Case Studies in Immunology: Deficiency of the C8 Complement Component: a Clinical Companion

14 Pages·2010·1.356 MB·English

by  Geha, Raif, Rosen, FRED

Deficiency of the C8 Complement
Component
•
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
ISBN 0-203-85347-4 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
Deficiency of the
C8 Complement
Component
A loss of the lytic function of complement.
The complement system of plasma proteins is an effector mechanism of both
innate and adaptive immunity that tags pathogens for destruction (see Cases
4 and 5). The assembly of the so-called terminal components of the
complement system (C5 through C9; Fig. 6.1) on the surface of a bacterial cell
or a human cell results in the formation of protein complexes that make
pores in the cell membrane, leading to cell lysis and death.
Assembly of the terminal complex is initiated when the fifth component of
complement, C5, binds to the cell surface and is cleaved by C5 convertase.
This reaction releases C5a, a peptide with potent chemotactic activity, from
the a, or heavy chain, of C5. The rest of the molecule, C5b, binds C6 to
initiate the formation of the so-called membrane-attack complex of terminal
complement components. The C5b6 complex binds one C7 molecule, result-
ing in the exposure of a hydrophobic site on C7 that enables the complex to
sink partway into the lipid bilayer of a cell membrane. Complement compo-
nent C8, unlike the single-chain C6 and C7, is composed of three chains, C8a,
C8b, and C8g. The C8g chain binds to the C5a67 complex and enables the
hydrophobic portion of C8 to embed itself in the cell membrane (Fig. 6.2).
This last event induces the polymerization of 10-16 molecules of C9 to make
a cylindrical structure, the membrane-attack complex, which forms a pore in Topics bearing on
the cell membrane. The diameter of the pore is approximately 100 Å, and this case:
through this channel sodium and water enter the cell, which swells until it
Classical pathway of
bursts (lysis). The cell-surface protein CD59, which is found in most complement activation
mammalian cell membranes, inhibits the action of C8 on C9, thereby
Terminal complement
preventing formation of the membrane-attack complex on the cells of the
components
body but not on those of bacteria.
2 Deficiency of the C8 Complement Component
Fig. 6.1 The terminal complement
The terminal complement components that form the membrane-attack complex
components that assemble to form the
membrane-attack complex.
Native Active
Function
protein component
C5a Small peptide mediator of inflammation (high activity)
C5
C5b Initiates assembly of the membrane-attack system
C6 C6 Binds C5b; forms acceptor for C7
C7 C7 Binds C5b6; amphiphilic complex inserts in lipid bilayer
C8 C8 Binds C5b67; initiates C9 polymerization
Polymerizes to C5b678 to form a membrane-spanning channel,
C9 C9n lysing cell
Curiously, humans with a genetic deficiency in C5, C6, C7, C8, or C9 have
an increased susceptibility to systemically invasive infection with bacteria of
the genus Neisseria. Two common pathogens, N. meningitidis and
N. gonorrhoeae, belong to this genus; the former causes endemic and
epidemic meningitis and the latter the sexually transmitted disease
gonorrhea.
The case of Dolly Oblonsky:recurrent meningococcal
infection leads to the discovery of a complement
deficiency.
Dolly Oblonsky was doing well in her first year at university when she developed a
cough and diarrhea. She felt very tired and achy and went to bed early in her
FtreeCemmadalpdlle iepsr hhasytt-uuspidruceiera,np nsltet, iu frfra gnsehenc.tkl,y. dsid(nfiouacfritskrymtm ,)a ,iw tanaordh ryr oye he serfmoopr uoienrnmraegdtc.oe kTtnrh yhcsa eyerta e nrDtmoeeoo xelomltdyf m .2t hoS4oa hrbd(neie nia nscs gbertei elfosafmh.os eHeded d ewp )rir o larelk onsaeodsn mue daar m esrtle oayommt few pe7 itew0tohr/oh4a aka0tu t sh( rcleeeoov rwon etf)for ,ue 3 ast 9hh e.pee2du a° uCltdson ae( ictev hohleeefer v s1.na i2Stuty4ehrdsee) .f eolnt
The nurse noticed a petechial rash (small areas of reddish-purple discoloration) on
Dolly’s chest and urgently summoned the physician on call, Dr Tolstoy. He found
that Dolly had a red throat with moderate enlargement of the tonsils. No other
physical symptoms were apparent except for the neck stiffness and the petechial
rash on her palate, trunk, and extremities. Dr Tolstoy immediately placed an
intravenous needle into a vein on the back of Dolly’s left hand, obtained blood for
blood counts and bacterial cultures, and started intravenous administration of the
antibiotic Cephtriaxone because he suspected meningococcal meningitis. He then
performed a lumbar puncture to obtain cerebrospinal fluid (CSF).
MSteanritn aginttisib?i otics CThSeF bplrooovde dc usltteurrieles bguret wco Nnetaisinseedri a2 0m wenhiinteg ibtildoiosd( mceelnlsin mmglo–1co(acnc uasb)n soerrmoaglrloy uhpig Ch. The
immediately. number; CSF usually contains five or fewer white blood cells mml–1). Dolly’s
hematocrit was 36.5% (slightly low) and her blood white-cell count was 8700
cells mml–1, of which 90% were neutrophils and 10% were lymphocytes.
Deficiency of the C8 Complement Component 3
C5b67 complexes C8 binds to the complex C9 molecules bind to 10–16 molecules of C9
C5b binds C6 and C7 bind to membrane and inserts into the complex bind to form a pore
via C7 the cell membrane and polymerize in the membrane
C8 C9
C6 C7
C5b67
C5b
complex
lipid bilayer
Pathogen
Schematic representation of the
Membranelesions—endon(rings) Membranelesions—sideon(tubes)
membrane-attack complex ‘pore’
15nm
3nm
10nm
Fig. 6.2 Assembly of the membrane-attack complex generates a also serves to induce the polymerization of C9, again with the
pore in the lipid bilayer membrane.The sequence of steps and their exposure of a hydrophobic site. Up to 16 molecules of C9 are then
approximate appearance are shown here in schematic form. C5b added to the assembly to generate a channel 100 Å in diameter in the
triggers the assembly of a complex of one molecule each of C6, C7, membrane. This channel disrupts the bacterial cell membrane, killing
and C8, in that order. C7 and C8 undergo conformational changes the bacterium. The electron micrographs show erythrocyte membranes
that expose hydrophobic domains that insert into the membrane. This with membrane-attack complexes in two orientations, end on and side
complex causes moderate membrane damage in its own right, and on. Photographs courtesy of S. Bhakdi and J. Tranum-Jensen.
Dolly quickly improved on continued intravenous antibiotic therapy. The fever
disappeared, she became alert, and her neck stiffness resolved over the next
72 hours. Blood taken after 24 hours of antibiotic treatment proved sterile on
culture and she was discharged from the infirmary.
Dolly told Dr Tolstoy that she had had meningococcal meningitis in her third year
of high school. She was told at the time that she had positive CSF and blood
cultures for N. meningitidisserogroup Y. Dr Tolstoy suspected that Dolly might
have a complement deficiency and sent a blood sample for a CH assay, which
50
tests the ability of the blood to perform complement-mediated hemolysis. A week
later he received the report: Dolly’s CH was zero, which means that her serum
50
contained no hemolytic complement activity.
Dolly was one of five sisters. Blood samples were obtained from all of them to
assay their CH , which turned out also to be zero in her three younger sisters,
50
aged 9, 14, and 17. The two youngest sisters were well; the 17-year-old sister had
had meningococcal meningitis the year before. An older sister, aged 20, had a
normal CH . The father was unavailable for testing, but the mother proved to have
50
a half-normal CH . The sera of all the sisters and the mother were tested in a
50