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，我们的摄入量还包括自身免疫性淋巴组织增生综合征（ALPS）或半胱天冬酶-8缺乏状态（CEDS），常见变异型免疫缺陷（CVID），X连锁淋巴组织增生综合征（XLP）和Evans综合征的变体患者。 在2009年，我们评估了103名新的患者和他们的亲属在过去的一年中，累计350，使用功能筛查和基因测序，以排除已知的疾病。 目前正在利用生物化学分析、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对大约20种基因进行深入研究。 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。 我们在2009年最重要的进展是发现胞质分裂奉献者8（DOCK 8）基因中的常染色体隐性功能丧失突变导致一种新形式的联合免疫缺陷。 患者有反复的上呼吸道和下呼吸道感染、严重和持续的皮肤病毒感染（由单纯疱疹病毒、传染性软疣和人乳头瘤病毒引起）、严重的食物和其他与过敏反应相关的过敏反应以及癌症。 他们的外周血含有数量少且功能差的淋巴细胞，包括在对抗病毒感染中重要的CD 8 T细胞，以及高水平的免疫球蛋白E和导致过敏的嗜酸性粒细胞。 我们对这种新疾病及其遗传原因的发现现在有助于对受影响患者的诊断和进一步研究。 此外，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。 在2009年，我们还为另外两项专注于X连锁淋巴增生性疾病（XLP）的进展做出了贡献。 在这种疾病中，男孩死于EB病毒（EBV）感染，除非他们接受骨髓移植来取代他们有缺陷的淋巴细胞。 EBV是一种常见的病毒，在健康人群中不会引起症状或自限性传染性单核细胞增多症。 XLP患者也可能发生淋巴增生性疾病，包括淋巴瘤，但为什么会发生这种情况尚不清楚。 我们的工作确定，这是因为在大多数形式的XLP中突变的基因的产物SH 2D 1A（SAP）通常不仅在激活淋巴细胞中起作用，而且在将该信号与淋巴细胞死亡的信号联系起来中起作用。 由于这种信号在大多数XLP患者中缺失，患者异常积累淋巴细胞，这可能使他们容易患上癌症。 最后，我们还帮助建立了一种基于快速流式细胞术的方法来诊断由BIRC 4（XIAP）突变引起的XLP。 由于XLP类似于其他疾病，需要骨髓移植治疗，这项工作将改善患者的诊断和护理。

Besides unique patients with immunodeficiency and immunodysregulation disorders lacking known diagnoses, our intake includes patients with 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 2009, we evaluated 103 new patients and their relatives over the past year, for 350 cumulatively, using functional screening and gene sequencing to exclude known disease. About 20 are 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. Our most important advance in 2009 was the discovery that autosomal recessive loss-of-function mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause a new form of combined immunodeficiency. Patients have recurrent upper and lower respiratory tract infections, severe and persistent viral infections of the skin (caused by herpes simplex virus, molluscum contagiosum, and human papillomavirus), severe food and other allergies associated with anaphylaxis, and cancers. Their peripheral blood contains low numbers of and poorly functioning lymphocytes, including the CD8 T cells that are important in fighting viral infections, as well as high levels of immunoglobulin E and eosinophils that contribute to allergy. Our discovery of this new disease and its genetic cause now facilitates the diagnosis and further study of affected patients. Moreover, 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 2009, we also contributed to two other advances focused on X-linked lymphoproliferative disease (XLP). In this disease, boys die from infection with Epstein-Barr virus (EBV), unless they receive a bone marrow transplant to replace their defective lymphocytes. EBV is a common virus that causes no symptoms or a self-limited infectious mononucleosis in healthy people. Patients with XLP can also develop lymphoproliferative disease, including lymphomas, but why this happens was not clear. Our work established that this occurs because the product of the gene that is mutated in most forms of XLP, SH2D1A (SAP), normally functions not only in activating lymphocytes but also in linking this signal to the signal for lymphocyte death. Because this signal is missing in most XLP patients, patients abnormally accumulate lymphocytes, which can predispose them to developing cancers. Finally, we also helped establish the utility of a rapid flow cytometry-based way to diagnose a form of XLP due to BIRC4 (XIAP) mutations. Because XLP mimics other diseases and requires curative bone marrow transplantation, this work will improve patient diagnosis and care.