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CLINICAL
Immunology
PRINCIPLES AND PRACTICE
CLINICAL
Immunology PRINCIPLES AND PRACTICE
SIXTH EDITION
Robert R. Rich, MD
Dean and Professor Emeritus
Medicine
University of Alabama at Birmingham;
Former Senior Vice President for Medicine
School of Medicine
University of Alabama at Birmingham
Birmingham, AL, United States
Jennifer M. Puck, MD
Professor of Pediatrics
University of California San Francisco
San Francisco, CA, United States
© 2023, Elsevier Ltd. All rights reserved.
First edition 1996
Second edition 2001
Third edition 2008
Fourth edition 2013
Fifth edition 2019
Sixth edition 2023
The right of Robert R. Rich, Thomas A. Fleisher, Harry W. Schroeder Jr., Cornelia M. Weyand,
David B. Corry, and Jennifer M. Puck to be identified as authors of this work has been asserted
by them in accordance with the Copyright, Designs, and Patents Act 1988.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Details on how to seek permission, further information about the
Publisher’s permissions policies, and our arrangements with organizations such as the Copyright Clearance
Center and the Copyright Licensing Agency can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).
Chapter 14, Cytokines and cytokine receptors; John J. O’Shea and Massimo Gadina︎ contributions are in the
public domain.
Chapter 15: Chemokines and Chemokine Receptors; Philip Murphy contributions are in the public domain
Chapter 28: Host Defenses to Fungi; Michail S. Lionakis︎ contributions are in the public domain
Chapter 45: Eosinophils and Eosinophilic Disorders; Amy D. Klion︎ contributions are in public domain
Chapter 78, Lymphomas; Elaine S. Jaffe and Stefania Pittaluga contributions are in the public domain.
Chapter 85, Protein kinase antagonists; John J. O’Shea and Massimo Gadina contributions are in the public
domain.
Chapter 90: Allogeneic Transplantation for Immunodeficiency is in the public domain
Chapter 93: Flow cytometry; Sergio Rosenzweig contributions are in the public domain.
Notices
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and
using any information, methods, compounds, or experiments described herein. Because of rapid advances
in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be
made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors, or
contributors for any injury and/or damage to persons or property as a matter of products liability,
negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas
contained in the material herein.
ISBN: 9780702081651
Printed in India
v
vi Contents
Clinical immunology is a discipline with a distinguished history, a detailed treatment of immunologic deficiency syndromes.
rooted in the prevention and treatment of infectious diseases in Pathogenic mechanisms of both congenital and acquired
the late nineteenth and early twentieth centuries. The conquest immune deficiency diseases are discussed, as are the infec-
of historical scourges such as smallpox and (substantially) polio tious complications that characterize these diseases. Befitting
and relegation of several other diseases to the category of medi- its importance, the subject of HIV infection and AIDS receives
cal curiosities is often regarded as the most important achieve- particular attention, with separate chapters on the problem of
ment of medical science of the past fifty years. Nevertheless, the infection in the immunocompromised host, HIV infection in
challenges facing immunologists in the efforts to control infec- children, anti-retroviral therapy, and current progress in the
tious diseases remain formidable; HIV infection, malaria, and development of HIV vaccines.
tuberculosis are but three examples of diseases of global import The classic allergic diseases are the most common immuno-
that elude control despite major commitments of monetary and logic diseases in the population, ranging from atopic disease to
intellectual resources. drug allergy to organ-specific allergic disease (e.g., of the lungs,
Although firmly grounded in the study and application eye, and skin). They constitute a foundation for the practice
of defenses to microbial infection, since the 1960s, clinical of clinical immunology, particularly for those physicians with
immunology has emerged as a far broader discipline. Dysfunc- a practice orientation defined by formal subspecialty training
tion of the immune system has been increasingly recognized as in allergy and immunology. A major section is consequently
a pathogenic mechanism that can lead to an array of specific devoted to these diseases, with an emphasis on pathophysiology
diseases and failure of virtually every organ system. Paradoxi- as the basis for rational management.
cally, although the importance of the immune system in dis- The next two sections deal separately with systemic and
ease pathogenesis is generally appreciated, the place of clinical organ-specific immunologic diseases. The diseases considered
immunology as a practice discipline has been less clear. As most in the first of these sections are generally regarded as the core
of the noninfectious diseases in the human immune system practice of the clinical immunologist with a subdisciplinary
eventually lead to the failure of other organs, it has been organ- emphasis in rheumatology. The second section considers dis-
specific subspecialists who have usually dealt with their conse- eases of specific organ failure as consequences of immuno-
quences. Recently, however, the outlook has begun to change as logically mediated processes that may involve virtually any
new diagnostic tools increasingly allow the theoretical possibility organ system. These diseases include, as typical examples,
of intervention much earlier in disease processes, often before demyelinating diseases, insulin-dependent diabetes mellitus,
irreversible target organ destruction occurs. More importantly, glomerulonephritides, and inflammatory bowel diseases. It is
this theoretical possibility is increasingly realized as clinical in the management of such diseases that the discipline of clini-
immunologists find themselves in the vanguard of translating cal immunology will have an increasing role as efforts focus on
molecular medicine from laboratory bench to patient bedside. intervention early in the pathogenic process and involve diag-
In many settings, clinical immunologists today function as nostic and therapeutic tools of ever-increasing sophistication.
primary care physicians in the management of patients with One of the major clinical areas in which the expertise of a
immune-deficiency, allergic, and autoimmune diseases. Indeed clinical immunologist is most frequently sought is that of allo-
many influential voices in the clinical disciplines of allergy and geneic organ transplantation. A full section is devoted to the
rheumatology support the increasing coalescence of these tradi- issue of transplantation of solid organs, with an introductory
tional subspecialties around their intellectual core of immunol- chapter on general principles of transplantation and manage-
ogy. In addition to his or her role as a primary care physician, ment of transplantation rejection followed by separate chapters
the clinical immunologist is increasingly being looked to as a dealing with the special problems of transplantation of specific
consultant, as scientific and clinical advances enhance his or her organs or organ systems.
expertise. The immunologist with a “generalist” perspective can Appreciation of both the molecular and clinical features
be particularly helpful in the application of unifying principles of lymphoid malignancies is important to the clinical immu-
of diagnosis and treatment across the broad spectrum of immu- nologist regardless of subspecialty background, notwithstand-
nologic diseases. ing the fact that primary responsibility for the management of
Clinical Immunology: Principles and Practice has emerged such patients will generally fall to the hematologist/oncologist.
from this concept of the clinical immunologist as both primary A separate section is consequently devoted to the lymphocytic
care physician and expert consultant in the management of leukemias and lymphomas that constitute the majority of malig-
patients with immunologic diseases. It opens in full apprecia- nancies seen in the context of a clinical immunology practice.
tion of the critical role of fundamental immunology in this The separate issues of immune responses to tumors and immu-
rapidly evolving clinical discipline. Authors of basic science nological strategies to treatment of malignant diseases are
chapters were asked, however, to cast their subjects in a con- subjects of additional chapters.
text of clinical relevance. We believe the result is a well-balanced Another important feature is the attention to therapy of
exposition of basic immunology for the clinician. immunologic diseases. This theme is constant throughout the
The initial two sections on basic principles of immunology chapters on allergic and immunologic diseases, and because of
are followed by two sections that focus in detail on the role of the importance the editors attach to clinical immunology as a
the immune system in defenses against infectious organisms. therapeutic discipline, an extensive section is also devoted specifi-
The approach is two-pronged. It begins first with a systematic cally to this subject. Subsections are devoted to issues of immu-
survey of immune responses to pathogenic agents followed by nologic reconstitution, with three chapters on the treatment of
ix
x Preface To The First Edition
immunodeficiencies, malignancies, and metabolic diseases In summary, we have intended to provide the reader with a
by bone marrow transplantation. Also included is a series of comprehensive and authoritative treatise on the broad subject
chapters on pharmaceutical agents currently available to clini- of clinical immunology, with particular emphasis on the diag-
cal immunologists, both as anti-allergic and anti-inflammatory nosis and treatment of immunological diseases. It is anticipated
drugs, as well as newer agents with greater specificity for that the book will be used most frequently by the physician
T cell-mediated immune responses. The section concludes with specialist practicing clinical immunology, both in his or her
a series of chapters that address established and potential appli- role as a primary physician and as a subsequent consultant. It
cations of therapeutic agents and approaches that are largely is hoped, however, that the book will also be of considerable
based on the new techniques of molecular medicine. In addition utility to the non-immunologist. Many of the diseases discussed
to pharmaceutical agents, the section deals in detail with such authoritatively in the book are diseases commonly encountered
subjects as apheresis, cytokines, monoclonal antibodies and by the generalist physician. Indeed, as noted, because clinical
immunotoxins, gene therapy, and new experimental approaches immunology involves diseases of virtually all organ systems,
to the treatment of autoimmunity. The book concludes with a competence in the diagnosis and management of immunologi-
section devoted to approaches and specific techniques involved cal diseases is important to virtually all clinicians. The editors
in the diagnosis of immunologic diseases. The use of the diag- would be particularly pleased to see the book among the refer-
nostic laboratory in the evaluation of complex problems of ences readily available to the practicing internist, pediatrician,
immunopathogenesis has been a hallmark of the clinical immu- and family physician.
nologist since the inception of the discipline, and many clini-
cal immunologists serve as directors of diagnostic immunology Robert R. Rich
laboratories. Critical assessment of the utilization of techniques Thomas A. Fleisher
ranging from lymphocyte cloning to flow cytometric phenotyp- Benjamin D. Schwartz
ing to molecular diagnostics is certain to continue as an impor- William T. Shearer
tant function of the clinical immunologist, particularly in his or Warren Strober
her role as an expert consultant. 1996
P R E FA C E T O T H E S I X T H E D I T I O N
At the time this preface was prepared, our world was being The book opens with three sections dedicated to the funda-
arguably faced with its worst infectious pandemic since the mental sciences that underlie clinical immunology. However,
global influenza A infection of the early 20th century. That pan- authors of the basic science chapters were asked to cast their
demic infected ~500 million people, or ~1/3 of the total world chapters in a context of clinical relevance. We believe this has
population, and caused at least 50 million deaths. The current been accomplished. The basic science chapters are followed by
21st century COVID-19 pandemic was estimated in September sections on Immune Deficiency and Immune Regulatory Dis-
2021 to have infected >230 million individuals out of 7.7 billion orders; Allergic Diseases; Systemic Immune Diseases; Organ-
(~3%), causing ~4.71 million deaths; and these numbers are Specific Inflammatory Disorders; Immunology and Immuno-
also staggering and are necessarily incomplete. But as we learn therapy of Neoplasia; Medical Management of Immunologic
more about the prevention, diagnosis, and care of persons with Diseases; Transplantation of Tissues and Organs; and the Tech-
COVID-19 infections (both symptomatic and asymptomatic), nologies of Diagnostic Immunology.
we have reason to believe that despite the enormous case load, We have preserved features in the book that were well re-
we will not approach the death rate of the 1918–20 pandemic. ceived in previous editions. Chapters are generously illustrated,
This improved survival reflects in part the knowledge that and all chapters contain a Key Concepts summary Box (com-
has been gained over the past century from research in immu- monly in bulleted form) as well as an On the Horizon box, in
nology, which has been contributed by investigators and clini- which authors look to research opportunities for important
cians throughout the world. This knowledge has advanced our advances over the next five to ten years. Furthermore, due to
ability to prevent and manage pandemics in general, giving the extraordinarily cross-disciplinary nature of clinical immu-
us hope to face future emerging infectious disease challenges nology, it is our hope that investigators working in one area
as well. might find new ideas and opportunities in the On the Horizon
Although clinical immunology and this book are strongly boxes outside their primary area of focus. Other boxes similarly
grounded in the study of and application to microbial infections, summarize content with Clinical Relevance, Clinical Pearls, and
both the book and the discipline are far broader. Dysfunction of Therapeutic Principles.
the immune system is recognized as a pathogenic mechanism Now in its 6th edition since it was first published in 1996, this
that can lead to diseases and failure of virtually every organ book represents the achievements and provides access to the ex-
system. Fortunately, advances in the prevention and treatment pertise of ~200 individual contributors. As editors, we are deep-
of immunologic diseases also offer enhanced intervention, of- ly grateful for the thousands of hours of work put into this effort
ten before irreversible target organ damage or destruction has by our colleagues in Clinical Immunology around the globe. We
occurred. Thus, clinical immunologists are frequently in the also note the exceptional support that the preparation of this
vanguard of translating molecular medicine from the labora- edition has received from publishing experts at Elsevier, in par-
tory bench to the patient bedside. ticular Robin Carter, Louise Cook, Jennifer Ehlers, and Andrew
In the United States, clinical immunologists often function Riley. Thank you so much, Robin, Louise, Jennifer, and Andrew.
as primary care providers for patients with a wide variety of The task would have been impossible without your expertise.
disorders of immune function, including immune deficiency,
allergic disease, and autoimmunity. As a result, although clinical Robert R. Rich
immunology has not been constituted in this country as a for- Thomas A. Fleisher
mal subspecialty, many influential voices in the “official” disci- Harry W. Schroeder Jr.
plines of allergy and rheumatology regard themselves foremost Cornelia M. Weyand
as clinical immunologists. We trust that this textbook will prove David B. Corry
useful to both clinical generalists and clinical immunology Jennifer M. Puck
subspecialists.
xi
LIST OF CONTRIBUTORS
The editors would like to acknowledge and offer grateful thanks Subash Babu, MBBS, PhD
for the input of all previous editions’ contributors, without Scientific Director
whom this new edition would not have been possible. ICER
National Institutes of Health-NIRT-ICER
Roshini Sarah Abraham, PhD Chennai, India;
Professor of Clinical Pathology; Director, Diagnostic Immunology Staff Scientist, Laboratory of Parasitic Diseases
Laboratory National Institute of Allergy and Infectious Diseases (NIAID)
Department of Pathology and Laboratory Medicine Bethesda, MA, United States
Nationwide Children’s Hospital and The Ohio State University College
Justin M. Balko, PharmD, PhD
of Medicine
Associate Professor of Medicine
Columbus, OH, United States
Associate Professor of Pathology, Microbiology and Immunology
Vanderbilt University Medical Center
Behdad Afzali, MBBS, PhD, MRCP
Nashville, TN, United States
Earl Stadtman Investigator
Kidney Diseases Branch Mark Ballow, MD
National Institute of Diabetes and Digestive and Professor of Pediatrics
Kidney Diseases Department of Pediatrics
National Insitute of Health Morsani College of Medicine
Bethesda, MD, United States St Petersburg, FL, United States;
Former Chief, Division of Allergy and Immunology
Ana Águeda, MD Department of Pediatrics
Department of Rheumatology SUNY Buffalo
Centro Hospitalar do Baixo Vouga Buffalo, NY, United States
Aveiro, Portugal
Rachel Bean, MD
Cem Akin, MD, PhD Special Volunteer
Professor of Medicine Division of Intramural Research
Division of Internal Medicine National Institute of Allergy and Infectious Diseases
University of Michigan National Institutes of Health
Ann Arbor, MI, United States Bethesda, MD, United States
Mark Boguniewicz, MD
Jean-Laurent Casanova, MD, PhD
Professor, Division of Allergy-Immunology
Levy Family Professor
Department of Pediatrics
The Rockefeller University;
National Jewish Health and University of Colorado School of
Investigator
Medicine
Howard Hughes Medical Institute;
Denver, CO, United States
Head
Bertrand Boisson, PhD St. Giles Laboratory of Human Genetics of Infectious Diseases
Assistant Professor Laboratory of Human Genetics of Infectious Diseases
Laboratory of Human Genetics of Infectious Diseases Institut Imagine/University of Paris
Institut Imagine/University of Paris Paris, France
Paris, France;
St. Giles Laboratory of Infectious Diseases Alice Y. Chan, MD, PhD
The Rockefeller University Department of Pediatrics
New York, NY, United States University of California San Francisco
San Francisco, CA, United States
Stéphanie Boisson-Dupuis, PhD
St Giles Laboratory of Human Genetics of Infectious Diseases Edwin S. L. Chan, MB, ChB, FRCPC
the Rockefeller University Adjunct Associate Professor of Medicine
New York, NY, United States Department of Medicine
New York University School of Medicine
Elena Borzova, PhD New York, NY, United States
Professor
Department of Dermatology and Venereology Walter Winn Chatham, MD
I.M. First Moscow State Medical University Professor of Medicine, Clinical Immunology and Rheumatology
Moscow, Russian Federation University of Alabama at Birmingham
Birmingham, AL, United States
Maria Bottazzi, PhD
Associate Dean
Javier Chinen, MD, PhD
National School of Tropical Medicine
Allergist and Immunologist
Baylor College of Medicine
Baylor College of Medicine
Houston, TX, United States
The Woodlands, Texas Children’s Hospital
Prosper N. Boyaka, PhD Humble, TX, United States
Professor
Veterinary Biosciences Lisa Christopher-Stine, MD
The Ohio State University Assistant Professor of Pathology and Laboratory Medicine
Columbus, OH, United States University of Rochester Medical Center
Rochester, NY, United States
John M. Bridges, MD
Associate and Fellow, Clinical Immunology and Rheumatology Emily Coates, PhD
Children’s Hospital of Alabama Director of Translational Science
University of Alabama at Birmingham Clinical Trials Program
Birmingham, AL, United States Vaccine Research Center
National Institute of Allergy and Infectious Diseases
Bethesda, MD, United States
List Of Contributors xv
Andrew P. Cope, BSc, MBBS, PhD, FRCP Stephen R. Durham, MA, MD, FRCP
Centre for Rheumatic Diseases Professor of Allergy and Respiratory Medicine
King’s College London Allergy and Clinical Immunology
London, UK NHLI, Imperial College London
London, UK
David B. Corry, MD
Professor Todd N. Eagar, PhD
Medicine and Pathology and Immunology Assistant Professor
Baylor College of Medicine Pathology and Genomic Medicine
Houston, TX, United States Houston Methodist Hospital Research Institute
Director of HLA and Transplant Immunology Laboratory
Joana Cosme, MD Pathology and Genomic Medicine
Allergy and Clinical Immunology Consultant Houston Methodist Hospital
Department of Immunoallergology Houston, TX, United States;
Centro Hospitalar Universitário de Lisboa Norte Assistant Professor
Lisbon, Portugal Laboratory Medicine
Weill Cornell Medical College
New York, NY, United States
Randy Q. Cron, MD, PhD
Professor of Pediatrics and Medicine Michelle Al-Hosni, MD
University of Alabama at Birmingham; Allergy and Clinical Immunology Fellow
Director of Pediatric Rheumatology University of Michigan
Children’s of Alabama Ann Arbor, MI, United States
Birmingham, AL, United States
Sarah Elitzur, MD
Marinos C. Dalakas, MD, FAAN Senior Physician
Professor of Neurology Pediatric Hematology-Oncology
Chief Neuromuscular Division Schneider Children’s Medical Center
Department of Neurology Petah Tikva, Israel
Thomas Jefferson University
Philadelphia, PA, United States Craig A. Elmets, MD
Professor and Chair
Sara M. Dann, PhD Dermatology
Assistant Professor University of Alabama at Birmingham
Internal Medicine Birmingham, AL, United States
University of Texas Medical Branch
Galveston, TX, United States Doruk Erkan, MD
Associate Professor
Satya Das, MD, MSCI Rheumatology
Assistant Professor Hospital for Special Surgery
Medicine New York, NY, United States
Vanderbilt University Medical Center
Thomas A. Fleisher, MD
Nashville, TN, United States
Executive Vice President
American Academy of Allergy, Asthma and Immunology
Molly M. Daughety, MD Milwuakee, WI, United States;
Physician Scientist Emeritus, National Institutes of Health Clinical Center
Hematology Oncology Bethesda, MD, United States
Duke University Medical Center
Durham, NC, United States Luz Fonacier, MD
Professor of Medicine
Betty Diamond, MD Department of Medicine
Feinstein Institutes for Medical Research NYU Long Island School of Medicine;
Northwell Health Head of Allergy
Manhasset, NY, United States Department of Medicine
NYU Langone Hospital, Long Island;
Angela Dispenzieri, MD Training Program Director
Professor of Medicine and Laboratory Medicine Allergy and Immunology
Mayo Clinic Department of Medicine
Rochester, MN, United States NYU Langone Hospital, Long Island
Mineola, NY, United States
xvi List Of Contributors
Aika oli jo pitkälle kulunut, kun minä jätin esivalden; ja kun aamulla
varhain taas saavuin, tulivat myös muutamat lapinmiehet esivaltaa
tervehtimään. Vouti, joka nuoruutensa aikana oli käynyt
paikkakunnalla, oli heille hyvin tunnettu. Mutta kun heille esitettiin
tuomari, nuori hovioikeuden auskultantti, sanoi heistä yksi hyvin
hämmästyneenä: "Tämäkös nyt on esivalde, nuori ja pieni".
Tuomaria seuraavan apulaisen, varatuomari V——n, joka edellisenä
vuonna oli pitänyt käräjiä Peltovuomassa, joku heistä tunsi ja lausui:
"No, mikäs tuo? Onko tuo pantu pois, koska tämä nyt on esivalde?"
Matkaseikkailuja.
*****
*****
*****
*****
Mutta nyt puhkesikin taas hirveä rajuilma, ja opas oli ainoa johon
voimme turvautua. Hän hiihti edellä, ja nopeasti lappalainen
hiihtääkin, mutta kun hänellä on perässään kuljetettava syvässä
lumessa kahlaava poro, joka tekee vastarintaa, hän ainoastaan
hitaasti edistyy, eikä sitä kestä reippainkaan mies muuta kuin
muutaman virstan, ennenkuin hänen täytyy levähtää.