV) infection,which is
described in this case study. EBV (also known as human herpesvirus 4) is a
member of the virus family Herpesviridae. It has a double-stranded linear
DNA genome enclosed in an icosahedral capsid and a lipid envelope and
replicates its DNA genome in the host cell nucleus. EBV infects only humans
Neighboring uninfected cells are not killed
and is one of the most successful infective agents on its obligate host. It can
even be thought of as a commensal that only seldom causes injury to the
host; anywhere from 60–98% of healthy adults show serological evidence of
infection with EBV. The virus infects mainly B cells and epithelial cells.
Fig. 27.2 Cytotoxic T cells kill target cells Specific recognition by the T-cell receptor
bearing specific antigen while sparing identifies which target cell to kill, and the
neighboring uninfected cells. All the cells polarized release of cytotoxic granules (see
in a tissue are susceptible to the induction of Fig. 27.3) ensures that neighboring cells are
apoptosis by the cytotoxins of armed effector spared.
CD8 T cells but only infected cells are killed.
Acute Infectious Mononucleosis 3
Fig. 27.3 The cytotoxic granules of
cytotoxic T cells are released in a
polarized fashion. Perforin molecules, as
G well as several other effector molecules, are
M contained in the granules of cytotoxic T cells
Go (panel a: G, granules; N, nucleus; M,
N mitochondria; Go, Golgi apparatus). When a
CD8 cytotoxic T cell recognizes its target, the
Go
granules are released onto the target cell
(panel b, bottom right quadrant).
G N
Photographs courtesy of E. Podack.
G
G
G
M
G
M
a b
The case of Emma Bovary: a bad sore throat from a
B-cell infection.
Emma Bovary was a healthy 15-year-old when she suddenly developed a very sore
throat accompanied by fever and malaise. Her throat was so swollen she had
difficulty swallowing. Over the next few days the fever waxed and waned, her sore
throat became worse and she became progressively more tired and anorectic (lost
her appetite). On the third day of illness her pediatrician noted severe pharyngitis
and took a throat culture for bb-hemolytic streptococci; the culture proved negative.
Emma’s symptoms persisted, and she was unable to eat as she could hardly
swallow. She said she had no difficulty breathing but that her left upper abdomen
fbhfeeualwtdt sddnliaiodgy hpnsta.olyrtt ihucanuvclaeor ms pufhocyrhts asicbealvele .s rEyemm smypmtao’pmst os1m,- yasen.a dHr -seoe lwde mabsre odmt hetoer err lebyce locisvatemlere sc siol lma anptd lte hfteeel ltys w aamafrteem rt. i amHee, 1w5th-ityrheoa asrte,- vfoeelrdvee frse omarneadle
malaise.
On physical examination on the tenth day of illness, Emma appeared very ill. She
had a high temperature (38.2∞∞C), pulse rate of 84, respiratory rate of 18, and blood
pressure 85/55. Her mouth was dry and her tonsils were red and enlarged. They met
in the midline, leaving a passage of only 2 ¥¥2 cm approximately. Palatal petechiae
(pleeavdnoreglsgrateyere sgbrsteiem odnirna;o cgldtlhe ehpersvea timlwicppaeoa lwrbr erllayhe 2sma 2 g¥¥ep ecah2sms nicu loybmn dedp.el eaoHsrlw pe wt raht ebhaerleb eem d rsuoiugwnmchdooetel snlcrea on)tf hes caltetoan lulsd eomlf dttfae tbc rnaoegdn siesndtrea. telT(h lnmhye.me alH irpsvgepehrirnla e a.dwenenatnes wor iepaonasrl t aaharnlygsd)eo; dth, ethe Saiomnnr deon ntsehowcnkro.ou laIlcnetl,nef eot clesytmimiso?pupehsr antoudrees
A blood test gave a white blood cell count of 18,590 mml–1with 39% neutrophils, 27%
lymphocytes, 22% atypical lymphocytes (very high), and 11% monocytes (high); her