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，我们的收治对象还包括联合免疫缺陷患者、高IgE综合征变异体、自身免疫淋巴增殖性综合征变异体(ALPS)或caspase-8缺陷状态变异体(CEDS)、常见变异型免疫缺陷(CVID)、X连锁淋巴增殖症(XLP)和埃文斯综合征。2011年，我们使用功能筛查和基因测序对过去一年中的247名新患者及其亲属进行了评估，累计为804名患者。一个子集正在使用生化分析、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性疾病的遗传原因。 使用这些技术，我们在2009年发现DOCK8突变与一种新的联合免疫缺陷有关，其中包括以前被称为常染色体隐性遗传性高IgE综合征的病例。从那时起，我们进一步扩大了DOCK8缺乏症的临床范围，确定了其他患有这种疾病的患者，他们也有不寻常的表现，并在造血细胞移植期间跟踪他们的疾病自然病史和他们的病程。此外，我们的研究重点是了解DOCK8的缺失如何导致淋巴细胞异常，从而导致患者处理病毒感染的问题。由于对DOCK8知之甚少，研究它在预防感染、过敏和癌症方面如何正常调节免疫细胞可能有助于我们更好地理解为什么普通人群中的患者会遭受类似的问题。 2011年，我们还促成了一种新的免疫缺陷疾病的令人兴奋的发现，即由MAGT1突变导致的X连锁镁缺陷症合并EBV感染和新生瘤(XMEN)。这一发现不仅带来了新的基础知识，即镁可以作为信号信使，对T细胞抗病毒反应至关重要，而且它也为更好地诊断和研究这种疾病的潜在治疗方法打开了大门。

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.