Published online before print June 13, 2008
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Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA
1 Correspondence: E-mail: hrosenberg{at}niaid.nih.gov
The manuscript "IgE accelerates in vitro development of mast cells and modifies their phenotype" was selected as a Pivotal Advance because of its unique focus on monomeric IgEs and the mechanisms via which they promote mast cell growth and differentiation. Here, Dr. Kawakami and colleagues demonstrate that IgEs, particularly highly cytokinergic IgEs, stimulate mast cell growth and promote maturation in association with augmented production of proteases and TNF-
.
Dr. Kawakami, before we begin, can you tell us a bit more about highly cytokinergic (HC) IgEs and poorly cytokinergic (PC) IgEs? How are these mediators defined? Can you explain a bit more about the initial observations that created the distinction between these two categories of IgE?
TK: My group and Gerald Krystal’s group first described effects of monomeric IgE on mast cell survival back in 2001 [1 , 2 ]. Although both groups showed the same biological effect, specifically, promotion of mast cell survival, the two studies differed in an important way. Specifically, the Krystal group detected secretion of several cytokines in response to IgE and suggested a mechanism based on cytokine-dependent survival, which correlated nicely with various signaling events. On the other hand, we could not detect any cytokine secretion, even after extensive expression analysis. Because both groups used monoclonal anti-DNP IgE molecules and bone marrow-derived cultured mast cells (BMMC), we were puzzled about the differences for some time. Later, we determined that different responses emerged from the IgE molecules used in each of the initial studies, and ongoing work revealed tremendous heterogeneity among IgE molecules, specifically related to their potency in promoting mast cell survival and their ability to induce antigen-dependent activation events [3 ]. Therefore, we coined the terms highly cytokinergic (HC) and poorly cytokinergic (PC) IgE for those that can induce strong and weak cytokine production, respectively. So, HC and PC IgEs are essentially defined operationally.
I need to emphasize that our definitions of HC and PC IgEs reflect differences in the abilities of these molecules to induce cytokine production in a standard assay system, i.e., incubation of BMMC with IgE for 10–24 h. However, it is important to recognize that cytokine production is not an all-or-nothing event; and, although we have defined two distinct categories, there should also be IgEs that exhibit intermediate levels of cytokine production. A good thing about this classification system is that there is a nice correlation between differences in cytokine production and differences in other activation events. This is actually not surprising because HC IgEs can cause stronger or more extensive aggregation of Fc
RI than PC IgEs.
Among your most interesting findings is the observation that HC IgE results in augmented mast cell differentiation in culture. In the Discussion, you note that this may be the result of autocrine stimulation. What cytokine is or cytokines are likely to be involved in such a pathway, given that IL-3 has already optimized for this activity? Can you envision other possible mechanisms, perhaps unrelated to specific cytokine stimulation?
TK: We do not have direct answers to these questions yet. However, I believe it is reasonable to assume that there are roles for autocrine/paracrine cytokines in augmented mast cell differentiation because HC IgE-stimulated mast cells should secrete various cytokines, many of which have the ability to affect mast cell differentiation, as discussed in our recent publication [4 ]. However, we have not tested another possibility, specifically, that cell-to-cell contacts might be involved in HC IgE-mediated enhancement of differentiation.
You also noted in the Discussion that this work provides the first morphologic evidence for IgE-mediated degranulation in absence of a multivalent antigen—was this a surprising finding?
TK: It was not surprising to us because we had previously shown that histamine is released from BMMC incubated with SPE-7 IgE [3 ]. However, others have reported negative results with similar experimental protocols, so this confirmatory result made us very happy. Seeing is believing! I thank our collaborators Bridget Wilson and Janet Pfeiffer in Albuquerque, New Mexico, for their beautiful electron micrographs for this manuscript.
Can you comment on any known in vivo correlates of these findings? Can IgE-FcR binding in the absence of antigen be detected in association with specific allergic states?
TK: The in vivo relevance of the effects of monomeric IgE has been investigated. For example, mice bearing an HC IgE-producing hybridoma have increased numbers of mast cells in various tissues compared with naive mice or to mice bearing a PC IgE-producing hybridoma [3
]. As another example, IgEs administered as topical treatments to mouse skin induce not only migration of mast cells but also degranulation of migrated mast cells, with higher potency effects observed in response to HC than to PC IgEs [5
]. Furthermore, injection of IgE into the sensitization area of the skin can restore contact sensitivity in IgE–/– mice, showing a biological effect of IgE in an antigen-non-specific manner [6
]. Interestingly, most of FcRI molecules on the surface mast cells are constitutively bound by IgE, although it is not know whether such IgE molecules exhibit HC or PC properties, let alone their effects on mast cell differentiation. This is the area we need to study in the future.
Dr. Kawakami, can you tell us a bit about yourself and your career? How did you become interested in mast cells and the field of allergic inflammation in general?
TK: I received my MD and PhD degrees from University of Tokyo, Japan, where I was trained as a molecular biologist by Dr. Tasuku Honjo when he was as Assistant Professor. My postdoctoral training was with Drs. Stuart A. Aaronson and Keith Robbins at the National Cancer Institute, at the NIH. At that time, I was interested in oncogene research and cloned and characterized the tyrosine kinase, Fyn [7 , 8 ] as a postdoctoral fellow. When I joined a newly established La Jolla Institute for Allergy and Immunology in 1990, I wanted to embark on a study on immune cell signaling because my interests had extended to include the larger field related to physiological functioning of Fyn and other tyrosine kinases. Drs. Teruko and Kimishige Ishizaka, the discoverers of IgE and founders of the new Institute, kindly introduced me to the field of mast cell research. After more than ten years of studies on the role of kinases Btk and Lyn in mast cell activation, we have elucidated issues related not only mast cell signal transduction per se, but also specific in vivo consequences of mast cell activation, i.e., allergic inflammation. We recently established a new, highly efficient protocol to induce atopic dermatitis (AD)-like skin lesions in mice [9 ]. This AD model is being fully used in my laboratory in order to analyze the mechanisms of AD pathogenesis and the susceptibility of AD patients to viral infection.
The lay public has recently become quite interested issues related to allergy, particularly severe allergy. Is allergic disease clearly on the rise in the Western world, or is it your impression that what we are seeing is the result of improved diagnosis, understanding, and/or perception of these conditions?
TK: There is no doubt that we are seeing an increasing number of allergic patients in the field of allergy research. There are ample data showing that the morbidity of allergic disease has increased in the past two to three decades, although there might be some contribution from the improved diagnosis and increased interest in these diseases by the general public.
What do you see as some of the more intriguing directions for improved anti-allergy therapeutics?
TK: A single most interesting therapeutic is anti-IgE monoclonal antibody, also known as omalizumab. When understood in the context of the findings presented here (together with some unpublished work), we would anticipate that patients who have high levels of HC IgEs would have numerous mast cells that can be activated by binding in the absence of allergen, while those who preferentially produce PC IgEs would have less activated mast cells in the absence of allergen [10 ]. Although patients with PC IgEs would benefit most by avoiding allergens, those with high HC IgEs would not respond effectively to such a strategy. Therefore, treating HC IgE-producing, but not PC IgE-producing, patients with anti-IgE therapy might be a reasonable therapeutic approach.
Is there anything else that you would like to tell us about this work?
TK: I would like to recognize the efforts of Dr. Jun-ichi Kashiwakura, a postdoctoral researcher in our laboratory, who was the major workforce behind this study. Jun-ichi not only works hard, but he also works very efficiently. He has been accumulating quite a bit of data regarding the effects of IgE on mast cells, and we will keep busy writing a few more papers on this subject later this year.
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Figure 1. Dr. Toshiaki Kawakami is a member of the Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California, USA.
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