Mast Cell Biology ADVVVANCES INEXPERIMENTTTALMEDICINEAND BIOLOGY Editorial Board: NATHAAANBACK,State University of New York at Buffalo IRUUUNR. COHEN, The Weizmann Institute of Science ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research JOHN D. LAMBRIS,University of Pennsylvania RODOLFO PAOLETTI,University of Milan Recent Volumes in this Series Volume 708 INVERTEBRATE IMMUNITY Kenneth Söderhäll Volume 709 HISTAMINE IN INFLAMMATION Robin L. Thurmond Volume 710 RECENT ADVANCES ON MODEL HOSTS Eleftherios Mylonakis Volume 711 EPIGENETIC CONTRIBUTIONS IN AUTOIMMUNE DISEASE Esteban Ballestar Volume 712 CYSTEINE PROTEASES OF PATHOGENIC ORGANISMS Mark W. Robinson and John P. Dalton Volume 713 CELL FUSION IN HEALTH AND DISEASE, I: CELL FUSION IN HEALTH Thomas Dittmar Volume 714 CELL FUSION IN HEALTH AND DISEASE, II: CELL FUSION IN DISEASE Thomas Dittmar Volume 715 BACTERIAL ADHESION: BIOLOGY, CHEMISTRY AND PHYSICS Dirk Linke and Adrian Goldman Volume 716 MAST CELL BIOLOGY: CONTEMPORARY AND EMERGING TOPICS (cid:2) (cid:2)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)(cid:5)(cid:8)(cid:9)(cid:2)(cid:10)(cid:11)(cid:2)(cid:12)(cid:8)(cid:4)(cid:13)(cid:4)(cid:4)(cid:5)(cid:14)(cid:2)(cid:5)(cid:14)(cid:7)(cid:2)(cid:15)(cid:16)(cid:5)(cid:14)(cid:2)(cid:15)(cid:11)(cid:2)(cid:10)(cid:16)(cid:17)(cid:18)(cid:5)(cid:4)(cid:19)(cid:16) AContinuation Order Plan is available for this series. Acontinuation order will bring delivery of each new volume immediately upon publication. Volumes are billed only upon actual shipment.For further information please contact the publisher. 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W1AD559 v.716 2011 / QS 532.5.C7] QR185.8.M35M363 2011 571.6--dc22 2011003740 DEDICAAATION The editors would like to dedicate this work to the many present and former members of the Laboratory of Allergic Diseases who have contributed to the success of the clinical and basic research programs in theLAD since the inception of the Laboratory in 1995. We feel privileged to have worked with so many talented and enthusiastic fellows, nurses, administrators and senior scientists. AA special thanks to Dr. Anthony Fauci, the Director of the National Institute of Allergy and Infectious Diseases who, along with Dr. TTTom Kindt, then the Director of the NIAID Division of Intramural Research, supported the creation of the LAD; and to Dr. Katherine Zoon for her encouragement and support in the contemporary expansion of the clinical research program of the LAD. We are especially indebted to the patients who have participated in clinical research protocols directed at understanding and treating allergic diseases and systemic mast cell disorders. v FOREWORD The editors of this book, Drs. Gilfillan and Metcalfe, have enlisted an outstanding group of investigators to discuss the emerging concepts in mast cell biology with respect to development of these cells, their homeostasis, their activation, as well as their roles in maintaining health on the one hand and on the other, their participation in disease. As noted by several of the contributors, there have been extraordinary advances in our understanding of these phenomena over the past 40 years since the tools became available to analyze these aspects at a molecular level. Initially, this ability was made possible by the use of so-called model systems by which phenomena such as the allergic response involving the IgE-mediated activation of mast cells, and the related basophils, could be investigated. The discovery of a rat mucosal mast cell tumor analog –the “rat basophilic leukemia” (RBL) cells—and the development of lines of IgE myeloma protein producing cell lines, permitted a rigorous analysis of the cellular receptor that triggered the explosive release of a variety of potent mediators. This was soon followed by the initial identification of the proximal post-receptor molecules that were activated when the receptor-bound IgE was aggregated by antigen or bivalent anti-IgE. As knowledge about similar systems expanded, extraordinarily powerful cell biological methods were developed. That knowledge and those methods have been productively applied to analyze those model systems and, increasingly, their normal counterparts in rodent cells and, even more recently, in human cells. At the same time, less reductive more physiological studies have vastly increased our insight into the role mast cells play in a variety of aspects of the immune response. These new insights not only expand our knowledge of cell biology in general but hopefully will be therapeutically applicable. Indeed, almost without exception, the authors of each of the articles in this compendium end their presentations by noting that their studies have helped to define new targets to which drugs could be directed in order to alleviate some of the pathological phenomena that are mediated by mast cells. However, as noted for example in the contribution byTsai et al, the fact that mast cells have both positive and negative immunomodulatory functions present the challenge of whether such functions can be manipulated for therapeutic ends by suppressing those vii viii FOREWORD actions that result in disease without interfering with those functions that promote health by enhancing beneficial immune responses. TTTwo recent events underscore this dilemma.On the down side is the case of Alzheimer disease. It has long been posited that the disease is caused by the accumulation of so- called amyloid beta plaques in the brain. Because gamma secretase is believed to play an important role in formation of the plaque, a drug designed to inhibit the activity of that enzyme was thought to be promising. Indeed, a trial of such a drug, Eli Lilly’s semagacestat, had advanced to a Phase III clinical trial involving some 2600 patients. But in August of this year the multi-million dollar trial had to be abruptly halted when the developing data showed that the drug not only failed to slow progression of the disease, but was associated with a worsening of cognition and the ability to perform the tasks of daily living. On the other hand, a more hopeful conclusion is prompted by a report published that same month by the laboratory of TTTak Mak.1That group has been studying the MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) -protein serine/ threonine kinases that are activated by ERKK or p38 and which phosphorylate eIF4E, a component involved in the initiation of cap-dependent translation. Surprisingly, they found that Mnk1/2 double knockout mice not only exhibited normal cell growth and development despite an absence of eIF4E phosphorylation, but that the tumorigenesis occurring in a mouse model was suppressed by the loss of Mnk1/2.Furthermore, stable knockdown of Mnk1 in a human glioma cell line resulted in dramatically decreased tumor formation when these cells were injected into athymic nude mice.Thus, their data demonstrate an oncogenic role for Mnk1/2 in tumor development, and highlight these molecules as potential anticancer drug targets that could be inactivated with minimal side effects.Clearly, translating such findings to warrant a clinical trial will require many more steps but it shows that despite the complexity of cellular biochemical pathways it may be possible to pin-point specific components that though participating in normal functions can be dispensed with when they become involved in pathological processes. Many other results from clinical trials of rationally designed therapeutics, some disappointing, others successful such as the inhibitor of theABLL tyrosine kinase, imatinib (Gleevec®) and the anti-tumor necrosis factor monoclonals infliximab (Remicade®) and adalimumab (Himura®), could be cited. So how realistic are the proposals that our increased insight into mast cell biology can be translated to yield therapeutic benefits?TTTo state my own cautious optimism in semi-quantitative terms, I believe that whereas our knowledge can be expected to continue to expand exponentially, the applicability of that knowledge will proceed only linearly and with a rather shallow slope. The enormous expense of clinical trials makes it critical that pre-clinical investigations should be exhaustive, and we must be careful not to let those who pay for our research, whether it be the general public or private investors, be encouraged to believe otherwise. Henry Metzger National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health, Bethesda, Maryland, USA (cid:2) (cid:28)(cid:11)(cid:2)’(cid:16)(cid:7)(cid:5)*(cid:30)(cid:31)(cid:5)(cid:6)(cid:5)<(cid:8)(cid:10)(cid:30)=(cid:4)(cid:8)(cid:5)(cid:3)>(cid:16)(cid:17)(cid:5)(cid:4)(cid:11)@(cid:21)(cid:25)(cid:20)(cid:8)(cid:14)(cid:16)(cid:7)(cid:7)(cid:16)(cid:13)(cid:18)(cid:8)(cid:16)(cid:14)(cid:18)(cid:23)(cid:19)(cid:21)(cid:9)(cid:10)(cid:3)\<(cid:8)(cid:14)(cid:5)(cid:6)(cid:16)^(cid:8)(cid:14)(cid:17)(cid:16)(cid:9)(cid:5)(cid:18)(cid:17)(cid:8)(cid:14)(cid:22)<(cid:8)(cid:14)(cid:5)(cid:6)(cid:16)(cid:28)(cid:5)(cid:14)(cid:7)_ (Mnk1 and Mnk2) delays tumor development. Proc NatlAcad Sci USAA 2010; 107:13964-13990. ABOUT THE EDITORS... ALASDAIR GILFILLAAAN, PhD received a BSc from the University of Strathclyde, Glasgow, Scotland and MSc and PhD degrees in Pharmacology from theUniversity of Manchester, England.Following completion of his PhD, he moved to the United States to undertake research in Cell Biology and Biochemistry in the Department of Pediatrics, Yale University Medical School; initially as a Postdoctoral Fellow, then as anAssociate Research Scientist. From there, Dr. Gilfillan moved toF. Hoffman-La Roche Ltd (Nutley, NewJersey,USA) where he spent several years conducting preclinical research in the areas of allergy and inflammation. In 1999, he joined theLaboratory of Allergic Diseases (LAD), at the National Institute of Allergy and Infectious Diseases (Bethesda, Maryland, USA), where he currently helps direct the basic research efforts within the Mast Cell Biology Section. Dr. Gilfillan has had a long term interest in mast cell biology, and his current research focuses on the elucidation of signaling mechanisms associated with the activation of mast cells throughFc(cid:2)RI, KIT and other receptors, in health and disease. Dr. Gilfillan is the author of more than 90 scientific articles, and more than 50 abstracts. From 1994-2001, he was on the editorial board of the Journal of Pharmacology and Experimental Therapeutics. He currently serves on the editorial boards of Journal of Immunology, Immunology Letters, The Open Immunology Journal, The Open Allergy Journal, and theWorld Journal of Biological Chemistry. ix ABOUT THE EDITORS... DEAAAN METCALFE, MD, received a BS from Northern Arizona University and an MD from theUniversity of TTTennessee. He completed a residency in Internal Medicine at the University of Michigan and received a MS in Microbiology from the University of Michigan. Dr. Metcalfe was a Fellow in Allergy and Immunology at NIHand a Fellow in RRRheumatology and Immunology at the Robert Brigham Hospital and the Harvard Medical School. In 1979, he returned to NIHas a Senior Clinical Investigator. His subsequent career has been devoted to research and public service at the NIH. There he combines clinical and basic research, patient care and administrative duties, as well as scholarly activities in the form of teaching, writing, and speaking on areas related to allergic diseases. In 1995, Dr. Metcalfe was appointed the first Chief of the newly created Laboratory of Allergic Diseases (LAD), NIAID. He is also Chief of the Mast Cell Biology Section/LAD and Associate Director of the NIHClinicalCenter Allergy and Immunology ClinicalFellowship Program which is administered through theLAD. Dr. Metcalfe is an author on over 490 scientific papers and 230 abstracts; and an editor on 12 books on mast cell biology, systemic mast cell disorders, food allergy and asthma. He is a past Chairman of the American Board of Allergy and Immunology; a past President of the American Academy of Allergy, Asthma and Immunology; and a past Chairman of theACGME-RRC for Allergy and Immunology. Dr. Metcalfe has been elected to membership in theAmerican Clinical and Climatological Association, the Collegium Internationale Allergologicum, the American Society for Clinical Investigation, and theAmerican Association of Physicians. xi PARTICIPPPANTS Soman N.Abraham Peter Bradding Departments of Pathology, Immunology, Department of Respiratory Medicine and Molecular Genetics (cid:12)(cid:4)(cid:16)(cid:14)(cid:13)(cid:16)(cid:4)(cid:7)‘(cid:21)(cid:6)(cid:26)(cid:8)(cid:17)(cid:5)(cid:4) and Microbiology Leicester DukeUniversity Medical Center UK Durham, North Carolina USA GeorgeH.Caughey Department of Medicine Sarah J.Austin Pulmonary and CriticalCare Division Laboratory of Allergic Diseases University of California at San Francisco National Institute of Allergy San Francisco, California and Infectious Diseases USA National Institutes of Health Bethesda, Maryland Enrico Crivellato USA Department of Medical and Morphological Research MichaelA. Beaven Section of Anatomy Laboratory of Molecular Immunology University of Udine Medical School National Heart, Lung Udine and Blood Institute Italy National Institutes of Health Bethesda, Maryland Maria Ekoff USA Clinical Immunology and Allergy Department of Medicine Ulrich Blank Karolinska Institutet InsermU699, Université Paris 7 Stockholm and Sweden Faculté de Médecine Paris Diderot Site Xavier Bichat Stephen J. Galli Paris Department of Pathology France Department of Microbiology and Immunology Stanford University School of Medicine Stanford, California USA xiii