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调节失调患者外，我们接受的治疗还包括联合免疫缺陷、常见变量免疫缺陷(CVID)、变异型高IgE综合征或自身免疫淋巴组织增殖性综合征(ALPS)、Evans综合征、caspase-8缺陷状态(CEDS)、X连锁镁缺陷合并EBV感染和新生血管病变(XMEN)以及Pasli(p110 Delta激活突变导致T细胞衰老、淋巴结病和免疫缺陷)疾病。我们的评估包括功能筛选和基因测序，还使用生化分析、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对部分患者进行了深入研究。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，我们正在使用比较基因组杂交(CGH)阵列、全外显子组测序、全基因组测序和其他技术，以公正的方式确定新的免疫性疾病的遗传原因。 在2015财年，使用这些方法，我们从我们的高免疫球蛋白血症E队列中发现了一种新的联合免疫缺陷疾病。三角病的特征是反复的鼻窦肺部感染，持续性的巨细胞病毒血症和其他病毒的问题，以及严重的自身免疫，包括细胞减少症和系统性红斑狼疮。患者也有发育迟缓。我们发现该病是由三肽基肽酶II(TPP2)基因的常染色体隐性突变引起的。TPPII的丢失扰乱了细胞内氨基酸的动态平衡，导致溶酶体的代偿性膨胀和关键的糖酵解酶己糖激酶-2的溶酶体降解。糖酵解受损进而导致免疫效应器功能缺陷。 在2015财年，我们还参与了几项合作研究，涉及识别两种新的具有淋巴增殖和免疫缺陷的多器官自身免疫性疾病(CTLA4单倍体功能不全伴自身免疫渗透(CHAI)疾病和STAT3功能获得疾病)和一种免疫缺陷和淋巴增殖联合疾病(由PIK3R1功能丧失突变引起的帕斯利病)。此外，我们还参与了一项合作研究，阐明了LRBA缺乏干扰CTLA4细胞内运输的机制，从而解释了为什么这种疾病对CTLA4靶向治疗有反应。 总而言之，这些发现现在为某些形式的复杂脑血管病提供了分子诊断。它们为人类免疫系统的调节提供了新的见解，我们对其致病机制的阐明也导致了为每一种分子诊断量身定做的新的医学疗法。

Besides unique patients with immunodeficiency and immunodysregulation disorders lacking known diagnoses, our intake includes patients with combined immunodeficiency, common variable immunodeficiency (CVID), variants of hyper-IgE syndrome or autoimmune lymphoproliferative syndrome (ALPS), Evans syndrome, caspase-8-deficiency state (CEDS), X-linked Magnesium defect with EBV infection and Neoplasia (XMEN), and PASLI (p110 delta activation mutation causing senescent T cells, lymphadenopathy, and immunodeficiency) disease. Our evaluation includes functional screening and gene sequencing, and a subset of patients is also 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 are using comparative genomic hybridization (CGH) arrays, whole exome sequencing, whole genome sequencing, and other technologies to determine genetic causes of new immunological diseases in an unbiased manner. In FY2015, using these approaches, we identified from our hyperimmunoglobulinemia E cohort a new combined immunodeficiency disease. TRIANGLE disease is characterized by recurrent sinopulmonary infections, persistent cytomegalovirus viremia and problems with other viruses, and severe autoimmunity including cytopenias and systemic lupus erythematosis. Patients also have developmental delay. We found that the disease is caused by autosomal recessive mutations in the tripeptidyl peptidase II (TPP2) gene. Loss of TPPII perturbs intracellular amino acid homeostasis, leading to compensatory lysosomal expansion with lysosomal degradation of a key glycolytic enzyme called hexokinase-2. The impaired glycolysis in turn causes defective immune effector functions. In FY2015, we also participated in several collaborative studies that involved the identification of two new multi-organ autoimmune diseases with lymphoproliferation and immunodeficiency (CTLA4 haploinsufficiency with autoimmune infiltration (CHAI) disease, and STAT3 gain-of-function disease) and one combined immunodeficiency with lymphoproliferation (PASLI disease caused by PIK3R1 loss-of-function mutations). Additionally, we also participated in a collaborative study that elucidated the mechanism of LRBA deficiency as interfering with CTLA4 intracellular trafficking and thus why this disease is responsive to CTLA4-targed therapy. Collectively, these discoveries now provide molecular diagnoses for some forms of complicated CVID. They have provided new insights into regulation of the human immune system, and our elucidating their pathogenic mechanisms has also led to new medical therapies tailored to each molecular diagnosis.