Translational studies in allergic reactions and inflammation

在2022财年（FY），我们继续推进对促进肥大细胞反应性、过敏反应和过敏性炎症的获得性和遗传性基因变化的理解。在我们本年度报告的进展中，最重要的是JACI作为编辑选择的手稿特征，其中我们领导了一项国际合作，证明遗传性α -胰蛋白酶血症(HaT) -我们实验室于2016年首次发现的遗传性状-是严重过敏反应的遗传风险因素和克隆和非克隆肥大细胞疾病的修饰剂，它增加了症状频率和严重程度。并与我们的一位国际合作者在第二项前瞻性研究中验证了与毒液过敏反应严重程度的联系。在我们小组领导的第二个多中心合作中，也被JACI列为编辑选择，我们报告了遗传性α -胰蛋白酶血症患者肠道黏膜的独特免疫变化，包括肠道屏障破坏和肥大细胞活化的证据，这可能有助于在有症状的个体中观察到的某些临床表型。我们还改进了与HaT相关的一些表型和遗传学，证明HaT可以改变先天性多动障碍患者的临床表型，但在患有先天性多动障碍的患者中并不增加患病率，并且TPSAB1的拷贝数丢失也可能发生。除了这些进展，我们澄清了血清胰蛋白酶水平的基线变异性，并重新定义了与即时超敏反应相关的阈值增加。

In Fiscal Year (FY) 2022, we continued to advance our understanding of acquired and inherited genetic changes that promote mast cell reactivity, anaphylaxis, and allergic inflammation. Foremost among the advances we reported this FY, was a manuscript features in the JACI as an Editor's Choice in which we led an international collaboration demonstrating that hereditary alpha-tryptasemia (HaT) - a genetic trait first discovered by our laboratory in 2016 - is a heritable risk factor for severe anaphylaxis and modifier of clonal and non-clonal mast cell disorders where it augments symptom frequency and severity. And validated the link to venom anaphylaxis severity in a second prospective study with one of our international collaborators. In a second multi-center collaboration led by our group, that was also featured as an Editor's Choice in the JACI, we report unique immunologic changes seen in the gut mucosae of individuals with hereditary alpha-tryptasemia that included evidence of gut barrier disruption and mast cell activation which may contribute to certain clinical phenotypes observed in symptomatic individuals with this trait. We also refined some of the phenotypes and genetics associated with HaT demonstrating that HaT can modify clinical phenotypes of patients with congenital hypermobility disorders, but is not increased in prevalence among those with them, and that copy number loss can also occur at TPSAB1. Beyond these advances, we clarified baseline variability of serum tryptase levels and redefined what a threshold increase is that would be associated with immediate hypersensitivity reactions.