As many other physicians and researchers, we have had the great pleasure to be fellows in the laboratory of Dean Metcalfe, the Laboratory of Allergic Diseases, National Institute of Allergic and Infectious Diseases (NIAID), NIH, Bethesda, USA (Figure (#fig-cap-0001)). The open atmosphere, research driven by curiosity, hypotheses originating from clinical observations, and mutual trust and respect are the cornerstones of Dean’s mentorship. Dean and his laboratory have made major contributions on mast cell biology, from basic studies on the regulation of mast cell development and functions, to clinical studies on mast cells in diseases, such as systemic mastocytosis. After more than 50 years of exploring human mast cells, Dean’s impact on what we know today about these cells, their biology and how they affect diseases is outstanding and unique.
Background: Immunohistochemical analysis of granule-associated proteases has revealed that human lung mast cells constitute a heterogeneous population of cells, with distinct subpopulations identified. However, a systematic and comprehensive analysis of cell-surface markers to study human lung mast cell heterogeneity has yet to be performed. Methods: Human lung mast cells were obtained from lung lobectomies, and the expression of 332 cell-surface markers was analyzed using flow cytometry and the LEGENDScreenTM kit. Markers that exhibited high variance were selected for additional analyses to reveal whether they were correlated and whether discrete mast cell subpopulations were discernable. Results: We identified the expression of 102 surface markers on human lung mast cells. Several markers showed high continuous variation in expression within the mast cell population. Six of these markers were correlated: SUSD2, CD49a, CD326, CD34, CD66 and HLA-DR. The expression of these markers was also correlated with the size and granularity of mast cells. However, no marker produced an expression profile consistent with a bi- or multimodal distribution. Conclusions: LEGENDScreen analysis identified more than 100 cell-surface markers on mast cells, including 23 that, to the best of our knowledge, have not been previously described on human mast cells. Several of the newly described markers are known to be involved in sensing the microenvironment, and their identification can shed new light on mast cell functions. The exhaustive expression profiling of the 332 surface markers failed to detect distinct mast cell subpopulations. Instead, we demonstrate the continuous nature of human lung mast cell heterogeneity.
Mast cells are (in)famous for their role in allergic diseases, but the physiological and pathophysiological roles of this ingenious cell are still not fully understood. Mast cells are important for homeostasis and surveillance of the human system, recognizing both endogenous and exogenous agents, which induce release of a variety of mediators acting on both immune and non-immune cells, including nerve cells, fibroblasts, endothelial cells, smooth muscle cells and epithelial cells. During recent years, clinical and experimental studies on human mast cells as well as experiments using animal models have resulted in many discoveries that help decipher the function of mast cells in health and disease. In this review we focus particularly on new insights into mast cell biology, with a focus on mast cell development, recruitment, heterogeneity and reactivity. We also highlight the development in our understanding of mast cell driven-diseases and discuss the development of novel strategies to treat such conditions.