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，我们的患者还包括合并免疫缺陷、高ige综合征变异体、自身免疫性淋巴细胞增生综合征（ALPS）变异体或caspase-8缺乏症（CEDS）、常见变异性免疫缺陷（CVID）、x连锁淋巴细胞增生综合征（XLP）和Evans综合征的患者。2013年，我们利用功能筛查和基因测序技术，对过去一年的240例新患者及其亲属进行了评估，共计1217例。目前正在利用生化分析、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个子集进行深入研究。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，我们开始使用比较基因组杂交（CGH）阵列、全外显子组测序和其他技术，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, variants of hyper-IgE syndrome, variants of autoimmune lymphoproliferative syndrome (ALPS) or caspase-8-deficiency state (CEDS), common variable immunodeficiency (CVID), X-linked lymphoproliferative syndrome (XLP), and Evans syndrome. In 2013, we evaluated 240 new patients and their relatives over the past year, for 1217 cumulatively, using functional screening and gene sequencing. A subset is 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 started using comparative genomic hybridization (CGH) arrays, whole exome sequencing, and other technologies to determine genetic causes of new immunological diseases in an unbiased manner. Using these technologies, in 2009 we discovered that DOCK8 mutations are associated with a combined immunodeficiency that includes cases of what was previously termed autosomal recessive hyper-IgE syndrome. Since then, our studies have focused on understanding how absence of DOCK8 leads to the lymphocyte abnormalities that contribute to the problems the patients have in handling viral infections. Because little is known about DOCK8, studying how it normally works to regulate immune cells in preventing infections, allergies, and cancers, may help us better understand why patients in the general population suffer similar problems. As part of this effort, we have contributed to a study in 2013 showing that invariant NK T cells show a survival defect that impairs their normal functions. In 2012, we contributed to the discovery of a new disease that results from gain-of-function CARD11 mutations, which we term B cell expansion with NF-κB and T cell anergy (BENTA) disease. Whereas somatic mutations in the same gene are associated with B cell lymphomas, germline mutations cause a polyclonal, non-malignant B cell expansion driven by NF-κB activation. However, patients unexpectedly have a mild immunodeficiency accompanied by T cell anergy, suggesting an unappreciated role of constitutive CARD11 expression in regulating T cell homeostasis. In 2011, we contributed to the discovery of X-linked Magnesium defect with EBV infection and Neoplasia (XMEN), a disease that results from mutations in MAGT1. We have defined further the clinical spectrum of disease as being hallmarked by EBV-related lymphoproliferative disease. In doing so, in 2013 we helped to establish that defects in NK cell function are crucial for the impairment in EBV control and that such defects can be reversed by treatment with magnesium supplementation, which has important therapeutic implications.