Fritz Melchers - Böcker

In recent years, major developments have been made in understanding various genetic and epigenetic regulatory processes that are critical for the generation of B cell repertoires. These include the role of chromatin regulation and nuclear organization in understating the IgH gene regulation. A role and mechanism of DNA repair proteins in somatic hypermutation has been elucidated. Genetic mutation studies have been instrumental in providing insight into some of the mechanisms involved in targeting CSR to various switch DNA regions located upstream of C region genes, especially a role of AID motifs, transcription, and R-loops. Recent studies support a dominant role of receptor editing in central B cell tolerance and signaling pathways that regulate receptor editing in self-reactive and non-self-reactive immature B cells. These were some of the topics of discussion at the 11th International Conference on B cell Biology. These proceedings highlight recent developments in lymphocyte development, Ig gene rearrangements and somatic hypermutation, chromatin structure modification, B lymphocyte signaling and fate, receptor editing, and autoimmunity.

In recent years, major developments have been made in understanding various genetic and epigenetic regulatory processes that are critical for the generation of B cell repertoires. These include the role of chromatin regulation and nuclear organization in understating the IgH gene regulation. A role and mechanism of DNA repair proteins in somatic hypermutation has been elucidated. Genetic mutation studies have been instrumental in providing insight into some of the mechanisms involved in targeting CSR to various switch DNA regions located upstream of C region genes, especially a role of AID motifs, transcription, and R-loops. Recent studies support a dominant role of receptor editing in central B cell tolerance and signaling pathways that regulate receptor editing in self-reactive and non-self-reactive immature B cells. These were some of the topics of discussion at the 11th International Conference on B cell Biology. These proceedings highlight recent developments in lymphocyte development, Ig gene rearrangements and somatic hypermutation, chromatin structure modification, B lymphocyte signaling and fate, receptor editing, and autoimmunity.

The intestine is the front line of the confrontation between pathogens and the immune system. However, it is also important to emphasize that we have a symbiotic relationship with innumerable bacteria in the intestine. In the gastrointestinal tract of mammals the lower intestine harbors around 1,000 12 species of anaerobic and aerobic bacteria, in densities up to 10 /mlinthe distal small intestine, the cecum, and the colon. A single layer of epithelial cells of the intestine protects the internal organs of the mammalian host from these bacteria. Below these epithelial cells the gut-associated lymphoid tissues (GALT), organized in Peyer's patches, cryptopatches, and isolated l- phoid follicles, as well as isolated, dispersed single cells in the epithelial layer (intraepithelial lymphocytes) and lamina propria, are composed of T l- phocytes, B lymphocytes, Ig-secreting plasma cells, and antigen-presenting cells such as dendritic cells. The importance of the gut barrier is striking, if we consider that in humans the epithelial surface, behind which the immune system faces and senses the endogenous bacteria, is estimated to be as large as a basketball court.Perhaps not surprising then, the gut contains appr- imately half of all lymphocytes of our immune system. Colonization of the intestine with the ?ora of commensal bacteria induces the development of the GALT, which in turn responds by the development of IgA-secreting plasma cells. Dimeric and multimeric IgAs can traverse the epithelial layer and are released in the gut lumen, where they bind bacteria.

It has been clear for a long time that after transplantation of a lymphoid organ, hematopoietic stem cells can regenerate the compartments of the organ, provided that the rest of its architecture - the strome, the epithelia and the vessels - is intact. Ahead lies the even greater challenge to assemble also these other architectural elements of a lymphoid organ by transplanting stem cells. The workshop on lymphoid organogenesis was convened to review current knowledge of and experimental skills involved in this grand project to build a lymphoid organ from its individual cellular components.

The intestine is the front line of the confrontation between pathogens and the immune system. However, it is also important to emphasize that we have a symbiotic relationship with innumerable bacteria in the intestine. In the gastrointestinal tract of mammals the lower intestine harbors around 1,000 12 species of anaerobic and aerobic bacteria, in densities up to 10 /mlinthe distal small intestine, the cecum, and the colon. A single layer of epithelial cells of the intestine protects the internal organs of the mammalian host from these bacteria. Below these epithelial cells the gut-associated lymphoid tissues (GALT), organized in Peyer's patches, cryptopatches, and isolated l- phoid follicles, as well as isolated, dispersed single cells in the epithelial layer (intraepithelial lymphocytes) and lamina propria, are composed of T l- phocytes, B lymphocytes, Ig-secreting plasma cells, and antigen-presenting cells such as dendritic cells. The importance of the gut barrier is striking, if we consider that in humans the epithelial surface, behind which the immune system faces and senses the endogenous bacteria, is estimated to be as large as a basketball court.Perhaps not surprising then, the gut contains appr- imately half of all lymphocytes of our immune system. Colonization of the intestine with the ?ora of commensal bacteria induces the development of the GALT, which in turn responds by the development of IgA-secreting plasma cells. Dimeric and multimeric IgAs can traverse the epithelial layer and are released in the gut lumen, where they bind bacteria.

It has been clear for a long time that after transplantation of a lymphoid organ, hematopoietic stem cells can regenerate the compartments of the organ, provided that the rest of its architecture - the strome, the epithelia and the vessels - is intact. Ahead lies the even greater challenge to assemble also these other architectural elements of a lymphoid organ by transplanting stem cells. The workshop on lymphoid organogenesis was convened to review current knowledge of and experimental skills involved in this grand project to build a lymphoid organ from its individual cellular components.

Workshops on the mechanisms of B cell neoplasia have been organized alternatively in Bethesda and Basel since 1983. Prog­ ress in our understanding of the development and responses of B lymphocytes is presented and discussed with the aim and hope to understand what might go wrong when B lymphocytes are transformed into malignant cells. Such knowledge might lead to better diagnosis, prevention and even cure of these terri­ ble diseases. The presentations at the Bethesda workshops are published as papers in volumes of Current Topics in Microbiol­ ogy and Immunology, while the presentations and discussions in Basel were transcribed and published in Editions Roche. For the first time, a Basel workshop (held 4th-6th October 1998) that has been recorded and, in part, transcribed is being published as papers and discussions within Current Topics. This volume is the latest of a long series which documents the excitements of ground-breaking discoveries as well as the frustrations of our inability to fully understand the mechanisms leading to B cell neoplasia. The papers at the workshop are presented when possible in the sequence in which they were given. However, to facilitate the organization and reading of the book and to highlight gen­ eral topics and themes, the papers are organized into five sec­ tions: I B Cell and Plasma Cell Development II Chemokines and Chemokine Receptors III Chromosomal Translocations, DNA Rearrangements and Somatic Hypermutations IV Biology of Lymphomagenesis, B-CLL, Autoimmunity V Myeloma, Plasmacytomas and Related Subjects.

The papers in this book were presented at the 14th Mechanisms in B-cell Neoplasia meeting that was held in Bethesda, Maryland October 21-23, 1996. In 1995 the organizers decided that the format of the meeting would be changed and that specific topics relevant to B-cell neoplasia would be discussed. This year's topic is on the c-myc oncogene in B-cell neoplasia which has been discussed in virtually every previous meeting. Some of the presentations announced for the first time dramatic advances in our understanding of c-myc and because this subject has become highly complex it was thought that devoting the whole meeting to this theme would be appropriate. The book, therefore, repre­ sents a review of many aspects of the myc problem but by no means is truly comprehensive. In a recent Medline search there were 8,505 references to myc, fully illustrating the magnitude of the interest and depth of this field. The organizers of the meeting have each contributed review chapters that summarize different aspects of the meeting. We thank the National Cancer Institute for sponsoring this workshop and the staff of Cygnus, Inc. , for their outstanding organizational assistance. The organizers are most grateful to Vickie Rogers for assembling the book and dealing with the edi­ torialization of the manuscripts. MICHAEL POlTER FRITZ MELCHERS Table of Contents M. POlTER and K. B. MARCU The c-myc Story: Where We've Been, Where We Seem to be Going. With 2 Figures . . . . . . . . . . . . . . . . . . . . . . . . I F.

The diversity of antigen-binding structures of antibody molecules is so vast that every conceivable antigen can be bound by an antibody molecule within the immune system. This is true even for the antigen binding sites of antibodies called idiotypes, which are bound by complementary bind­ ing sites of other antibodies called anti-idiotypes. Thus, anti-idiotypes are structural homologues of antigens. These idiotypic-anti-idiotypic interactions constitute a network within the immune system. Since one lymphocyte produces only one type of antibody molecule, this network is in fact a network of cells. We expect that the network is functional: the appearance of antigen will disturb the equilibrium of the network at the point where it competes with the anti­ idiotypic lymphocyte for binding to the idiotypic lympho­ cyte. It has been known for quite some time that anti­ idiotypic antibody can be used to prime the immune system for memory to an antigen that it has never seen. This phe­ nomenon is now being explored for possible use in immuni­ zation against viruses, bacteria, parasites and tumors as well as for the modulation of autoimmunity. The ability of anti-idiotypes to mimic, both antigenically and function­ ally, the corresponding biologically active molecules seen by an idiotypic antibody was first demonstrated for the hormone insulin and is now being observed in many other systems. The papers assembled in this volume· bring the reader to the cutting edge of the potential practical applica­ tions of the network theory of the immune system.

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.

The fourth workshop on Mechanisms in B-Ce11 Neoplasia was held in Bethesda. Maryland. at the National Institutes of Health on March 24. 25 and 26. 1986. The meeting was attended by approximately 150 participants and 58 presentations were given. The purpose of these workshops and the yearly publications has been to provide a means for exchanging the rapidly developing information in this field and to bring maJor problems into focus. Edited trans- cripts of the 1983 and 1985 workshops were published by Editiones Roche Bas1e, Switzerland. Papers brought to the 1984 workshop were published in Current Topics in Microbiology and Immunology, Vol. 113. Numerous retrovira1 recombinant viral constructs are now in general use in a variety of test systems, both in vivo and in vitro. These are proving to have interesting bio10gica1-prQperties.------- Kecent1y developed systems for inducing B cell tumors are described: 1) The development of spontaneous ~-ce11 tumors in transgenic mice carrying deregulated mlGBP genes and the Ig heavy chain promoter; 2) a method for inducing *p1asmacytomas in BAL~/c mice with short latent periods of ca 70 days by infecting pristane treated mice with retroviruses carrying various types of deregulated mlGBP genes; 3) induction of pre-B cell tumors with erbB containing recombinant retroviruses; 4) induction of B-ce11 and other tumors by infection of neonates with recombinant retroviruses. Several retrovira1 constructs containing mlGBP sequences do not induce B-ce11 tumors in pristane conditioned mice *.

The papers in this book were presented at the 6th Workshop on Mechanisms in B-Cell Neoplasia, held in Bethesda, March 23-25, 1988. On alternate years this meeting is sponsored by the . ;. Basel Institute of Immunology in Basel, Switzerland and by the National Cancer Institute in Bethesda, and is attended by 100 to 150 parti­ cipants. This 6th workshop, like the preceding five, was characterized by intense and enthusiastic discussion which reflects, we think, the exciting growth and development of this field. It is quite clear, however, that despite many general advances an understanding of the precise underlying mechanisms in B-cell tumor development is not yet defined. Probably, there is no single mechanism for all the various forms of B-cell neo­ plastic development. Many different forms of B-cell neoplasms are known, and these are distinguished by several characteristics: 1) the stage of development attained by the tumor stem cells; 2) mode of growth (slow or fast); 3) association with natural or inductive etiologic agents and 4) specific and consistent mutational mechanisms such as retroviral insertion, chromosomal rearrangement. Those charac­ teristic forms which arise naturally in relatively high frequency or those tumors with hallmark properties which can be induced consistently are the models most frequently studied, e. g. , endemic Burkitt's lymphoma, follicular lymphoma, acute and chronic lymphocytic leukemia and mUltiple myeloma in man; bursal lymphoma in chickens; Abelson virus induced pre B cell lymphomas and plasmacytomas in mice and immunocytomas in rats. Each model system, has special problems and advantages.

The eighth workshop in this series on Mechanisms in B-Cell Neoplasia 1990 was held in Wilson Hall at the National Institutes of Health, Bethesda, Maryland on March 28-30. Five major topics formed the basis for the discussions: 1) progress in experimental models of B-cell tumorigenesis, 2) the role of IL-6 in plasma cell tumor formation with particular emphasis on human myeloma, 3) immortaliza­ tion and regulation of mitosis in B-cells, 4) the mYQ gene in B-cell neoplasia, and 5) the role of EBV and other oncogenes in transforma­ tion of human B-Iymphocytes. A meeting on the Epidemiology of Myeloma was held at the N. I. H. on the preceding day, and many of those interested in the clinical aspects of myeloma were also participants at the workshop. Experimental Models of B-Cell Tumor Development We have seen in the last eight years the steady growth of model experimental systems, many of which have been designed to be counter­ parts of the major forms of human B cell tumors, e. g. , follicular lymphomas, Burkitt's lymphomas, acute B-cell leukemia and multiple myeloma. A variety of novel ways of inducing these tumors has been described. Advantage has been taken of the "experiments in nature" to identify critical genes that playa role in tumor pathogenesis. These genes have been identified by being near to viral insertion and chromosomal translocation sites, or by having been incorporated or transduced into a defective transforming retrovirus.

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)