Case studies in immunology: a clinical companion: lepromatous leprosy

15 Pages·1.283 MB·English

by  Geha, Raif;Rosen, Fred S

X-linked Lymphoproliferative
Syndrome
•
Harvard Medical School
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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 0-203-85364-4 Master e-book ISBN
Published by Garland Science, Taylor & Francis Group, LLC, an informa business
270 Madison Avenue, New York, NY 10016, USA, and
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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
X-linked
Lymphoproliferative
Syndrome
A defect in the immune response to a virus.
Viruses pose a constant challenge to our immune system. Unable to repro-
duce on their own, they have evolved as parasites, capable of residing within
living cells whose biosynthetic machinery they subvert for their own repro- Topics bearing on
duction. An effective two-pronged immune response to these hidden this case:
invaders is to kill the host cells within which they reside by means of the cyto-
NK-cell activating
toxic cells of the immune system, and to reduce the number of extracellular
receptors and killer
virus particles by means of antibodies. function
NK T cells
Both innate and adaptive immune responses control viral infections. The
natural killer (NK) cells of innate immunity (Fig. 23.1)are constantly on sur- Cell signaling from
veillance for cells with telltale markers of viral infection. These cells are large tyrosine kinase-
granular cells of the lymphocyte lineage, which differ from cytotoxic T lym- associated receptors
phocytes in not expressing antigen-specific receptors. Instead they carry a
Activation and function
number of receptors that recognize virus-infected cells in other ways and,
of cytotoxic T cells
like cytotoxic T cells, release cytotoxic proteins that induce apoptosis and
2 X-linked Lymphoproliferative Syndrome
death of the virus-infected cell. These proteins include perforin and
Natural killer (NK) cell
granzyme, which are also released by cytotoxic CD8 T cells. This response
does not require any previous immunological experience with the virus and
is particularly important when an individual first encounters a virus.
In the adaptive immune response, virus-specific cytotoxic T lymphocytes are
generated during the primary immune response to the virus and specifically
kill infected cells through the release of cytotoxic granules similar to those of
NK cells. Naive virus-specific CD8 T cells are activated to their effector status
as cytotoxic T cells through engagement of the T-cell antigen receptor, which
interacts with a complex of antigen-derived peptide and major histocompat-
ibility complex (MHC) class I molecule at the surface of a cell presenting viral
antigens. For naive CD8 T cells, however, engagement of T-cell receptors,
although necessary, is not sufficient for activation. Strong co-stimulation by
antigen-presenting dendritic cells together with co-stimulatory help from
activated CD4 T cells are usually required to activate naive cytotoxic T cells.
Releases cytotoxic granules that kill some During the primary immune response to viruses, memory cytotoxic T cells
virus-infected cells are also produced. In the event of reexposure to the same virus, either by
reinfection from the environment or by reactivation of virus latent in the
body, these cytotoxic T cells rapidly recognize and kill infected host cells
Fig. 23.1 Natural killer (NK) cells.These
displaying viral antigens. Equally important to antiviral immunity are virus-
are large granular lymphocyte-like cells with
specific primary and secondary antibody responses.
important functions in innate immunity.
Although lacking antigen-specific receptors,
they can detect and attack certain virus- In this case we look at the effects of a deficiency in an intracellular signaling
infected cells. Photograph courtesy of molecule found in both NK cells and T cells on the ability of the immune sys-
N.Rooney and B. Smith. tem to control infection by the Epstein–Barr virus (EBV). EBV infects epithe-
lial cells and B cells and is present in small numbers in most humans over the
age of 15 years. Its expansion is usually well controlled by cytotoxic T cells
and NK cells. A primary EBV infection triggers the activation and cell division
of B cells infected by the virus. The infected B cell expresses a number of viral
antigens that are targets for specific cytotoxic responses by NK cells and CD8
T cells that keep the proliferation of infected B cells under control. In most
people, EBV infection remains asymptomatic, but in a minority of cases (a
subset of patients who first encounter the virus in adolescence) it gives rise to
acute infectious mononucleosis, which eventually subsides within a span of
6–10 weeks. The normal course of an EBV infection in a healthy teenager is
described in Case 27, and you may find it helpful to read that case before
embarking on this one. After resolution of the acute infection, the virus per-
sists in a latent form in B cells, salivary glands, and epithelial cells of the nose
and throat, and can be shed in saliva. Occasional reactivation of the virus
later in life is rapidly brought under control by EBV-specific memory cyto-
toxic T cells. This cellular immune surveillance is critical in maintaining the
balance between host and virus. Primary and acquired deficiencies of T-cell
function are associated with a marked susceptibility to lethal EBV infection.
For example, in very rare instances acute EBV infection in boys is not con-
tained, and results in a failure to eliminate the virus that is accompanied by
massive overproliferation of lymphocytes (lymphoproliferation), overpro-
duction of cytokines, liver and bone-marrow destruction, B-cell lymphoma
and/or dysgammaglobulinemia (selective deficiencies of one or more, but
not all, classes of immunoglobulins), in most cases resulting in death. Such
susceptibility to overwhelming infection can be inherited through unaffected
females, an indication that it is carried by a gene on the X chromosome, and
the condition is called X-linked lymphoproliferative syndrome (XLP). The
gene involved has been found to encode an intracellular signaling protein
called SAP, and defects in SAP are responsible for XLP.
X-linked Lymphoproliferative Syndrome 3
The case of Nicholas Nickleby: inefficient killing of
EBV-infected B cells by cytotoxic lymphocytes.
Nicholas was brought to the pediatrician at 5 years old because of several days of
fever (38–39∞∞C). He had no cough, runny nose, rash, diarrhea, or any other
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Finally, after 6 weeks of illness, Nicholas complained of abdominal pain and was
referred to the Children’s Hospital.
The past medical history was significant, revealing problems with persistent and
recurrent middle ear infections (otitis media) as well as several episodes of bacterial
pneumonia between the ages of 2 and 3 years. Immunological evaluation at the time
had revealed decreased blood levels of IgG of 314 mg dl–1(normal 600–1500 mg
dl–1), and normal IgA and IgM. At the time, Nicholas was briefly treated with History of recurrent
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to Children’s Hospital. The family history was notable for the presence of a maternal
uncle with persistent unexplained low blood platelet count (thrombocytopenia).
Nicholas’s maternal grandfather had recurrent lymphomas.
On admission to hospital, Nicholas appeared tired but not acutely ill. His
temperature was 38.5∞∞C and his heart rate, respiration, and blood pressure were all
normal. His height and weight were both in the 25th percentile for age. A few
scattered small skin hemorrhages (petechiae) were noted on his legs and feet.
Several lymph nodes were palpable in his neck, and these appeared significantly
larger than on previous examinations. Supraclavicular, axillary, or inguinal lymph
nodes were not enlarged. The tonsils were moderately enlarged but were not red,
and there was no evidence of inflammation. The heart sounds were normal. The
abdomen was moderately distended but soft, and slightly tender in the right upper
quadrant. The liver was enlarged and its edge was palpable 4 cm below the right
costal margin.
Laboratory evaluation showed a mild anemia with a hematocrit of 28% (normal
35–40%). The white blood cell count was 6400 mml–1 (normal 5–10,000 mml–1) and the
platelet count was decreased at 47,000 mml–1(normal 150–200,000 mml–1). The count of
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Epstein–Barr nuclear antigen (EBNA) and early antigen (EA) were undetectable,
consistent with an acute EBV infection (see Fig. 27.4). Circulating EBV genome was
detected in Nicholas’s blood cells by the polymerase chain reaction (PCR).
A chest X-ray showed clear lungs and a normal-sized heart, but the lymph nodes in
the mediastinum were enlarged. Ultrasound examination of the abdomen revealed a
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