Translational studies in allergic reactions and inflammation

在2019财年（FY），我们继续推进对促进肥大细胞反应性和过敏反应的获得性和遗传性基因变化的理解；我们有机会在《实验医学杂志》上对其中的许多疾病进行了全面的总结，以便将这些新概念传达给更广泛的人群。在Sabato等人的研究中，我们首次发现，在具有肥大细胞激活严重临床表现的个体中，遗传和获得性遗传病变都会影响肥大细胞腔室。鉴于这两种发现都很罕见，本报告指出，遗传的α -胰蛋白酶编码TPSAB1拷贝的增加可能会影响骨髓稳态。Le等人提出了一种可能的机制，其中我们首次与校外研究人员合作证明，α -胰蛋白酶编码基因拷贝数的增加导致α / β异四聚体胰蛋白酶的质量增加，具有独特的酶和生理特性。我们还报道了胚系GATA2单倍体不足对肥大细胞室的影响。这些患者有明显的髓系异常，有发生髓系白血病的危险。这些患者肥大细胞中GATA2的缺失（在模型系统中已被证明对该谱系至关重要）与由于这些细胞表面低水平的FceRI和KIT而导致的ige依赖性反应性受损有关。此外，这种缺陷可以用一种小分子的GATA2抑制剂重现，这提示了一种新的靶向临床过敏的途径。

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.