Table Of Content

Editors Leslie C. Grammer M.D. Professor of Medicine Department of Medicine; Vice Chief, Division of Allergy-Immunology; Director, Ernest S. Bazley Asthma and Allergic Diseases Center, Northwestern University Medical School; Attending Physician, Northwestern Memorial Hospital, Chicago, Illinois Paul A. Greenberger M.D. Professor of Medicine Department of Medicine; Associate Chief, Education and Clinical Affairs, Division of Allergy- Immunology, Northwestern University Medical School; Attending Physician, Northwestern Memorial Hospital, Chicago, Illinois Contributing Authors Howard L. Alt M.D. Assistant Professor of Clinical Medicine Department of Psychiatry, Northwestern University Medical School, Chicago, Illinois Andrea J. Apter M.D., M.Sc. Chief; Associate Professor Department of Allergy and Immunology, Division of Pulmonary, Allergy, and Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Banani Banerjee Ph.D. Instructor of Pediatrics (Allergy/Immunology) and Medicine Medical College of Wisconsin, Milwaukee, Wisconsin Melvin Berger M.D. Ph.D. Professor Departments of Pediatrics and Pathology, Case Western Reserve University; Chief, Department of Pediatrics, Rainbow, Babies and Children's Hospital, University Hospitals Health System, Cleveland, Ohio David I. Bernstein M.D. Professor of Medicine Department of Immunology, University of Cincinnati College of Medicine, Cincinnati, Ohio Jonathan A. Bernstein M.D. Associate Professor Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio Michael S. Blaiss M.D. Clinical Professor Departments of Pediatrics and Medicine, University of Tennessee, Memphis, Department of Pediatrics, Le Bonheur Children's Medical Center, Memphis, Tennessee Bernard H. Booth III M.D. Clinical Professor Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi G. Daniel Brooks M.D. Department of Medicine, University of Wisconsin, Department of Medicine, University of Wisconsin Hospitals and Clinics, Madison, Wisconsin Robert K. Bush M.D. Professor Department of Medicine, University of Wisconsin-Madison; Chief, Department of Allergy, William. S. Middleton V.A. Hospital, Madison, Wisconsin Rakesh K. Chandra M.D. Chief Resident Department of Otolaryngology Head & Neck Surgery, Northwestern Memorial Hospital, Northwestern University, Chicago, Illinois David B. Conley M.D. Assistant Professor Department of Otolaryngology Head & Neck Surgery, Northwestern University Medical School, Chicago, Illinois Thomas Corbridge M.D., F.C.C.P. Associate Professor Department of Medicine, Northwestern University Medical School; Director, Medical Intensive Care Unit, Northwestern Memorial Hospital, Chicago, Illinois Anne M. Ditto M.D. Assistant Professor Department of Medicine, Division of Allergy-Immunology, Northwestern University Medical School, Chicago, Illinois Jordan N. Fink M.D. Professor and Chief Department of Medicine, Division of Allergy-Immunology, Milwaukee County Medical Complex, Milwaukee, Wisconsin Leslie C. Grammer M.D. Professor of Medicine Department of Medicine; Vice Chief, Division of Allergy-Immunology; Director, Ernest S. Bazley Asthma and Allergic Diseases Center, Northwestern University Medical School, Chicago, Illinois Thomas H. Grant D.O. Associate Professor Department of Radiology, Northwestern Memorial Hospital, Northwestern University Medical School, Chicago, Illinois Paul A. Greenberger M.D. Professor of Medicine Department of Medicine; Associate Chief, Education and Clinical Affairs, Division of Allergy- Immunology, Northwestern University Medical School, Chicago, Illinois Kathleen E. Harris B.S. Senior Life Sciences Researcher Department of Medicine, Division of Allergy-Immunology, Northwestern University Medical School, Chicago, Illinois Mary Beth Hogan M.D. Assistant Professor Department of Pediatrics, West Virginia University School of Medicine, Morgantown, West Virginia Carla Irani M.D. Section of Allergy and Immunology, Division of Pulmonary, Allergy, Critical Care Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Kevin J. Kelly M.D. Professor and Chief Department of Allergy/Immunology, Medical College of Wisconsin; Chief, Department of Medicine, Division of Allergy/Immunology, Children's Hospital of Wisconsin, Milwaukee, Wisconsin Robert C. Kern M.D., M.S., F.A.C.S. Chairman Division of Otolaryngology, Cook County Hospital; Associate Professor, Department of Otolaryngology-Head & Neck Surgery, Northwestern University Medical School, Chicago, Illinois Theodore M. Lee M.D. Peachtree Allergy and Asthma Clinic, PC, Atlanta, Georgia Donald Y M Leung M.D., Ph.D. Professor Department of Pediatrics, University of Colorado Health Sciences Center; Head, Department of Pediatric Allergy-Immunology, National Jewish Medical and Research Center, Denver, Colorado Phil Lieberman M.D. Clinical Professor Department of Internal Medicine and Pediatrics, University of Tennessee College of Medicine , Cordova, Tennessee Kris G. McGrath M.D. Associate Professor Department of Medicine, Northwestern University Medical School; Chief, Department of Allergy-Immunology, Saint Joseph Hospital, Chicago, Illinois Roger W. Melvold Ph.D. Professor and Department Chair Department of Microbiology & Immunology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota W. James Metzger M.D. Professor and Section Head Department of Allergy, Asthma and Immunology, East Carolina University School of Medicine, Greenville, North Carolina Babak Mokhlesi M.D. Assistant Professor Department of Medicine, Division of Pulmonary and Critical Care, Rush Medical College/Cook County Hospital, Chicago, Illinois Michelle J. Naidich M.D. Department of Radiology, Northwestern Memorial Hospital, Northwestern University Medical School, Chicago, Illinois Sai R. Nimmagadda M.D. Assistant Professor Department of Pediatrics, Northwestern University Medical School, Department of Pediatrics/Allergy, Children's Memorial Hospital, Chicago, Illinois Peck Y. Ong M.D. Fellow Department of Pediatrics, Division of Allergy and Immunology, National Jewish Medical and Research Center, Denver, Colorado Roy Patterson M.D. Ernest S. Bazley Professor of Medicine Department of Medicine; Chief, Division of Allergy-Immunology, Northwestern University Medical School, Chicago, Illinois Neill T. Peters M.D. Clinical Instructor Department of Dermatology, Mercy Hospital and Medical Center, Chicago, Illinois Jacqueline A. Pongracic M.D. Assistant Professor Department of Pediatrics and Medicine, Northwestern University Medical School; Acting Division Head, Department of Allergy, Children's Memorial Hospital, Chicago, Illinois Jacob J. Pruzansky Ph.D. Emeritus Professor of Microbiology Department of Medicine, Division of Allergy-Immunology, Northwestern University Medical School, Chicago, Illinois Robert E. Reisman M.D. Clinical Professor Departments of Medicine and Pediatrics, State University of New York at Buffalo, Department of Medicine (Allergy/Immunology), Buffalo General Hospital, Buffalo, New York Anthony J. Ricketti M.D. Associate Professor of Medicine Seton Hall University, Graduate School of Medicine, Chairman, Department of Medicine, St. Francis Medical Center, Trenton, New Jersey Eric J. Russell M.D., F.A.C.R. Professor Departments of Radiology, Neurosurgery, and Otolaryngology, Northwestern University, Chief of Neuroradiology, Department of Radiology, Northwestern Memorial Hospital, Chicago, Illinois Carol A. Saltoun M.D. Clinical Instructor Department of Medicine, Division of Allergy-Immunology, Northwestern University Medical School, Chicago, Illinois Andrew Scheman M.D. Associate Professor of Clinical Dermatology and Department of Dermatology Northwestern University Medical Center, Chicago, Illinois William R. Solomon M.D. Professor Emeritus Department of Internal Medicine (Allergy), University of Michigan Medical School and, University of Michigan Medical Center, Ann Arbor, Michigan Abba I. Terr M.D. Associate Professor Department of Medicine, University of California-San Francisco, School of Medicine, San Francisco, California Anju Tripathi M.D. Assistant Professor Departments of Medicine and Allergy, Northwestern University Medical School , Chicago, Illinois Stephen I. Wasserman M.D. The Helen M. Ranney Professor Department of Medicine, University of California-San Diego, La Jolla, California; Professor and Chief of Allergic Diseases, Department of Medicine, University of California-San Diego Medical Center, San Diego, California Carol Ann Wiggins M.D. Department of Allergy and Immunology, Emory University School of Medicine, Department of Allergy and Immunology, Piedmont Hospital, Atlanta, Georgia Nevin W. Wilson M.D. Associate Professor Department of Pediatrics, West Virginia University, School of Medicine, Morgantown, West Virginia Lisa F. Wolfe M.D. Assistant Professor of Medicine Clinical Instructor, Division of Pulmonary & Critical Care Medicine and the Center for Sleep and Circadian Biology, Northwestern University Medical School, Chicago, Illinois Michael C. Zacharisen M.D. Assistant Professor Departments of Pediatrics and Medicine, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, Wisconsin C. Raymond Zeiss M.D. Emeritus Professor of Medicine Department of Medicine, Division of Allergy-Immunology, Northwestern University Medical School, VA Chicago Health Care System–Lakeside Division, Chicago, Illinois In Memoriam In Memoriam Jacob J. Pruzansky, Ph.D. June 20, 1921–April 5, 2001 Jack Pruzansky served as an author in five editions of Allergic Diseases. He spent many hours mentoring fellows in the Allergy-Immunology Division during his 35-year tenure at Northwestern University. After his retirement, he still functioned as a consultant and provided scientific expertise to the division. Jack was an expert on in vitro basophil histamine release and discovered how dilute hydrochloric acid would allow for removal of IgE from basophils. This discovery allowed him to study passive transfer experimentally and led to studies of histamine releasing factors. His intellect and advice helped fellows and faculty stay out of “dark alleys” as he would say. He will be missed. In Memoriam Martha A. Shaughnessy, B.S. December 3, 1943– September 9, 1997 Martha Shaughnessy was a chapter author in the last two editions of Allergic Diseases. She had a terrific sense of humor and quick wit. Her contributions to the division included performing immunologic research, writing research papers and grants, teaching fellows, and administration of the Allergy-Immunology Division. She coauthored 71 peer-reviewed papers, 66 of which were in collaboration with other members of the Allergy-Immunology Division. She also coauthored ten book chapters, primarily in areas of allergen immunotherapy and occupational immunologic lung disease, her two major research interests. She was admired and respected by her co-investigators and all who worked with her. We, her colleagues and friends, now honor her. In Memory of Ernest S. Bazley The Ernest S. Bazley Grant to Northwestern Memorial Hospital and Northwestern University has provided continuing research support that has been invaluable to the Allergy-Immunology Division of Northwestern University. In Memoriam W. James Metzger, Jr., M.D. October 30, 1945– November 17, 2000 Jim was a fellow at Northwestern University from 1974 to 1976 and spent his career in academic medicine at the University of Iowa and East Carolina Medical School where he was Division Chief of Allergy Asthma and Immunology and Vice-Chair of the Department of Medicine. He moved to Denver to the National Jewish Hospital in the months before he became ill. He was an author in three editions of Allergic Diseases. Jim had many accomplishments in Allergy-Immunology including the early discovery that allergen vaccine therapy inhibited some of the late airway response to allergen. Jim was liked by everyone and is deeply missed. It was stated, “As in so many things, Jim was the catalyst that altered and enlarged an experience, while managing to stay almost invisible himself.” Foreword A Major Honor I was informed by the publisher that the name Roy Patterson would be on all future editions of Allergic Diseases: Diagnosis and Management. I consider this a great honor and at this time I would like to acknowledge several colleagues for their contributions to my personal achievements. As of this writing, I am 75 years old (as of 4/26/01) and am the Ernest S. Bazley Professor of Medicine of Northwestern University Medical School and the Chief of the Allergy-Immunology Division of the Department of Medicine. I owe a debt of gratitude to the following for all their support during my academic career. I wish to thank: The Ernest S. Bazley Trustees: Catherine Ryan of the Bank of America, Illinois, the late Ernest S. Bazley, Jr., and the late Gunnard Swanson. A major effort of the Northwestern Allergy-Immunology program has been the diagnosis and management of all forms of asthma. Research funding from the Bazley Trust has made many of our accomplishments in the area possible. The National Institute of Allergy and Infectious Diseases: Richard Krause, M.D., Anthony Fauci, M.D., Sheldon Cohen, M.D., and Dorothy Sogn, M.D. Full time faculty: particularly the late Jacob J. Pruzansky, Ph.D. Voluntary faculty: particularly Richard S. DeSwarte, M.D. Technical and support staff: Mary Roberts, R.N., Kathleen E. Harris, B.S., Margaret A. Mateja-Wieckert, and the late Martha A. Shaughnessy, B.S. Finally, the Graduates of the Allergy-Immunology training program. Roy Patterson M.D. Preface The sixth edition covers allergic and immunologic problems that are encountered in the ambulatory practice or in hospitalized patients. The quantity and complexity of general and specific knowledge in the field of Allergy-Immunology continues to expand at an exciting but daunting pace. Further, the practice of Allergy-Immunology requires familiarity with many specific details. The 42 chapters contain useful, applicable, and up-to-date information on how to diagnose and manage nearly all of the conditions in Allergy-Immunology. The history of Allergic Diseases: Diagnosis and Management through six editions includes being a useful textbook where important, crucial information can be found and applied. Edition six has 15 new chapters, and the classic Drug Allergy chapter originated by Richard DeSwarte has been divided into three parts. The new chapters covering radiologic findings of the sinuses and lungs, role of rhinoscopy and surgery for chronic sinusitis, and work-up for immunodeficiency reflect the broadened base of knowledge required for the practice of Allergy-Immunology. In that asthma is now recognized as of one the most complicated disorders a physicians must treat, five new chapters were prepared to cover medications for asthma, inhaler devices and delivery systems, and novel approaches to treatment. There are shortages of specialists in Allergy-Immunology in practice and even more so in academic medical centers. We hope this textbook assists physicians to provide better care for their patients, inspires medical students and residents to pursue training in Allergy- Immunology, and assists investigators in advancing our knowledge. We will always have much more to learn. We are grateful to the authors for their superb chapters, each of which has been approved by us, should there be any oversights. We could not have completed this textbook without the love and support from our families who give us the time to continue in the Northwestern University Allergy-Immunology tradition that is now over 40 years old! Special appreciation goes to our support staff, especially Kathleen E. Harris and Margaret Mateja Wieckert, our trainees and graduates, and our patients, from whom we can always learn. Leslie C. Grammer M.D. Paul A. Greenberger M.D. 1 Review of Immunology Roger W. Melvold Department of Microbiology and Immunology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota Contents • ANTIGENS • MOLECULES OF THE IMMUNE SYSTEM • MOLECULES FOR ADHESION, RECIRCULATION, AND HOMING • CELLS OF THE IMMUNE SYSTEM • PRIMARY ORGANS: BONE MARROW AND THYMUS • INTERACTIONS IN IMMUNE RESPONSES • THE IMMUNE SYSTEM: A DOUBLE-EDGED SWORD • TOLERANCE Although immunology is a relative newcomer among the sciences, its phenomena have long been recognized and manipulated. Ancient peoples understood that survivors of particular diseases were protected from those diseases for the remainder of their lives, and the ancient Chinese and Egyptians even practiced forms of immunization. Surgeons have also long understood that tissues and organs would not survive when exchanged between different individuals (e.g., from cadaver donors) but could succeed when transplanted from one site to another within the same individual. However, only during the past century have the mechanisms of the immune system been illuminated, at least in part. Keep in mind that the immune system, as we usually think of it, is the body's second line of defense. The first line of defense consists of a number of barriers, including the skin and mucous membranes, the fatty acids of the skin, the high pH of the stomach, resident microbial populations, and cells that act nonspecifically against infectious organisms (1). Like the nervous and endocrine systems, the immune system is adaptive, specific, and communicative. It recognizes and responds to changes in the environment, and it displays memory by adapting or altering its response to stimuli that it has encountered previously. It can detect the presence of millions of different substances (antigens) and has an exquisite ability to discriminate among closely related molecules. Communication and interaction, involving both direct contact and soluble mediators, must occur among a variety of lymphoid and other cells for optimal function. The complexity of the immune system is extended by genetic differences among individuals. This is because the “repertoire” of immune responses varies among unrelated individuals in an outbred, genetically heterogeneous species such as our own. Furthermore, each of us, in a sense, is “immunologically incomplete” because none of us is able to recognize and respond to all of the possible antigens that exist. Several factors contribute to this: (a) genetic or environmentally induced conditions that nonspecifically diminish immune functions, (b) variation among individuals in the genes encoding the antigen receptors of lymphocytes, (c) genetically encoded differences among individuals (often determined by the highly polymorphic genes of the human leukocyte antigen [HLA] complex) that dictate whether and how the individual will respond to specific antigens, and (d) the fact that each individual's immune system must differentiate between self (those substances that are a normal part of the body) and foreign, or nonself, in order to avoid autoimmunity. However, because self differs from one individual to the next, what is foreign also differs among individuals. ANTIGENS Part of "1 - Review of Immunology" Antigens were initially defined as substances identified and bound by antibodies (immunog-lobulins) produced by B lymphocytes. However, because the specific antigen receptors of P.2 T lymphocytes are not immunoglobulins, the definition must be broadened to include substances that can be specifically recognized by the receptors of T or B lymphocytes or both. It is estimated that the immune system can specifically recognize at least 106 to 107 different antigens. These include both substances that are foreign to the body (nonself) and substances that are normal constituents of the body (self). The immune system must distinguish between nonself and self antigens so that, under normal conditions, it can attack the former but not the latter. Thus, the immune system should be tolerant of self but intolerant of nonself. Autoimmune diseases arise when such distinctions are lost and the immune system attacks self antigens, a phenomenon originally described by Paul Erlich as horror autotoxicus. Well-known examples include rheumatoid arthritis, psoriasis, systemic lupus erythematosus, and some forms of diabetes. Antigens can be divided into three general types—immunogens, haptens, and tolerogens—depending on the way in which they stimulate and interact with the immune system (2,3 and 4). An immunogen can, by itself, both stimulate an immune response and subsequently serve as a target of that response. The terms immunogen and antigen are often, but inappropriately, used interchangeably. A hapten cannot, by itself, stimulate an immune response. However, if a hapten is attached to a larger immunogenic molecule (a “carrier”), responses can be stimulated against both the carrier and the hapten, and the hapten itself can subsequently serve as the target of a response so invoked. A tolerogen is a substance that, after an initial exposure to the immune system, inhibits future responses against itself. Because of the genetic diversity among individuals, a substance that is an immunogen for one person may be a tolerogen for another and may be ignored completely by the immune system of still others. Also, a substance that acts as an immunogen when administered by one route (e.g., intramuscularly) may act as a tolerogen when applied by a different route (e.g., intragastrically). Antigens are usually protein or carbohydrate in nature and may be found as free single molecules or as parts of larger structures (e.g., expressed on the surface of an infectious agent). Although some antigens are very small and simple, others are large and complex, containing many different sites that can be individually identified by lymphocyte receptors or free immunoglobulins. Each such individual part of an antigen that can be distinctly identified by the immune system is called an epitope or determinant (i.e., the smallest identifiable antigenic unit). Thus, a single large antigen may contain many different epitopes. In general, the more complex the molecule and the greater the number of epitopes it displays, the more potent it is as an immunogen. Adjuvants are substances that, when administered together with an immunogen (or a hapten coupled to an immunogen), enhance the response against it (5). For example, immunogens may be suspended in mixtures (e.g., colloidal suspensions of mycobacterial proteins and oil) that induce localized inflammations and aid in arousal of the immune system. MOLECULES OF THE IMMUNE SYSTEM Part of "1 - Review of Immunology" Immunoglobulin B lymphocytes synthesize receptors (immunog-lobulins) able to recognize and bind specific structures (antigens, determinants, epitopes). All immunoglobulins produced by a single B cell, or by a clonally derived set of B cells, have the same specificity and are able to recognize and bind only a single antigen or epitope (2,3 and 4). Immunoglobulin exists either as a surface membrane-bound molecule or in a secreted form by B cells that have been appropriately stimulated and matured. The immunoglobulin molecule is a glycoprotein composed of two identical light chains and two identical heavy chains (Fig. 1.1) linked by disulfide bonds (6). Enzymatic cleavage of the immunoglobulin molecule creates defined fragments. Papain produces two antigen-binding fragments (Fab) and one crystallizable fragment (Fc). Pepsin produces only a divalent antigen-binding fragment termed F(ab′) , and the remainder of the molecule tends to be degraded and lost. 2 FIG. 1.1. The immunoglobulin molecule. P.3 Each chain (heavy and light) contains one or more constant regions (C or C ) and a variable region H L (V or V ). Together, the variable regions of the light and heavy chains contribute to the antigen- H L binding sites (Fab) of the immunoglobulin molecule. The constant regions of the heavy chain (particularly in the Fc portion) determine what subsequent interactions may occur between the bound immunoglobulin and other cells or molecules of the immune system. When the antigen-binding sites are filled, a signal is transmitted through the immunoglobulin molecule, which results in conformational changes in the Fc portion of the heavy chain. These conformational changes permit the Fc portion to then interact with other molecules and cells. The conformationally altered Fc may be recognized by receptors (Fc receptors [FcR]) on macrophages and other cells, which allow them to distinguish bound from unbound immunoglobulin molecules (7,8), increasing their efficiency of phagocytosis. Other conformational changes in the Fc portion of bound immunoglobulin permit the binding of complement component C1q to initiate the classic pathway of complement activation. The Fab and F(ab′) fragments are useful experimental and therapeutic tools that can bind antigens 2 without the ensuing consequences resulting from the presence of the Fc region (9). Immunoglobulin light chains contain one of two types of constant regions, κ or λ. The constant regions of the heavy chains exist in five major forms (Table 1.1), each associated with a particular immunoglobulin isotype or class: Cα (immunoglobulin A [IgA]), Cδ (IgD), Cε (IgE), Cγ (IgG), and Cµ (IgM). Some of these can be subdivided into subclasses (e.g., IgG1, IgG2, IgG3, and IgG4). Each normal individual can generate all of the isotypes. Within a single immunoglobulin molecule, both light chains are identical and of the same type (both κ or both λ), and the two heavy chains are likewise identical and of the same isotype. IgD, IgG, and IgE exist only as monomeric basic immunoglobulin units (two heavy chains and two light chains), but serum IgM exists as a pentamer of five basic units united by a J (joining) chain. IgA can be found in a variety of forms (monomers, dimers, trimers, tetramers) but is most commonly seen as a monomer (in serum) or as a dimer (in external body fluids, such as mucus, tears, and saliva). P.4 The dimeric form contains two basic units, bound together by a J chain. In passing through specialized epithelial cells to external fluids, it also adds a “secretory piece,” which increases its resistance to degradation by external enzymes (10). TABLE 1.1. Immunoglobulin isotypes In addition to antigen-binding specificity, variability among immunoglobulin molecules derives from three further sources: allotypes, isotypes, and idiotypes. Allotypes are dictated by minor amino acid sequence differences in the constant regions of heavy or light chains, which result from slight polymorphisms in the genes encoding these molecules. Allotypic differences typically do not affect the function of P.5 the molecule and segregate within families like typical mendelian traits. Isotypes, as already discussed, are determined by more substantial differences in the heavy chain constant regions affecting the functional properties of the immunoglobulins (11) (Table 1.1). Finally, many antigenic determinants may be bound in more than one way, and thus there may be multiple, structurally distinct, immunoglobulins with the same antigenic specificity. These differences within the antigen- binding domains of immunoglobulins that bind the same antigenic determinants are termed idiotypes. Generation of Antigen Binding Diversity among Immunoglobulins Each immunoglobulin chain, light and heavy, is encoded not by a single gene but by a series of genes occurring in clusters along the chromosome (11). In humans, the series of genes encoding κ light chains, the series encoding λ light chains, and the series encoding heavy chains are all located on separate chromosomes. Within each series, the genes are found in clusters, each containing a set of similar, but not identical, genes. All of the genes are present in embryonic and germ cells and in cells other than B lymphocytes. When a cell becomes committed to the B-lymphocyte lineage, it rearranges the DNA encoding its light and heavy chains (11,12) by clipping out and degrading some of the DNA sequences. Each differentiating B cell chooses either the κ series or the λ series (but not both). In addition, although both the maternally and paternally derived chromosomes carry these sets of genes, each B cell uses only one of them (either paternal or maternal) to produce a functional chain, a phenomenon termed allelic exclusion. For the light chains, there are three distinct clusters of genes that contribute to the synthesis of the entire polypeptide: variable genes (V ), joining genes (J ), and constant genes (C ) (Fig. 1.2). In L L L addition, each V gene is preceded by a leader sequence encoding a portion of the polypeptide that is important during the synthetic process but is removed when the molecule becomes functional. The V L and D genes are used to produce the variable domain of the light chain. This is accomplished by the L random selection of a single V gene and a single J gene to be united (V –J ) by splicing out and L L L L discarding the intervening DNA. Henceforth, that cell and all of its clonal descendants are committed to that particular V –J combination. Messenger RNA for the light chain is transcribed to include the L L V –J genes, the C gene or genes, and the intervening DNA between them. Before translation, the L L L messenger RNA (mRNA) is spliced to unite the V –J genes with a C gene so that a single L L L continuous polypeptide can be produced from three genes that were originally separated on the chromosome. FIG. 1.2. Synthesis of immunoglobulin light chains. For heavy chains, there are four distinct clusters of genes involved (Fig. 1.3): variable genes (V ), H diversity genes (D ), joining genes (J ), and a series of distinct constant genes (C , C , C , C , and H H µ δ γ ε C ). As with the light chain genes, each V gene is preceded by a leader sequence (L) that plays a α role during synthesis but is subsequently lost. One V gene, one D gene, and one J gene are H H H randomly selected, and the intervening DNA segments are excised and discarded to bring these genes together (V –D –J ). Messenger RNA is then transcribed to include both the V –D –J and H H H H H H constant genes, but unlike for the light chains, the processes involving constant genes are distinctly different in stimulated and unstimulated B lymphocytes. FIG. 1.3. Synthesis of immunoglobulin heavy chains. Unstimulated B cells transcribe heavy chain mRNA from V –D –J through the C and C genes. This H H H µ δ transcript does not contain the information from the C , C , or C genes. The mRNA is then spliced to γ ε α bring V –D –J adjacent to either C or C , which permits the translation of a single continuous H H H µ δ polypeptide with a variable domain (from V –D –J ) and a constant domain (from either C or C ). H H H µ δ Thus, the surface immunoglobulin of naïve unstimulated B cells includes only the IgM and IgD isotypes. After antigenic stimulation, B cells can undergo an isotype switch in which splicing of DNA, rather than RNA, brings the united V –D –J genes adjacent to a constant region gene (13,14). This H H H transition is controlled by cytokines secreted by T lymphocytes. Depending on the amount of DNA excised, the V –D –J genes H H H P.6 P.7 may be joined to any of the different C genes (Fig. 1.4). As a result of the isotype switch, B-cell H “subclones” are generated that produce an array of immunoglobulins that have identical antigen- binding specificity but different isotypes.