Defining New Human Immunodeficiency and Immunodysregulation Disorders

除了缺乏已知诊断的独特免疫缺陷和免疫失调患者外，我们接受的治疗还包括联合免疫缺陷、常见变量免疫缺陷(CVID)、变异型高IgE综合征或自身免疫淋巴增殖性综合征(ALPS)、Evans综合征、caspase-8缺陷状态(CEDS)、B细胞增殖伴核因子-kB和T细胞无能(Benta)病、X连锁镁缺陷合并EBV感染和肿瘤(XMEN)、Pasli(p110 Delta激活突变导致T细胞衰老、淋巴病变和免疫缺陷)疾病，以及Chai(CTLA4单倍体功能不全伴自身免疫渗透)疾病。对EBV、鼻病毒、流感病毒、呼吸道合胞病毒和其他呼吸道病毒敏感的患者也在接受调查。我们的评估包括功能筛选和基因测序，还使用生化分析、基因表达微阵列、流式细胞仪分析、体外功能测试和其他技术对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。 在2022财年，我们继续研究几种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病史和最佳治疗方法。我们完成了一种新的免疫紊乱的研究工作，该研究已提交发表。我们在人类IFIH1(MDA5)缺乏症方面做出了贡献，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。我们还对发表在2022财年的其他几项研究做出了贡献，即帕斯利病分子效应的进一步表征，以及补充镁治疗XMEN病的临床试验结果。

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.