For the last 35 years, this laboratory has focused on understanding the regulation of secretion from human basophils and mast cells. These two cell types are considered central participants in the allergic reaction as well as having a variety of other physiological or pathophysiological roles in other diseases. For these two cells types, there is a hallmark reaction, degranulation in response to stimulation through cell bound IgE. By electron microscopy, the transition from a resting unstimulated cell to a well degranulated version looks like the image above.
Our interests lie in how the cells make the transition, i.e., the signaling mechanisms that control this dramatic cell response and the factors that regulate the extent of the reaction.
This laboratory has been involved in a wide variety of projects. Some examples, going back to the early 1980s, include:
First methods of purification of both human basophils and tissue mast cells that resulted in sufficient cells to engage in mechanistic studies of secretion. A fruitful association with mathematical biologists involved in characterizing the nature and functional significance of the cell surface aggregating reaction leading to mediator secretion.
A long-standing project to characterize the secretion of non-granule mediators from both mast cells and basophils. For example, we first demonstrated the IgE-mediated generation of leukotrienes from both human mast cells and basophils.
Studies in the mid 1990s also established some of the characteristics of cytokine secretion from these two cell types. Studies throughout the late 1980s and 1990s have addressed whether these cells undergo secretion in an all-or-nothing manner. More generally, we have had a basic interest in the characteristics of the single cell response and how it differs from what is observed in the average population response. Much of this work centered on the characteristics of cytosolic calcium signaling.
There has also been a long history in developing a better understanding of how cytokines modify basophil or mast cell function. Much of the effort has focused on how interleukin-3 upregulates human basophil function.
Over the three decades of research, we have sought to understand the signal transduction pathways involved in secretion but, in particular (and in distinction with elegant studies others have done in cell lines), the relationship of known signaling pathways to the differences in cell function observed in the general human population.
A recent demonstration, both in vivo and in vitro, that IgE antibody regulates the expression of its own high affinity receptor on basophils.
Currently, there are four major areas of research (along with a host of smaller developing projects). It is worth noting that the vast majority of what we do focuses on the behavior of the wild-type basophil or mast cell rather than employing a variety of cell line or animal cell models. This does not mean that we exclude studies using other types of cells but have chosen to devote precious resources to determining important characteristics of these very difficult to study cells. It should go without saying that there are a wide variety of collaborative efforts, many with members of this division.
As part of a long-standing funded NIH grant, we remain deeply involved in working out the mechanisms that down-regulate an ongoing IgE-mediated reaction in these cells. Current efforts are focused on regulation of syk expression and the role of CD32b in modulating basophil function, especially in the context of classical allergen immunotherapy.