By Henry Ehrlich
This is the 50th anniversary of the discovery of IgE, known to allergy patients everywhere as the allergic antibody that when attached to mast cells and basophils via high affinity receptors called FceRI can unleash a toxic soup of mediators after encountering specific allergens. Here at AAC world headquarters, we call it IgE{vil], to distinguish it from its tolerogenic counterpart IgG[ood].
The Annals of Allergy, Asthma & Immunology has observed this watershed by publishing two articles. One of these is “Immunoglobulin E—What is it Good For?” after the 1969 Edwin Starr song, which asked the same question about war. Without getting into the theological, philosophical, and political notions of the “just war”, I reached out to the authors of this piece, Brian T. Kelly, MD and MA and Mitchell H. Grayson MD. Clearly their answer is much more nuanced than the Starr lyric “absolutely nothing.”
AAC: Thank you Dr. Kelly and Dr. Grayson for taking this time for our readers. I can see from your bibliographies that you are frequent collaborators. Can you tell us how you arrived at the decision to explore this subject for Annals readers? Does it come from frustrated patients, colleagues, or both?
Dr. Kelly: The discovery of IgE in 1966 was monumental for the field of allergy and immunology. Not only was it instrumental in describing the mechanisms behind allergic reactions but also led to diagnostic tools to aid in the treatment of patients with allergic disease (e.g. RAST testing). 50 years later we felt it was important to honor the incredible work of Drs. Ishizaka, Bennich, and Johannson by writing an update of the importance and relevance of IgE today.
AAC: You mention the term “natural IgE.” This was new to me. I knew that IgE is the least abundant of all the immunoglobulins. Does this “natural IgE” constitute the normal fraction that we all have before Th2 cells start to go crazy and produce allergic antibodies? Also is this counted as part of the “total IgE” figure that parents worry so much about, and therefore should they worry less about that number?
Dr. Grayson: Natural IgE is a relatively new concept. It is based upon studies in
animal models where the investigators found IgE production in mice that lacked T cells (a white blood cell that normally drives another cell, the B cell, to produce antibodies) and through a mechanism that did not entail traditional antigen presentation. These IgE antibodies slowly increased in concentration as the animals aged. The “purpose” for natural IgE is unknown, although some investigators propose it is produced to maintain mast cell and basophil function (via the high-affinity receptor, FceRI).
The natural IgE would add to the total IgE level. In general, total IgE is not a helpful lab test – it really depends more (at least for allergies) against what the IgE is directed (i.e., the specificity of the IgE). So, most allergists really only look at specific IgE by performing skin testing or obtaining serum specific IgE (sIgE) levels in blood testing (what was formally referred to as RAST testing, and now is usually an ImmunoCAP).
AAC: You seem to have started your inquiry guided by the principle that millions of years of evolution shouldn’t have led to asthma and allergies for their own sake. Therefore, the mechanisms of allergic reactions must have other protective purposes such as fighting parasites. I was particularly struck by the “toxin hypothesis” which sounds like a series of allergic reactions in service of a good cause. Most vivid is the hypotension that leads to the catastrophic collapse of blood pressure in anaphylaxis. Could you please describe those mechanisms and then speculate on how they go wrong?
Dr. Kelly: Anaphylaxis is the clinical response to a complex set of interactions resulting in the release of various preformed and newly formed mediators (e.g. histamine and platelet activating factor). Central to this reaction is the development of allergen specific IgE. Once produced, IgE binds to its high affinity receptor, FceRI. The next time an allergen is introduced it binds two IgE molecules resulting in cross-linking of FceRI, and ultimately release of pre-formed mediators. These mediators then drive the typical clinical features of an allergic reaction (e.g. hypotension, hives, angioedema, wheezing, vomiting, diarrhea).
As discussed in our manuscript, it makes no evolutionary sense that humans would develop a system to create illness. We touched on several hypotheses as to why IgE may be produced for beneficial effect including host defense against parasites, wound healing, and toxin elimination (“toxin hypothesis”). Unlike responses against parasites or toxins, allergies are an exaggerated and maladaptive response against specific proteins, which are otherwise not dangerous to the person.
AAC: I was quite aware of the high-affinity receptors known as FceRI that bind IgE to mast cells and basophils thereby arming them for allergic reactions. I knew less about the CD23 receptors. What determines whether IgE floating in the blood binds to one or the other?
Dr. Grayson: Well, in general, IgE will bind quite well to FceRI and if both FceRI and CD23 were available to the same IgE molecule, it would be more likely to bind to FceRI than CD23. However, in practice it probably depends on the location of the IgE and which receptor it finds first. FceRI is on mast cells, basophils, and dendritic cells (a type of white blood cell that presents proteins to lymphocytes) primarily (although this is still under investigation), while CD23 is really more of a B cell receptor (the cells that make antibodies). It is important to note that IgE bound to FceRI is much less likely to fall off (dissociate) from the receptor than CD23 (hence the reason FceRI is known as the high-affinity receptor).
AAC: I am interested in how researchers choose directions for their work. This article makes very clear that science is driven both by what you see and what you don’t see, which compels you to look further. Dr. Grayson, since one of your papers is cited, I’d like to know about how you go about choosing your next inquiry.
Dr. Grayson: My science is really based upon where our research takes us. Initially, I was interested in understanding the role of a specific cell type (the dendritic cell) in the immune response against a respiratory virus and how that might lead to development of asthma and allergies. That initial work led to the work based on IgE in the immune response to a respiratory virus and its receptor (FceRI) on dendritic cells in the lung. We now are trying to understand what anti-viral IgE might be doing in the immune response and how FceRI is regulated on these dendritic cells. So, I guess the way I choose my inquiries is to base it upon the knowledge we have gained from our previous studies. The key is to stay focused but to let the science decide where you go next.
AAC: I see that among other attributes IgE has the capacity to detect minute quantities of toxins and allergens. Does this account for the incredibly rapid succession of symptoms among organ systems in anaphylaxis?
Dr. Kelly: IgE is present in blood in small quantities when compared to other immunoglobulins (IgG, IgA, and IgM). In fact, IgE is present in quantities 200,000 fold less than IgG! However, the ability of IgE to bind small quantities is not really different from IgG. What is different is the outcome of IgE binding to a protein. Unlike IgG, when IgE is produced it binds to its receptor, FceRI, with high affinity (tight binding) on mast cells. Because of this high affinity, IgE can persist bound to FceRI for months. The ability to detect small quantities of proteins relates to the fact that IgE is “loaded” on mast cells. As described earlier, once a protein binds to several IgE molecules and brings their FceRIs together (cross-linking the receptors), there is a rapid signal that causes the mast cells to release their preformed mediators. These preformed mediators are likely the reason for the immediacy of the symptoms in anaphylaxis. However, late effects occur in anaphylaxis and allergic reactions that may be due to production of new mediators formed as a result of the activation of the mast cells.
AAC: Thank you both for your time.
Dr. Kelly received his MD from the University of Missouri – Kansas City School of medicine. He completed his pediatric residency and allergy/immunology fellowship at the Medical College of Wisconsin where Dr. Grayson was his mentor. Currently, he works as an allergist/immunologist at St. Paul Allergy and Asthma in St. Paul, Minnesota. His main clinical interests include food allergy, anaphylaxis, and asthma.
Dr. Grayson received his MD from the University of Chicago, Pritzker School of Medicine, and following an internal medicine residency at the Hospital of the University of Pennsylvania, he completed his allergy/immunology fellowship at Johns Hopkins University. Dr. Grayson is currently an Associate Professor of Pediatrics, Medicine, Microbiology and Molecular Genetics at the Medical College of Wisconsin where he has an active translational science research lab that is funded by National Institutes of Health research grants. He has published over 50 peer-reviewed articles and trained over 14 post-doctoral or clinical research fellows. Dr. Grayson is a board certified diplomate of the American Board of Allergy and Immunology, as well as being Director for Fight Asthma Milwaukee (FAM) Allies, the Milwaukee asthma consortium, and is the co-leader of the Infection, Inflammation, and Immunity Research Unit of the Children’s Research Institute of the Children’s Hospital of Wisconsin. Dr. Grayson has been named a “Best Doctor in America” every year since 2009. His clinical interests are primarily asthma, allergic rhinitis, food allergy, and anaphylaxis.