Keynote Lecture - IgE, FcεRI, and Numbers
Donald W. MacGlashan, Jr., MD, PhD
Director of the Division of Allergy and Clinical Immunology at Johns Hopkins University
IgE-mediated secretion from mast cells and basophils is a hallmark of an allergic response. For the past 5 decades, studies have begun to elucidate the relationship between this response and serum IgE levels, the nature of the reaction that mediates the secretion of mediators from mast cells and basophils and some understanding of the conditions that lead to secretion. Knowing that IgE binds to the high affinity receptor for IgE on these cells is not enough information to understand why clinical phenotypes exist. Efforts to understand how the “numbers” help predict cellular behavior and clinical phenotypes are the focus of this seminar. While reviewing the quantitative aspects of this reaction, several examples of how these “numbers” help us to understand the qualitative aspects of the reactions will be discussed.
The seminar will cover:
- FceRI density (and therefore IgE density) on mast cells and basophils and how this relates to circulating IgE.
- The nature and number of crosslinks or aggregates of FceRI required to initiate a response on basophils and mast cells and how this helps to understand the significance of the relationship between specific and total IgE and help predict the efficacy of omalizumab.
- A unique characteristic of human basophils and mast cells that may explain the clinical efficacy of omalizumab, notably the expression of SYK and its role in the cellular response and response to omalizumab treatment.
Dr. Donald MacGlashan's educational training began with dual degrees in Chemistry and Biology at California Institute of Technology followed by an MD and PhD at Johns Hopkins University. His background in chemistry resulted in an interest in biophysics. With this background he was studying molecular assembly –self-aggregation—and this led him to studies of antibody-antigen aggregation reactions as applied to stimulation of mast cells and basophils. Dr. Lawrence Lichtenstein was his mentor for both his Ph.D. and post-doctoral training at Johns Hopkins where he developed a research program to study IgE-mediated activation of basophils and mast cells.
What began as an interest in aggregation reactions quickly led to studies of signaling in these cells with a specific interest in how the cells turn themselves off after stimulation. In the early years, he developed methods to purify human basophils and mast cells in order to study signaling. These methods have mutated over the decades but still provide the means to study these rare cells. Along the way, his research has focused on different aspects of the biology of these cells. Early studies identified the released mediator profiles and these efforts led to the first studies to identify leukotriene release from mast cells and basophils followed by being first to demonstrate IL-4 secretion from basophils but not mast cells. In projects to find ways to blunt the activation of these cells he joined the development team at Tanox (and later Genentech) that produced the first therapeutic anti-IgE antibodies that eventually led to FDA approval of omalizumab. Because we had first shown that IgE up-regulated expression FceRI, in the context of a therapeutic reagent like omalizumab we could determine that it was this property of the IgE-FceRI system that allowed omalizumab to be therapeutically efficacious. With a larger team at Hopkins, we developed projects that used omalizumab to explore the underlying biology of the human allergic response. Running in parallel with these projects was an evolving project to define signal transduction in these cells and combined with the omalizumab projects, we identified an unexpected modulation of SYK expression that is unique to human basophils during treatment with omalizumab. We also discovered the mechanisms of tachyphylaxis/desensitization in basophils and mast cells that are unique from animal models of these cells, and which offer a possible therapeutic approach to turning off these cells.
Carl Prausnitz Lecture - Insights into Atopic Dermatitis
Raif Geha, MD
Medical School and the Chief of the Division of Immunology, Allergy, Rheumatology and
Dermatology Division at Boston Children’s Hospital
The lecture will cover the role of basophil derived IL-4 in promoting the capacity of dendritic cells (DCs) to drive Th2 polarization in Atopic Dermatitis (AD). It will dissect the mechanisms by which S. aureus skin colonization promotes IgE mediated anaphylaxis in AD. The mechanism by which cutaneous exposure to S. aureus triggers AD will be explored.
- Understand the multifaceted roles innate cell derived IL-4 plays in allergic sensitization
- Understand the skin to gut crosstalk that mediates the exacerbation of food allergy in AD by S. aureus skin colonization
- Gain insight into the mechanisms by which cutaneous exposure to S. aureus triggers AD
Dr. Geha received his M.D. degree in 1969 from the American University of Beirut, Lebanon, and trained in Pediatrics and Immunology at Boston Children’s Hospital and Harvard Medical School. Dr. Geha’s research interests are in molecular and cellular mechanisms of primary immunodeficiencies and atopic dermatitis/food allergy. He has contributed to more than 475 original articles, 150 reviews, several monographs and a book. His publications have appeared in Cell, Immunity, Nature, Nature Genetics, Molecular Cell, PNAS, Journal of Experimental Medicine, Journal of Immunology, Journal of Allergy and Clinical Immunology, Journal of Clinical Investigation, and Science Immunology. Information about Dr. Geha’s current research can be found on https://www.gehalab.org.
Dr. Geha has received the E. Mead Johnson Award for Pediatric Research, considered the highest award for pediatric research, the Kuwait Foundation for the Advancement of Sciences Prize, and the American Association of Immunologists Prize in Human Immunology Research. He has served on a number of NIH study sections and on the NIAID council, has been a director of the American Board of Allergy and Immunology, was elected to the American Society of Clinical Investigation and the American Association of Physicians, has presided over the Clinical Immunology Society and chaired the WHO/IUIS Committee on Immunodeficiency. Dr. Geha has trained more than 150 postdoctoral fellows, many of whom are leaders in the fields of Allergy and Immunology.
Paul Kallos Memorial Lecture - Microbial Future-proofing - How Early Life Microbiomes Shape Immune Function and Childhood Allergy
Susan Lynch PhD
Professor of Medicine and Pediatrics,
Director Benioff Center for Microbiome Medicine,
Associate Director Microbiome in IBD Program,
University of California San Francisco
Several very early life exposures known to increase risk of allergy and asthma also shape gut microbiomes. This has led to the discovery that the infant gut microbiome is characteristically perturbed and metabolically dysfunctional in those who subsequently develop atopy and asthma in childhood. The products of this high-risk infant gut microbiome promote canonical features of allergic inflammation, leading to the identification of key infant gut bacterial products that regulate airway immunity. These observations have led to an interest in the prenatal determinants of atopy and the observation that inter-generational transmission of microbes and their encoded genes relate to early life markers of allergy. Thus, a growing body of evidence indicates that pre- and post-natal perturbations to the microbiome and early life microbiome metabolic dysfunction promotes allergic immune development in childhood.
- Compare infant microbiota features that distinguish high and low risk for atopy and asthma in childhood
- Define a mechanism by which microbial metabolites promote allergic inflammation
- Identify inherited microbial functional features that protect against early life markers of allergic sensitization
Dr. Lynch received her undergraduate and graduate degrees in Microbiology from University College Dublin, Ireland, before performing her postdoctoral research as a Dean’s Fellow in the Department of Microbiology and Immunology at Stanford University in the laboratory of Dr. A.C. Matin. She is currently a Professor in the Departments of Medicine and Pediatrics at the University of California San Francisco, where she also serves as Director of the Benioff Center for Microbiome Medicine. Dr. Lynch’s research program focuses primarily on the gut and airway microbiome and their role in the developmental origins and maintenance of chronic inflammatory disease, with a specific focus on allergy and asthma. Her integrative research program examines microbiome functional relationships with chronic inflammatory outcomes to inform cellular and molecular mechanisms underlying these relationships. Her translational research program develops novel microbiome-based interventions to engineer microbiome colonization and productivity to regulate immune tone. She has served on the National Academy of Science and Engineering committee on Advancing Understanding of the Implications of Environmental-Chemical Interactions with the Human Microbiome, and as an American Society of Microbiology, Distinguished Lecturer (2017-2019). She delivered the Rebecca Buckley Lectureship at the AAAAI in 2015 and was named one of Foreign Policy Magazine’s "Global Thinkers" in 2016. She sits on the board of directors of Siolta Therapeutics, a company she co-founded in 2017, that is currently testing a first-in-human neonatal gut microbiome reengineering strategy for the prevention of childhood atopy and asthma.
Presidential Lecture - The Long and Winding Road to Siglec-based Therapeutic Strategies
Bruce Bochner, MD
Northwestern University Feinberg School of Medicine
Division of Allergy and Immunology
Siglecs (sialic acid-binding, immunoglobulin-like lectins) are a family of single-pass transmembrane cell surface proteins found predominantly on leukocytes. Their unique structural characteristics include an N-terminal carbohydrate-binding (“lectin”) domain that recognizes specific sialic acid-containing glycosides, followed by a variable number of immunoglobulin-like domains, hence these structures are a subset of the immunoglobulin gene superfamily. Another unique feature of Siglecs is that most, but not all, possess so-called immunoreceptor tyrosine-based inhibitory motifs (“ITIMs”) in their cytoplasmic domains, suggesting that these molecules function in an inhibitory capacity. Siglec-8, the eighth member identified at the time, was discovered as part of efforts initiated in the late 1990’s to identify novel human eosinophil proteins. Since that time, its selective expression on human eosinophils has been confirmed, but its expression on mast cells was also detected. Subsequent efforts over more than 20 years have delineated the unique sialoside ligands for Siglec-8, as well as the inhibitory effects of its engagement by antibodies or specific ligands on cell function and survival. In 2012, a biotech company named Allakos was founded to take Siglec-8 based therapies into the clinic for eosinophil and mast cell-associated disorders. More recently, Siglec-6, expressed predominantly on human mast cells, has garnered attention as another potential therapeutic target. This talk will review Siglecs relevant to eosinophils and mast cells, how they function, and how they are being targeted for therapeutic benefit.
- Describe unique expression patterns and structure/function features of Siglecs.
- Define similarities and differences between mouse and human Siglecs.
- Understand how Siglec-6 and Siglec-8 function on human eosinophils and/or mast cells.
- Summarize how Siglecs can be targeted for therapeutic benefit in eosinophil and mast cell-associated disorders.
Bruce S. Bochner, MD attended medical school and Internal Medicine residency training at the University of Illinois College of Medicine in Chicago, followed by postdoctoral allergy and immunology training at Johns Hopkins in the Division of Allergy and Clinical Immunology of the Department of Medicine, where he joined the faculty in 1988, was promoted to professor in 1999 and subsequently served as Division Director from 2003 to 2013 before accepting the professorship at Northwestern. His primary clinical and NIH-funded research interests center on the function and regulation of eosinophils and mast cells. He is involved in improving treatments of these diseases through inhibiting the function of these cells and in this regard cofounded the company, Allakos, Inc. that is actively pursuing such antibody-based therapies. Dr. Bochner has supervised over 40 MD, PhD/MD, and PhD postdoctoral fellows and graduate students. He has served on NIH study sections, on several editorial boards including the JACI, as Editor-in-Chief for Allergy and Immunology for UpToDate, as a Director of the American Board of Allergy and Immunology, and on the Board of AAAAI. He is an author on over 300 manuscripts with an H-index of 85. Honors include multiple teaching awards, election to ASCI and AAP, recipient of the 2019 Mentorship Award from the AAAAI and serving in leadership roles for the International Eosinophil Society and the Collegium Internationale Allergologicum.
Relaxing Lecture - Misinformation: The Battle Continues!
Timothy Caulfield, LLM, FRSC, FCAHS
Canada Research Chair in Health Law & Policy
Professor, Faculty of Law and School of Public Health
Research Director, Health Law Institute, University of Alberta
Timothy Caulfield is a Canada Research Chair in Health Law and Policy, a Professor in the Faculty of Law and the School of Public Health, and Research Director of the Health Law Institute at the University of Alberta. His interdisciplinary research on topics like stem cells, genetics, research ethics, the public representations of science, and public health policy has allowed him to publish over 350 academic articles. He has won numerous academic, science communication, and writing awards, and is a Fellow of the Royal Society of Canada and the Canadian Academy of Health Sciences. He contributes frequently to the popular press and is the author of two national bestsellers: The Cure for Everything: Untangling the Twisted Messages about Health, Fitness and Happiness (Penguin 2012) and Is Gwyneth Paltrow Wrong About Everything?: When Celebrity Culture and Science Clash (Penguin 2015). His most recent book is Relax, Dammit!: A User’s Guide to the Age of Anxiety (Penguin Random House, 2020) (US Title: Your Day, Your Way). Caulfield is also the co-founder of the science engagement initiative #ScienceUpFirst and the host and co-producer of the award-winning documentary TV show, A User’s Guide to Cheating Death, which has been shown in over 60 countries, including streaming on Netflix in North America.
Pro/Con Debate: Biologics have Solved the Problem of Type 2 Asthma
Pro: Parameswaran Nair MD, PhD, FRCP, FRCPC, FCAHS
Frederick E. Hargreave Teva Innovation Chair in Airway Diseases & Professor of Medicine in the Division of Respirology at McMaster University in Hamilton, Ontario, Canada
Dr Nair is the Frederick E. Hargreave Teva Innovation Chair in Airway Diseases & Professor of Medicine in the Division of Respirology at McMaster University in Hamilton, Ontario, Canada, providing tertiary care to patients with severe asthma and other complex airway and eosinophilic lung diseases. He directs a patient-centred translational research program at the Firestone Institute of St Joseph’s Healthcare, focussed on charactering bronchitis using sputum biomarkers, and targeted therapy with biologics and small molecule antagonists. The research program has been recognized by a Canada Research Chair, The American Thoracic Society’s Ann Woolcock Award, The Asthma Society of Canada’s Bastable Potts Award, Fellowships of the Canadian Academy of Health Sciences, The European Respiratory Society, and The American College of Chest Physicians, and Memberships of the Collegium Internationale Allergologicum and National Academy of Medical Sciences of India. His laboratory has contributed to over 300 peer-reviewed publications in high impact general medical, allergy, and respiratory journals (h-index 70).
Con: Sally E. Wenzel, MD
Department Chair, Environmental and Occupational Health
Professor of Medicine and Immunology
Rachel Carson Chair in Environmental Health
Director, University of Pittsburgh Asthma and Environmental Lung Health Institute @UPMC
Dr. Sally Wenzel completed her MD degree at the University of Florida and spent 19 years at National Jewish and the University of Colorado before moving to the University of Pittsburgh. She received numerous awards from the American Thoracic Society and the European Respiratory Society. She is currently Director of the University of Pittsburgh Asthma and Environmental Lung Health Institute at UPMC, and Chair for the Department of Environmental and Occupational Health, at the School of Public Health, University of Pittsburgh. Dr. Wenzel has a passion for improving the understanding of the prevention and treatment of asthma, in particular severe asthma, where both genetic and environmental factors are likely to be playing a role. She has performed research bronchoscopies on hundreds of asthma patients, studies critical to identifying the heterogeneity of asthma, including the influence of T2, T1 and innate immunity. Her current bench-lab interests include the role of epithelial cells in the modulation of redox balance, inflammation, mucus production and clearance in the airways. She now chairs the Department of Environmental and Occupational Health at the University of Pittsburgh, where she is leading efforts to address the effects of the environment and its various pollutants to impact oxidative stress in airway epithelial cells of asthmatic patients. She has authored more than 350 publications and is the recipient of numerous awards including the European Respiratory Society (ERS) Presidential Award in 2017, the American Thoracic Society (ATS) Foundation Breathing for Life 2016 Award, and the ATS Amberson Lecture in 2021 for her career work in all aspects of asthma. As Chair of Environmental and Occupational Health, she is dedicated to improving the air and water quality of our region and its disproportionate impact on the health of people of color.