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，我们的病例还包括联合免疫缺陷、高IgE综合征变体、自身免疫性淋巴增生综合征（ALPS）或半胱天冬酶-8缺乏状态（CEDS）变体、常见变异型免疫缺陷（CVID）、X连锁淋巴增生综合征（XLP）和Evans综合征患者。 在2011年，我们评估了247个新的患者和他们的亲属在过去的一年里，累计804，使用功能筛查和基因测序。 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。 利用这些技术，我们在2009年发现DOCK 8突变与一种新的联合免疫缺陷相关，包括以前称为常染色体隐性高IgE综合征的病例。 从那时起，我们进一步扩大了DOCK 8缺陷症的临床范围，确定了其他患有这种疾病的患者，他们也有不寻常的表现，并遵循他们的疾病自然史以及造血细胞移植过程中的病程。 此外，我们的研究集中在了解DOCK 8的缺乏如何导致淋巴细胞异常，导致患者处理病毒感染的问题。 由于对DOCK 8知之甚少，研究它通常如何调节免疫细胞以预防感染，过敏和癌症，可能有助于我们更好地理解为什么普通人群中的患者会遇到类似的问题。 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X连锁镁缺陷伴EBV感染和肿瘤（XMEN），其由MAGT 1突变引起。 这一发现不仅带来了新的基础知识，即镁可以作为T细胞抗病毒反应的重要信号信使，而且它为更好地诊断和研究这种疾病的潜在疗法打开了大门。

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.