Defining New Human Immunodeficiency and Immunodysregulation Disorders

除了缺乏已知诊断的免疫缺陷和免疫失调疾病的独特患者外，我们的纳入包括患有联合免疫缺陷、常见变异型免疫缺陷（CVID）、高IgE综合征或自身免疫性淋巴增生综合征（ALPS）变体、Evans综合征、半胱天冬酶-8缺陷状态（CEDS）、B细胞扩增伴NF-κ B和T细胞无反应性（BENTA）疾病的患者，X连锁镁缺陷伴EBV感染和瘤形成（XMEN）、PASLI（p110 δ激活突变导致T细胞衰老、淋巴结病和免疫缺陷）疾病和CHAI（CTLA 4单倍不足伴自身免疫浸润）疾病。对EB病毒、鼻病毒、流感病毒、呼吸道合胞病毒和其他呼吸道病毒易感的患者也在研究中。我们的评估包括功能筛查和基因测序，并且还使用生化分析、基因表达微阵列、流式细胞术分析、体外功能测试和其他技术对一部分患者进行了深入研究。这些实验为以前与疾病无关的新候选基因的测序提供了线索。此外，我们正在使用比较基因组杂交（CGH）阵列，全外显子组测序，全基因组测序和其他技术，以公正的方式确定新的免疫性疾病的遗传原因。 于2022财政年度，我们继续研究若干尚未描述的免疫缺陷-免疫失调疾病的分子发病机制，以及先前报告的罕见免疫疾病的自然史和最佳治疗。我们完成了一个新的免疫失调疾病的工作，已提交出版。我们对人类IFIH 1（MDA 5）缺陷的研究做出了贡献，将表型从对呼吸道病毒的易感性扩展到现在包括肠道病毒菱形脑炎。我们还参与了2022财年发表的其他几项研究，即PASLI疾病分子效应的进一步表征，以及XMEN疾病镁补充剂临床试验的结果。

Besides unique patients with immunodeficiency and immunodysregulation disorders lacking known diagnoses, our intake includes patients with combined immunodeficiency, common variable immunodeficiency (CVID), variants of hyper-IgE syndrome or autoimmune lymphoproliferative syndrome (ALPS), Evans syndrome, caspase-8-deficiency state (CEDS), B cell expansion with NF-kB and T cell anergy (BENTA) disease, X-linked Magnesium defect with EBV infection and Neoplasia (XMEN), PASLI (p110 delta activation mutation causing senescent T cells, lymphadenopathy, and immunodeficiency) disease, and CHAI (CTLA4 haploinsufficiency with autoimmune infiltration) disease. Patients with susceptibility to EBV, rhinovirus, influenza virus, respiratory syncytial virus, and other respiratory viruses are also being investigated. Our evaluation includes functional screening and gene sequencing, and a subset of patients is also being intensively studied using biochemical analyses, gene expression microarrays, flow cytometric analyses, in vitro functional tests, and other technologies. These experiments have provided leads for sequencing of new candidate genes not previously associated with disease. Additionally, we are using comparative genomic hybridization (CGH) arrays, whole exome sequencing, whole genome sequencing, and other technologies to determine genetic causes of new immunological diseases in an unbiased manner. In FY2022, we continued our work on investigating the molecular pathogenesis of several as yet undescribed immunodeficiency-immunodysregulation disorders, as well as the natural history and optimal treatment of previously reported rare immunological disorders. We completed work on a new immunodysregulation disorder that has been submitted for publication. We contributed to work on human IFIH1(MDA5) deficiency to extend phenotype beyond susceptibility to respiratory viruses to now include enterovirus rhombencephalitis. We also contributed to several other studies that were published in FY2022, namely further characterization of molecular effects in PASLI disease, and the results of a clinical trial of magnesium supplementation in XMEN disease.