Translational studies in allergic reactions and inflammation

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In Fiscal Year (FY) 2019, we continued to advance our understanding of acquired and inherited genetic changes that promote mast cell reactivity and anaphylaxis; many of these disorders we had the opportunity to summarize in a comprehensive review in the Journal of Experimental Medicine in order to convey these new concepts to a broader population. In Sabato et al., we showed for the first time that both inherited and acquired genetic lesions affecting the mast cell compartment in an individual with severe clinical manifestations of mast cell activation. Given that both findings were rare, this report points to the concept that inherited increases in alpha-tryptase encoding copies of TPSAB1 may affect myeloid homeostasis. One putative mechanism of how this may occur was put forward in Le et al., where we demonstrated in collaboration with extramural investigators for the first time that increasing copies of alpha-tryptase encoding genes results in greater mass of alpha/beta-heterotetrameric tryptase with unique enzymatic and physiologic properties. We also reported the effects within the mast cell compartment of germline haploinsufficiency of GATA2. These patients have significant myeloid abnormalities and are at risk for myeloid leukemias. Absence of GATA2 in the mast cells of these patients - which in model systems has been shown to be critical for this lineage - was associated with impaired IgE-dependent reactivity owing to low levels of FceRI and KIT on the surface of these cells. Further, this defect could be recapitulated with a small molecule inhibitor of GATA2, suggesting a novel pathway to target for clinical allergy.