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障碍的独特患者外，我们的患者包括合并免疫缺陷，常见变异性免疫缺陷（CVID），高ige综合征或自身免疫性淋巴细胞增生综合征（ALPS）的变体，Evans综合征，caspase-8缺乏症（CEDS）， NF-kB和T细胞能量（BENTA）病的B细胞扩增，EBV感染和肿瘤（XMEN）的x -联镁缺陷，PASLI（引起衰老T细胞、淋巴结病和免疫缺陷的p110 δ激活突变）疾病和CHAI （CTLA4单倍体功能不全伴自身免疫浸润）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正在进行调查。我们的评估包括功能筛选和基因测序，并且还使用生化分析、带有PAR-CLIP的RNA-seq、流式细胞分析、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疾病的遗传原因。

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, RNA-seq with PAR-CLIP, 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 FY2023, 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 additional work on two new immunodysregulation disorders that were submitted for publication. We also contributed to several other studies that were published in FY2023, namely further characterization of molecular effects in BENTA disease and natural history of patients with STAT3 gain-of-function disease.