Several discoveries are noteworthy for allowing us to probe the recesses of the virus infected cell and to search for cryptic viral genomes which might provide clues in our studies of cancer etiology or developmental biology. One of the most notable was the dis covery of reverse transcriptase. This marked a momentous occasion in the history of molecular biology. Not only did it provide insight into the mechanism of persistence of retroviruses but it also provided us with an enzyme that could synthesize a DNA copy of any RNA. This DNA copy could then be used as a hybridization reagent to search for both complementary DNA and viral-specific RNA. Thus one could follow the course of any viral infection or probe in tumor cells for hidden viral genomes. Second, a great deal of credit must be given to the geneticists who isolated the various deletion mutants in the 'avian retrovirus system and thus provided us with the frrst means of isolating gene-spe cific probes. Finally, the laboratories which have mapped the genome have provided us with the framework in which to ask very specific questions with our gene-specific probes. Recently, numerous excellent reviews concerning various aspects of the retroviruses have appeared. In this review I shall not even attempt to present a comprehensive review of retroviruses."

The purpose of this volume is to highlight some current areas of poxvirus research which are likely to be particularly fruitful in the upcoming few years. The first chapter, by Drs. Condit and Niles, discusses poxvirus genetics. Work in this area has provided mutants, produced practical procedures to simplify the manipulation of viral genes, and generated information about the molecular architecture and organization of genes characteristic of pox viruses. One of the most intensively studied regions of the viral genome is the HindIII D region of vaccinia, in which a combination of classical and molecular genetic analysis of the region has been particularly revealing. Within this region are open reading frames, some of which are expressed early and others late, organized in a fashion which is now known to be typical of these viruses. Other studies, related to temperature sensitive, drug resistant, and drug dependent mutants, are also discussed. Each of the other reviews included in this volume summarizes areas of research which have depended heavily on the genetics of the system. The intracellular site of a poxvirus infection is mostly, if not exclusively, limited to the cytoplasm which dictates several interesting biological ramifications. For example, poxvirus transcription must occur in the cytoplasm, rather than in the nucleus. The virus copes with this situation by incorporating into the virion the enzymatic machinery necessary to initiate transcription from input virus.

Main topics covered: B-Cell Development; Immunoglobulin Gene Rearrangement; Multiple Myeloma, Plasmactomas; Lymphomas: B-CLL, Folli- cular Lymphomas BCL-2, BCL-1; Lymphomas: EBV, AIDS Associa- ted Lymphomas; Oncogenes and Transcriptional Factors (text to follow)

At this writing the decade of the 1980s is rapidly coming to a close, and it is an appropriate time to review the picornavirus field. During the past decade there has been a remarkable reemergence of interest in picornaviruses and a virtual explo- sion of experimentation. The renaissance of picorna viruses can be attributed to several developments near the beginning of the 1980s. In 1981 the nucleotide sequence of the first picornavirus genome, that of poliovirus, was determined, providing a genetic map that would be the basis for a number of experimental questions regarding gene function and expression (Kitamura et ai. , Nature 291: 547; Racaniello and Baltimore, Proc Natl Acad Sci USA 78: 4887). In the same year it was reported that a cloned eDNA copy of the poliovirus genome is infectious when transfected into cultured mammalian cells (Racaniello and Baltimore, Science 214: 916, 1981). This discovery, which enables construction of poliovirus mutants and recombinants, has since been used for the study of many picornaviruses. Furthermore, the availability of cloned copies of viral genomes permits manipulation of gene products apart from infected cells. Third, the use of hybridoma technology to generate anti- picornavirus neutralizing monoclonal antibodies permitted mapping of antigenic sites (for example, Evans et ai. , Nature 304: 459, 1983). Finally, at mid-decade the three-dimensional structures of poliovirus (Hogle et ai. , Science 229: 1358, 1985) and rhinovirus (Rossmann et ai. , Nature 317: 145, 1985) were solved.

The newest volume in the Current Topics in Microbiology and Immunology series edited by Dr. Vogt and dealing with oncogenes and retroviruses contains four review articles by international authorities in the field. These articles presenting the latest research results continue the tradition of excellence for which the series is so well known.

It is fourteen years since insulin was last reviewed in The Handbook of Ex perimental Pharmacology, in volume 32. The present endeavor is more modest in scope. Volume 32 appeared in two separate parts, each having its own subeditors, and together the two parts covered nearly all areas of insulin pharmacology. Such comprehensiveness seemed impractical in a new volume. The amount of in formation related to insulin that is now available simply would not fit in a reasonable amount of space. Furthermore, for better or worse, scientists have be come so specialized that a volume providing such broad coverage seemed likely in its totality to be of interest or value to very few individuals. We therefore decided to limit the present volume to the following areas: insulin chemistry and structure, insulin biosynthesis and secretion, insulin receptor, and insulin action at the cellular level. We felt these areas formed a coherent unit. We also felt, perhaps as much because of our own interests and perspectives as any objective reality, that these were the areas in which recent progress has been most dramatic, and yet, paradoxically and tantalizingly, these were the areas in which most has yet to be learned. Even with this limited scope, there are some major gaps in coverage. Regrettably, two important areas, the beta cell ATP-sensitive potassium channel and the glucose transporter, were among these. Nevertheless, the authors who con tributed have done an excellent job, and we would like to thank them for their diligence.

Research in diabetes has accelerated in two areas, both of which are being reviewed in CTMI. The first is the use of a variety of animal models; the second is basic research in human investigation, islet cell antigens, and mapping of genes as sociated with susceptibility to disease. Dr. Thomas Dyrberg accepted editorial responsibility for this volume, which covers the first area. A second book, to be published later in the year, is edited by Drs. Brekkeskov and Hansen (CTMI 164, see page VI for contents). Although the contributors to both volumes represent the international scientific community, the editors are from the Hagedorn Research Laboratory in Denmark. Work at this institute and the Steno Memorial Hospital has been dedicated to research in diabetes for decades, and the insti tutions were appointed WHO Collaborating Centres for Re search and Training on the Pathogenesis of Diabetes Mellitus in 1983. It is worth noting that while addressing the hypothesis of the role of class II major histocompatibility glycoproteins in autoimmune diabetes (insulin-dependent diabetes, IDDM) a number of investigators established animal models in which class II molecules were expressed under the control of the rat insulin promoter. While generating interesting information on 100M, the finding of immunologic tolerance in such transgenic mice has attracted the attention of several basic immunologic laboratories for quite different reasons. Thus, we are reminded again of the Pasteur dictum that "chance favors the prepared mind. " Michael B. A. Oldstone, M. D."

Malignant melanoma is the focus of investigations which range from basic re search to clinical trials with conventional therapy and with biological response modifiers. The involvement of investigators with different backgrounds in combi nation with recent progress in biotechnology has facilitated the characterization of the antigenic profile of melanoma cells, the analysis of the structural and function al properties of melanoma-associated antigens, and the application of immuno diagnostic and immunotherapeutic approaches to melanoma. As a result, a large body of information about various aspects of melanoma has been rapidly accumu lated during the past few years. In organizing this book I aimed at providing a readily available source of infor mation on the current research in melanoma. To this end I invited investigators with active research programs to contribute chapters describing and discussing the significance of their most recent results. To facilitate the preparation of the manu scripts and to avoid duplicating other recently published books on melanoma, I discouraged the contributors from providing extensive reviews of the literature on the various topics. Although I made every effort to be as complete as possible in the selection of the contributors, while writing this preface I realized that I had overlooked at least three investigators whose work should have been included.

"Le secret d'ennuyer est celui de tout dire. " Voltaire (Discours sur l'homme) Atopic dermatitis (AD) is frequently seen by dermatologists and pediatricians, by allergologists, and by many practitioners. The amount of data on AD is vast as it has been recognized for a very long time, has a worldwide distribution, and has a chapter or section devoted to it in every textbook or review of skin diseases. Difficulty arises in evaluating certain aspects of this complex disease, for many studies have been concerned with only some of its facets and with small numbers of patients. In addition a monograph on AD should also try to encompass the important theoretical aspects of this fascinating disease. There fore, the problem in presenting a monograph on AD lies more in the critical se lection than in the gathering of information, much of which is conflicting. This applies both to basic data and to details. Furthermore, the many divergent opinions in almost every field make it extremely difficult to draw unanimous conclusions. Consequently, the author has no option but to quote antagonistic views, try to make a compromise between these, and express his own opinion based on clinical experience and fundamental literary work.

The Second International Symposium on Narcolepsy was held at Fairchild Auditorium, Stanford University, on 6-7 July 1985 under the presidency of Drs. William C. Dement and Christian Guillemi nault. It succeeded the First International Symposium on Narco lepsy held in La Grande Motte, France, organized by Pierre Pas souant in July 1975 in commemoration of the 100th anniversary of the publication of Jean B. E. Gelineau's paper which proposed the naming of narcolepsy. At the second narcolepsy symposium, many important research reports on both basic and clinical aspects of narcolepsy were given by investigators from many countries of the world. Audience inter est was particularly attracted by the section on the relationship be tween HLA and narcolepsy, in which recent evidence that almost all narcoleptic patients are HLA-DR2 positive was reported by in vestigators from Japan, England, France, Canada, and the United States. The close relationship between the HLA antigens, hitherto considered as immune-related genetic markers encoded by genes on human chromosome 6, and narcolepsy appeared to open a new approach not only for the research of narcolepsy but also for the mechanism of sleep in general. Publication of all these new findings on the association of HLA and narcolepsy was considered; an outline was worked out and all the groups agreed to prepare a contribution covering the various aspects of this topic."

Immunopharmacology is defined as that part of pharmacology that deals with drugs acting on the immune system and, in addition, with the pharmacological actions of substances derived from the immune system. In order to lend sharper definition to the term immunopharmacology the subject matter has been divided according to clinical and pragmatic criteria. The division into immunosubstituion, immunosuppression, antiallergic substances and immunostimulation gives the heterogeneous material a tighter structure than would any classification according to origin, chemical structure or mechanism of action.

If tumor viruses did not exist in nature they might have been created by scientists interested in basic mechanisms of develop- ment, differentiation, and tumorigenesis. In contemporary euka- ryotic cell biology tumor viruses playa similar role to that which bacteriophages once had for the molecular biology of prokary- otes. Tumor viruses provide extremely useful probes for the above cellular processes since their life cycle is genetically pro- grammed and can be followed at DNA, RNA, and protein levels. The experimental systems reviewed in this volume utilize a wide variety of viruses. A comprehensive introduction to this field has recently been published in the volumes of Molecular Biology o/Tumor Viruses: DNA Tumor Viruses, 2nd edition, edited by J. Tooze; and Molecular Biology o/Thmor Viruses: RNA Tumor Viruses, 2nd edition, edited by R. Weiss, N. Teich, H. Varmus, and J. Coffm, by Cold Spring Harbor Laboratories in 1980 and 1982. Polyoma and SV40 viruses (see the chapter by A. Levine) and adenoviruses (see the chapter by W. Doerfler) are double- stranded DNA-containing viruses. Polyoma and SV40 are struc- turally related viruses which contain a genome of approximately 5 kilo basepairs, while the DNA of adenovirus is about 7 times more complex. These DNA tumor viruses are understood at a genetic and molecular level which is comparable to our know- ledge of A and T4 bacteriophages. Retroviruses, the subject of the remaining four chapters, con- tain a single-stranded RNA genome of 5-8 kilobases.

This second volume reports on the reaction patterns of lymph nodes in neoplastic and immunodeficient diseases. Based on the contents of volume 1, it presents a detailed survey of lymph node structures and their cellular components under these conditions. The patterns of nodal reactions to the development and spread of cancer have recently been investigated and discussed by several authors. Here, the immediate interactions between tumor tissue and the regional nodes have been assessed in experimental models and in human material. Using modern morphological methods such as im munohistochemistry on the light and electron microscopic level, new insights have been gained into the stepwise process of lymphogenous metastasis. Macrophages/reticulum cells were found to playa signifi cant role in this process, which is duly emphasized. Based on appro priate animal models, one chapter focuses on various subtypes of these cellular elements and their role in the two separate phases of tumor spread and the development of true metastases. The induction of fibronectin in lymph nodes is effected by tumor cells forming a special part of the extracellular matrix. The multifunctional fibronec tin molecule serves as a mediator between tumor cells and fibroblasts, furthering the formation of tumor stroma. This volume also contains a comprehensive survey of primary im munodeficiency syndromes and their nodal manifestations, reference being made to the most recent immunological knowledge."

The great majority of bacterial infections are initiated by the adhesion of pathogenic bacteria to cells and mucosal surfaces of the host. The sequela of adhesion may range from the action of toxins outside target cells to their penetration into or through tissue. Besides the consequences of bacterial adhesion related in infection, the result may be colonization of mucosal surfaces with normally harmless bacteria, which in stress situations may become virulent, a phenomenon known as nosocomial infections. With very few exceptions, adhesion is carbohydrate speci fic. It is mediated by bacterial recognition proteins that are, according to the phenomenon studied, termed adhesins or hem agglutinins; the term "lectin" is sometimes also used. The chemical nature of the ad he sins and their organization on the bacterial surface have been studied intensively in many laboratories. The application of genetic and biochemical techniques has led to substantial progress in the molecular characterization of adhesins in recent years. We now know that adhesins may occur as structural subunits of fimbriae and that they may form fimbriae which can be considered as mono- or multifunctional linear adhesin polymers. Other adhesins do not form recognizable structures and are tenta tively called nonfimbrial. Adhesins may even be components of bacterial cell walls. Adhesin-receptor specificities have been unravelled. The study of the distribution of receptors in tissue has created implications about the possible susceptibility to infections.

This volume forms part of a prestigious series and covers the latest advances in our understanding of the pathophysiology and treatment of asthma. Our understanding of asthma has changed dramatically in recent years, and much of this new information is brought together in this volume written by inter nationally recognised authorities. The aim of the book is to review in depth the changing concepts of inflammatory processes in asthma and to discuss the implications for research of this common chronic disease. Many of the advances in and future therapy our understanding of asthma have originated from a pharmacological approach, and this volume highlights the promising new options for pharma cological intervention. It is hoped this book will be invaluable for research scientists and clinic ians involved in asthma research and will be a major reference resource for chest physicians and those involved in the development of novel pharmaceu tical entities. Each chapter is extensively referenced, generously illustrated with clear diagrams and photographs, and represents a state-of-the-art review of this growing area. c.P. PAGE P.l. BARNES Contents CHAPTER 1 The Pathology of Asthma: An Overview L.A. LAmNEN and A. LAmNEN. With 10 Figures ...................... 1 A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . 1 . . . . . . . . . . . . . . . B. Methods to Investigate the Pathology of Human Asthma ............ 1 C. Bronchial Epithelium and Inflammatory Cells in Asthmatic Patients Between Attacks ........................... 2 I. Mast Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . 4 . . . . . . . . . . . . . . II. Eosinophils ............................................... 7 III. Neutrophils.............................................. 10 D. Bronchial Epithelial Inflammation During an Asthma Attack. . . . . .. . 10 E. Epithelial Regeneration .... . . . . . . . . . . . . . . . . . . . . . . .. . . 12 . . . . . . . . ."

Biological response modifiers are increasingly used in viral and cancer therapy. Since alterations of the immune system are the primary symptoms of HIV infection, especially therapies directed towards the modulation of the immune response have been under intense evaluation. This volume summarizes current knowledge of the interferon-based natural antiviral protection system including 2',5'-oligoadenylate and double-stranded RNA. It will also help to develop further a solid scientific rationale for the practical use of heterologous immunomodulators in the clinics.

Important progress in the elucidation of the mechanisms influencing bacterial pathogenicity has recently been made through the introduction of modem genetic techniques. Molecular cloning allows the isolation of genes for pheno- types that epidemiological surveys have suggested play an important role in pathogenesis. The structural analysis of determinants for pathogenic traits can lead to the identifica- tion not only of the primary sequence but also of the possi- ble secondary and tertiary structures for important viru- lence factors such as toxins and adhesins. From these data, the prediction of antigenic domains suitable for the devel- opment of new vaccines appears to be feasible. The regula- tion of virulence determinants by endogenous and exoge- nous factors can be more clearly understood through the functional analysis of the cloned virulence genes. This volume surveys representative virulence properties of gram-positive and gram-negative bacteria to which the genetic approach has been successfully applied. The exam- ples described here include important bacterial toxins (e.g., diphtheria toxin, cholera toxin, toxic shock syndrome toxin, hemolysins), adhesion structures from E. coli and Neisseria gonorrhoeae, and factors supporting iron uptake, serum resistance, and invasiveness in a variety of bacteria. Both the present state and the possible futural develop- ments of these systems are described.

During routine genetic screening of several immunoglobulin heavy chain congenic mouse strains in 1980, one of us (MB) was surprised to find that several mice in the C.B-17IIcr strain, which was being maintained in a specific-pathogen-free facility of the Fox Chase Cancer Center (Philadelphia, PA), did not express serum immunoglobulin of the appropriate allotype. Fearing an error in the breeding of these mice, the sera of the suspect mice were screened for other allotypes. When these tests revealed a complete absence of serum immunoglobulin, it became apparent that a mutation had probably occurred in the C.B-17IIcr line. Further analysis revealed that a single breeding pair was respon sible for all of the immunoglobulin negative mice and that the defect showed recessive inheritance. Thus was the C.B-17/Icr scid or severe combined immune deficient (scid) mouse discovered. Although it has taken most animal facilities several years to breed scid mice of high quality for experimental purpose, it was clear by 1987 that many investigators were beginning to exploit the unique qualities of the scid mouse for studies in several areas.

Named for the enlarged, inclusion-bearing cells characteristic of infection by these viruses, cytomegaloviruses present a significant challenge to both microbiologist and immunologist. Although most primary infections in humans are subclinical, cytomegalovirus can be associated with a wide spectrum of disease, particularly when infection occurs in the immuno compromised individual or as a result of congenital or perinatal infection. Although reinfection with cytomegalovirus has been demonstrated, most recurrent and persistent infections result from the reactivation of latent virus. Cytomegaloviruses, like other members of the Herpesviridae family, have the capacity to establish latency after a primary infection but the mechanisms for establishing the nonreplicating but reactivat able state have not been defined. The factors responsible for the spectrum of manifestations of cytomegalovirus infection are largely undetermined but host immunological function, route of infection, and size of inoculum all contribute to the extent and severity of disease. Cytomegaloviruses have the largest genomes in the herpes virus family, approximately 240 kilo base pairs, providing a potential coding capacity for more than 200 proteins of which less than one-fourth have been mapped and described. There are many similarities to other herpes viruses in genome structure and gene expression; for example, three temporal classes of genes can be identified as rx (immediate-early), f3 (early), and y (late) products. The first five chapters of this volume review and describe recent developments in understanding the trans cription and regulation of these gene classes.

Many RNA viruses have been known for decades to be genetically and biologically quite variable. Some well-known examples are influenza viruses, foot and mouth disease viruses, and Newcastle disease virus. During the past decade, it has become clear that most, it not all. , RNA viruses (riboviruses and retroviruses) are much more mutable than was recognized previously, and that this great mutability generates extremely complex populations consisting of indeterminate mixtures of related variants (Le. , "mutant swarms" or "quasispecies" populations). This is also true of DNA viruses (such as hepatitis DNA genomes via RNA transcripts B virus) which replicate their that are reverse-transcribed back to DNA. This hypermutability of RNA replicons provides great biological adaptability for RNA virus genomes. It also allows (but does not necessitate) RNA viruses, so that they can extremely rapid evolution of evolve over a million times more quickly than their eukaryotic DNA-based hosts. The genetics of RNA replicons is so unusual (and often counterintuitive) that it has many important biological conse quences which are neither readily apparent nor widely under stood. Failure to understand the distinctive aspects of RNA genetics frequently generates confusion and controversy and can adversely impact vaccine and antiviral drug programs and other applications of medical virology. The 14 chapters in this volume describe advances in a number of significant areas of RNA virus genetics and evolution.

The humoral response of the immune system to a foreign antigen usually requires the recognition of two antigenic determinants. The one, called the carrier, is recognized by T-Iymphocytes, the other, called the hapten, by B-Iympho cytes. As a consequence, T - and B-Iymphocytes proliferate, B-Iymphocytes produce hapten-specific antibodies, and the system develops memory to the antigens. It was long thought that antigens would form a bridge to mediate the cooperation of T - and B-Iymphocytes. However, it now appears that antigens are broken down to fragments which then act as carrier determinants for T -lymphocytes. The cells which originally process antigen are called an tigen-presenting cells. They have phagocytic properties. They can take up and degrade antigens, in the case of pro teins to peptides. The peptides of protein antigens reappear on the surface of the antigen-presenting cells, where they must become associated with membrane proteins encoded by genes of the major histocompatibility complex (MHC) in order to be recognized by T-Iymphocytes. To activate helper T-Iym phocytes which cooperate in antibody responses, MHC class II molecules have to be expressed on the surface of the antigen-presenting cells. Once T -lymphocytes have be come activated, they are ready to cooperate with B cells."

Molecular recognition undoubtedly governs any aspect of cellular interaction. To understand tumor cell growth regulation and spread, analysisof protein carbohydrate interactions can contribute to lead to the establishment of rational methods for diagnosis and therapy. Chemically and biochemically optimized preparation of adequate tools, their application for localization of receptor (tissue lectin) and ligand (cellular glycoconjugate) pairs in tumor cells and tumor sections and the usefulness of a lectin from a plant extract as potent immunomodulator indicate the prospect for a place of such techniques in pathology and oncology.

The mouse was first used in immunological research by Paul Ehrlich in 1891 in an extraordinary series of experiments on the maternal transfer of antitoxic immunity. A short 22 years later in 1913 Halsey Bagg acquired a stock of albino mice from a commercial dealer and used them in a series of experiments on learning. Because he was interested in the genetics of intelligence, Halsey Bagg began breeding a pedigreed line of these mice that were subsequently named for him - Bagg Albino. Though Halsey Bagg is not credited with initiating the inbred strains of mice, his stock curiously has played an indisputably important role. Bagg Albinos were progenitors of the present day BALB/c family of sublines - the subject of this book. They were also used as one of the parents in the development of inbred strains A, CBA and C3H, three other very famous strains. Today the BALB/c mouse is among the five most widely used inbred strains in biomedical research and a particular favorite in immunology and infectious disease research. The hallmark of the BALB/c response to so many kinds of infections is susceptibility and sometimes an exaggerated susceptibility, but this paradoxically is not associated with immunodeficiency as BALB/c is an excellent responder to immuni zation. These characteristics have made the BALB/c mouse a model for identifying genes that determine susceptibility to infectious and neoplastic diseases. In 1985 the laboratory BALB/c mouse became 72 years old. The current filial generations are somewhere around 350 generations MURPHY]."