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。2010年，我们使用功能筛查和基因测序对过去一年中的142名新患者及其亲属进行了评估，累计为508人。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，去年我们发现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。2010年，我们进一步确定了DOCK8缺乏症的临床谱系，确定了更多患有这种疾病的患者，他们也具有免疫系统以外的显著特征。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以及他们患癌症的倾向。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。2010年，我们还促成了一项专家共识意见，其中我们制定了自身免疫淋巴增殖性综合征(ALPS)及相关疾病的最新诊断和分类标准，这将改善临床实践。

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 2010, we evaluated 142 new patients and their relatives over the past year, for 508 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, last year 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. In 2010, we further characterized the clinical spectrum of disease in DOCK8 deficiency by identifying additional patients with this disorder who also have prominent features outside the immune system. 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 and their predilection for developing cancer. 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 2010, we also contributed to an expert consensus opinion in which we established updated criteria for diagnosis and classification of the autoimmune lymphoproliferative syndrome (ALPS) and related disorders, which will improve clinical practice.