Case Studies in Immunology: Immune Dysregulation, Polyendocrinopathy, Enteropathy X-linked Disease: a Clinical Companion

13 Pages·2010·1.265 MB·English

by  Geha, Raif, Rosen, FRED

Immune Dysregulation,
Polyendocrinopathy, Enteropathy
X-linked Disease
•
Harvard Medical School
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© 2008 by Garland Science, Taylor & Francis Group, LLC
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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
Published by Garland Science, Taylor & Francis Group, LLC, an informa business
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ISBN 0-203-85366-0 Master e-book ISBN
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
Immune
Dysregulation,
Polyendocrinopathy,
Enteropathy
X-linked Disease
A failure of peripheral tolerance due to defective
regulatory T cells.
The primary role of the immune system is to recognize pathogens and elimi-
nate them from the body. However, an equally important task is to distin- Topics bearing on
guish potentially dangerous antigens from those that are harmless. Countless this case:
innocuous foreign antigens are encountered every day by the lungs, gut, and
Central tolerance
skin, the interfaces between the body and the environment. Similarly, the
body contains numerous self antigens that might bind to the specific antigen Peripheral tolerance
receptors on B and T cells. Activation of the immune system by such innocu-
Regulatory T cells
ous antigens is unnecessary and may lead to unwanted inflammation.
Allergic and autoimmune diseases are well-known examples of such unwant-
Autoimmunity
ed and potentially destructive responses.
2 Immune Dysregulation, Polyendocrinopathy, Enteropathy X-linked Disease
Normal Immunological ignorance Deletion Inhibition Suppression
APC APC APC APC APC
B7.1 B7.1 FasL
CD28 CD4 Fas CTLA-4 IL-10
TGF-(cid:2)
T cell T cell T cell T cell
Anatomical barrier Treg
CD28 CD4
Activated T cell Ignorant T cell Apoptosis No activation No activation
Fig. 25.1 Mechanisms of peripheral Fortunately, unwanted immune responses are normally prevented or regu-
immunologic tolerance. T cells that are lated by the phenomenon of immunologic tolerance. This is defined as non-
physically separated from their specific responsiveness of the lymphocyte population to the specific antigen, and
antigen—for example, by the blood–brain arises at two stages of lymphocyte development. Central tolerance is the
barrier—cannot become activated, a result of the removal of self-reactive lymphocytes in the central organs; an
circumstance referred to as immunologic
autoimmune disease due to a defect in central tolerance is described in Case
ignorance. T cells that express Fas (CD95)
38. Peripheral tolerance, in contrast, inactivates those T and B cells that
on their surface can receive signals from
escape central tolerance and exit to the periphery. Defects in either central or
cells that express Fas ligand, leading to their
peripheral tolerance can result in unwanted or excessive immune responses.
deletion. The activation of naive Tcells can
be inhibited if the cell-surface protein
CTLA-4 (CD152) binds B7.1 (CD80) on Several mechanisms of peripheral tolerance exist (Fig. 25.1). One whose
antigen-presenting cells (APCs). Regulatory importance is increasingly being recognized is the network of regulatory cells
T cells (mainly CD4 CD25 Foxp3- that prevent or limit the activation of T cells, including self-reactive T cells,
expressing) can inhibit, or suppress, other and the consequent destructive inflammatory processes. When these regula-
Tcells, most probably through the tory cells do not function properly, problems can arise. A key cell type
production of inhibitory cytokines such as responsible for the maintenance of peripheral tolerance is the CD4 CD25 reg-
IL-10 and TGF-b. ulatory T cell (T ), also known as the natural regulatory T cell, which seems
reg
to become committed to a regulatory fate while still in the thymus and repre-
sents a small subset of circulating CD4 T cells (5–10%).
Although these cells were first characterized by their cell-surface CD25 (the a
chain of the IL-2 receptor), this protein also appears on other T cells after
activation. Natural T cells are better characterized by their expression of
reg
the transcription factor Foxp3, which is essential for their specification and
function as regulatory cells. Over the past decade they have emerged as cru-
cial to the maintenance of peripheral tolerance. Neonatal thymectomy in
mice and thymic hypoplasia in humans (DiGeorge syndrome) result in
impaired generation of natural T cells and the development of organ-spe-
reg
cific autoimmune disease. The generation of natural T cells in the thymus
reg
requires interaction with self-peptide:MHC class II complexes on cortical
epithelial cells.
Immune Dysregulation, Polyendocrinopathy, Enteropathy X-linked Disease 3
A second group of regulatory T cells seem to be induced from naive CD4
Tcells in the periphery. They are CD4+CD25–and are heterogeneous, includ-
ing subsets known as T 3, T 1, and a CD4+CD25–Foxp3-positive subset. NK
H R
cells and NK T cells have also been shown to be able to regulate immune
responses. As a group, regulatory cells represent just one mechanism in a
complex system of immunologic tolerance, acting to prevent or rein in
unwanted immune responses.
The following case illustrates how a breakdown in peripheral tolerance as a
result of a defect in regulatory T cells leads to a constellation of allergic symp-
toms, gastrointestinal symptoms, and autoimmune disease in infancy.
The case of Billy Shepherd: a defect in peripheral
tolerance leading to dermatitis, diarrhea, and
diabetes.
Billy was born at full term and developed atopic dermatitis (see Case 34) shortly
after birth. This was treated by skin hydration, local application of hydrocortisone
and antihistamines to control itching, the treatment being only partly successful. At
4in mitioalnlyth gsa oinf eadg ew Beiigllhyt dweevlel,l obpye ndo awn hinistr wacetiagbhlte h waadt efaryll ednia brerhloewa. tAhlet hthoiurgdh c hene thilea dfor Idnefarmnta wtititish, diarrhea,
hgilsu caogsee. Aint t6h em uorninthes. Holed ,w Baisll yd isatganrtoesde dto w diethv etyloppe h1i gdhia bbleotoeds (ginluscuolisne- dleevpeelnsd aenndt aUnndd derialybientge sc.ause?
diabetes mellitus; see Case 46) and was referred by his pediatrician to the
endocrine clinic at the Children’s Hospital.
When first seen at the clinic, Billy weighed 5 kg (the third centile for age is 6.3 kg).
He had diffuse eczema and sparse hair (Fig. 25.2). His cervical and axillary lymph
nodes and spleen were enlarged. Laboratory tests revealed a normal white blood
cell count of 7300 ml–1, normal hemoglobin of 11.3 g dl–1, and a normal platelet
c(noournmt aolf <453%5,)0, 0a0n dm lI–g1E. Twhaes p aelrscoe nelteavgaet eodf ,e aots 1in3o4p5 hIUils m inl– 1th(en obrlmooadl <w5a0s I Uh igmhl– a1)t. 15% Take family history.
Autoantibodies were found against glutamic acid decarboxylase (the GAD65
antigen) and to pancreatic islet cells. Billy was started on insulin therapy, which
controlled his blood glucose level.
Because of the persistent diarrhea and failure to thrive, Billy required parenteral
(intravenous) nutrition to maintain his weight. An endoscopy was ordered to
ascertain the cause of his persistent diarrhea, and a duodenal biopsy revealed
almost total villous atrophy—an absence of villi in the lining of the duodenum—
with a dense infiltrate of plasma cells and T cells (Fig. 25.3).
When Billy’s mother was questioned, she revealed that there had been another
son, who had died in infancy with severe diarrhea and a low platelet count. On the
basis of Billy’s symptoms and the family history, IPEX (immune dysregulation,
polyendocrinopathy, enteropathy X-linked) was suspected. A FACS analysis of
Billy’s peripheral blood mononuclear cells revealed a lack of CD4 CD25 cells as
well as a lack of CD4 Foxp3+cells. Sequencing of Billy’s FOXP3 gene revealed a
missense mutation, confirming the diagnosis.
With the diagnosis established, immunosuppressive therapy, including cyclosporin Fig. 25.2 Eczematous rash on the face of
and tacrolimus, was started. Billy’s diarrhea, glucose control, and eczema all a baby boy with IPEX.Photograph courtesy
improved markedly. After several months, however, his symptoms began to return of Talal Chatila, UCLA.