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。2011年，我们利用功能筛查和基因测序技术，对247名新患者及其亲属进行了评估，共计804人。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）阵列和其他基因组技术，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 2011, we evaluated 247 new patients and their relatives over the past year, for 804 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 and other genomic 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 new combined immunodeficiency that includes cases of what was previously termed autosomal recessive hyper-IgE syndrome. Since then, we have further expanded upon the clinical spectrum of disease in DOCK8 deficiency by identifying additional patients with this disorder who also unusual presentations, and following the natural history of their disease as well as their course during hematopoietic cell transplantation. Additionally, our studies have focused on understanding how absence of DOCK8 leads to the lymphocyte abnormalities that contribute to the problems the patients have handling viral infections. Since 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. In 2011, we also contributed to the exciting discovery of a new immunodeficiency disease, X-linked Magnesium defect with EBV infection and Neoplasia (XMEN), which results from mutations in MAGT1. This discovery has not only led to new basic knowledge that Magnesium can act as a signaling messenger that is important for T cell antiviral responses, but it has opened the door to better diagnosis and studies into potential therapy for this disease.