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A definitive reference on the molecular biology of B cells.

Table of Contents

1. Ig loci: structure and expression regulation

2. The mechanisms of V(D)J recombination

3. Transcriptional regulation of B lymphocyte differentiation

4. B cell transcriptome

5. The role of microRNA in B cell development and function

6. Proliferation and differentiation program of developing B cells

7. Development and function of B cell subsets

8. Evolution of primordial B cell antigen receptor

9. The evolutionary origin of V(D)J diversification

10. Receptor organization on B cells and its signaling

11. Fc and complement responses

12. The dynamic structure of germinal center: generation of high affinity Ab

13. Cell Migration

14. B cell as regulator

15. B cell memory and plasma cell development

16. Roles of lymphotoxin and Baff on B cells

17. The mucosal immune system: host-bacteria interaction and regulation of IgA synthesis

18. Gut microbiota and their regulation

19. Regulation and function of activation-induced cytidine deaminase

20. Molecular mechanism of CSR

21. Molecular mechanism of SHM

22. Aberrant AID expression by pathogen infection

23. Chromosomal translocation and mutations in B cell leukemia and lymphomas

24. B cells producing pathogenic autoantibodies

25. HIV neutralizing Ab

26. Immune deficiency caused by B cell defects

27. IMGT® for immunoglobulin repertoire analysis and antibody humanization

28. Humanized monoclonal Ab production

29. Ab therapy against lymphoma

30. Anti-interleukin-6 receptor antibody therapy against autoimmune inflammatory diseases

31. Ab therapy against chronic inflammatory immune-mediated diseases

About the Author

Dr. Tasuku Honjo graduated from Kyoto University Faculty of Medicine in 1966 (M.D.). After obtaining his Ph.D. in Biochimistry (Dr. O. Hayaishi), he spent 4 years in the U.S.A. as a postdoctoral fellow first in Carnegie Institution of Washington (Dr. D. Brown), and then in NIH (Dr. P. Leder) where he initiated studies on immunoglobulin genes. He returned to Tokyo University as an assistant professor in 1974, and then moved to Osaka University School of Medicine as Professor of Genetics in 1979. He succeeded to Dr. O. Hayaishi after his retirement at the Department of Medical Chemistry in Kyoto University. He also served as Dean of Medical School (1996-2000 and 2004-2005), and Executive Member of Council for Science and Technology Policy, Cabinet Office (2006-2012). Currently, he is Professor of Department of Immunology and Genomic Medicine, Kyoto University, and also Chairman of Board of Directors, Shizuoka Prefectural University Corporation.

Dr. Honjo is well known for his discovery of activation-induced cytidine deaminase that is essential for class switch recombination and somatic hypermutation. He has established the basic conceptual framework of class switch recombination starting from discovery of DNA deletion (1978) and S regions (1980), followed by elucidation of the whole mouse immunoglobulin heavy-chain locus. His contribution further extended to cDNA cloning of IL-4 and IL-5 cytokines involved in class switching and IL-2 receptor alpha chain. Aside from class switching recombination, he discovered PD-1 (program cell death 1), a negative coreceptor at the effector phase of immune response and showed that PD-1 modulation contributes to treatments of viral infection, tumor and autoimmunity. In addition, he is known to be a discoverer of RBP-J, a nuclear protein that interacts with the intracellular domain of Notch in the nucleus. Notch/RBP-J signaling has been shown to regulate a variety of cell lineage commitment including T and B cells.

For these contributions, Dr. Honjo has received many awards, including the Noguchi Hideyo Memorial Prize for Medicine (1981), Imperial Prize, Japan Academy Prize (1996), Robert Koch Prize (2012), and Order of Culture (2013). He is an honorary member of the American Association of Immunologists. He has been honored by the Japanese Government as a person of cultural merits (2000). He has also been elected as a foreign associate of National Academy of Sciences, USA in 2001, as a member of Leopoldina, the German Academy of Natural Scientists in 2003, and as a member of Japan Academy in 2005.

Prof. Dr Michael Reth has won the Paul Ehrlich and Ludwig Darmstaedter Prize, awarded by the Paul Ehrlich Foundation, for his research on the immune system. For the first time since 1996, the prize goes to a scientist working in Germany. Dr Reth is Professor for Molecular Immunology at the Institute of Biology III of the University of Freiburg and Scientific Director of the Cluster of Excellence BIOSS, Centre for Biological Signalling Studies. He is also head of the department for Molecular Immunology at the Max Planck Institute of Immunobiology and Epigenetics (MPI-IE). The prize is endowed with €100,000 and is one of the highest honours in science in Germany. By awarding the prize to Dr Reth, the Foundation has chosen to honour a scientist who, like Nobel laureate Paul Ehrlich, decodes how immunity operates at a molecular level, in order to find new therapies for cancer and infectious diseases.

“This award is a great honour for me, because I deeply admire Paul Ehrlich’s work in immunology,” Dr Reth said. “He was one of the first scientists to consider the molecular level in this field.” Following Ehrlich’s scientific tradition, Dr Reth chose to focus his research on how the human body recognises foreign substances. “Due to the success of vaccinations, which was one of the greatest achievements in medicine, immunology has been an applied science from the beginning. However, we still do not fully understand the processes that underlie immunisation,” Dr Reth remarks. That is why his research revolves around the B cell component of the immune system. When activated, these blood cells produce antibodies to fight off infection. Dr Reth investigates the structure and organisation of the B cell antigen receptors. These molecules on the surface of B cells recognise foreign substances, so-called antigens, and trigger the activation of the immune system. Dr Reth was able to describe the basic structure of the antigen receptor of B cells for the first time in 1989. Together with his research group, he developed a new model for the activation of this receptor and recently provided further experimental evidence for this model.

Furthermore Dr Reth has shown that receptors on the plasma membrane have a more complex structure than previously assumed. They are not freely diffusing on the cell surface but are organized in 50 to 150 nanometre sized membrane patches also called protein islands. The detailed analysis of the organization of receptors on the cellular membrane is a focus of research at the BIOSS Centre for Biological Signalling Studies, the cluster of excellence directed by Dr Reth since 2007.

Located in the Signalhaus in Freiburg, BIOSS brings together engineers and biologists to investigate signalling processes using methods of synthetic biology. In the spirit of BIOSS’s motto “from analysis to synthesis”, researchers re-construct signalling cascades or develop new kinds of systems altogether – for example, hydrogels that release medication in a temporally controlled way, or signalling proteins that can be switched on and off with light.

About Michael Reth:

In 1989 Michael Reth joined Nobel laureate George Köhler’s laboratory at the MPI and later on was appointed Chair of Molecular Immunology at the University of Freiburg. He was awarded the Gottfried Willhelm Leibniz Prize of the German Research Foundation in 1995 and the EFIS-Schering-Plough European Immunology Prize in 2009.

In 2012, Michael Reth was awarded an advanced grant by the European Research Council (ERC).

Andreas Radbruch did his PhD at the Genetics Institute of the Cologne University, Germany, with Klaus Rajewsky. He later became Associate Professor there and was a visiting scientist with Max Cooper and John Kearney at the University of Alabama, Birmingham. In 1996, he became Director of the German Rheumatism Research Centre Berlin, a Leibniz Institute, and in 1998, Professor of Rheumatology at the Charité, the Medical Faculty of the Humboldt University of Berlin.

A biologist by education, Andreas Radbruch early on worked on somatic variants in myeloma and hybridoma cells lines, modeling antibody class switching and somatic hypermutation. In this context, his lab originally developed the MACS technology. Andreas Radbruch then showed that recombination is the physiological mechanism of class switching in vivo, in plasmablasts isolated ex vivo. Moreover, he could show that in vivo, class switch recombination is targeted to the same Ig class on both IgH loci of a cell, reflecting a tight control of targeting of recombination. An essential element of this control is transcription of recombinogenic sequences, and the processing of these switch (germline) transcripts, as became evident from targeted deletion of the control regions involved. The switch transcripts are induced by cytokines of T helper cells, e.g. interleukin-4. The Radbruch lab contributed essentially to our current understanding of the polarization and imprinting of T helper cells expressing interleukin-4 (Th2) versus those expressing interferon- (Th1).

The lab then addressed the organization of immunological memory as such. First they identified longlived (memory) plasma cells, mostly residing in bone marrow but also in secondary lymphoid organs and in inflamed tissues. They could show that these cells individually persist in dedicated survival niches, organized by CXCL12-expressing mesenchymal stroma cells. They identified different, dedicated niches for CD4+ and CD8+ memory T cells in the bone marrow, too, and could show that, at least in immune responses to vaccines, memory T cells are mostly maintained in bone marrow, resting in terms of proliferation and gene expression. Thus memory niches organize and maintain memory, and bone provides a privileged environment for resting memory cells. In chronic antibody-mediated diseases, Andreas Radbruch´s lab identified pathogenic antibody-secreting memory plasma cells as critical mediators of chronicity, refractory to conventional immunosuppression, and thus representing a novel therapeutic target. Similarly, in chronic T cell-mediated diseases, the pathogenic T cells induce and adapt to chronicity. Recently, the Radbruch group has identified Twist1, HopX and the microRNAs miR-182 and miR148a as molecular adaptations of proinflammatory T cells to chronicity, and innovative therapeutic targets.

Andreas Radbruch´s work has been recognized by the Carol Nachman Prize for Rheumatology (2011), an Advanced Grant of the European Research Council (ERC, 2010), the Federal Cross of Merit (2008) and the Aronson Award (2000). He is a member of the Berlin-Brandenburg Academy of Sciences and Humanities (BBAW), the European Molecular Biology Organization (EMBO) and the German National Academy of Sciences Leopoldina.

Frederick W. Alt is a Howard Hughes Medical Institute (HHMI) Investigator and Director of the Program in Cellular and Molecular Medicine (PCMM) at Boston Children's Hospital (BCH). He is the Charles A. Janeway Professor of Pediatrics and Professor of Genetics at Harvard Medical School. He works on elucidating mechanisms that generate antigen receptor diversity and, more generally, on mechanisms that generate and suppress genomic instability in mammalian cells, with a focus on the immune and nervous systems. Recently, his group has developed senstive genome-wide approaches to identify mechanisms of DNA breaks and rearrangements in normal and cancer cells. He has been elected to the U.S. National Academy of Sciences, the U.S. National Academy of Medicine, and the European Molecular Biology Organization. His awards include the Albert Szent-Gyorgyi Prize for Progress in Cancer Research, the Novartis Prize for Basic Immunology, the Lewis S. Rosensteil Prize for Distinugished work in Biomedical Sciences, the Paul Berg and Arthur Kornberg Lifetime Achievement Award in Biomedical Sciences, and the William Silan Lifetime Achievement Award in Mentoring from Harvard Medical School.

Reviews

"...comprehensively describes how B cells are generated, selected, activated, and engaged in antibody production and the normal immune response...This field has seen rapid advances...and it is an excellent resource. Score: 83 - 3 Stars" --Doody's