Defining New Human Immunodeficiency and Immunodysregulation Disorders

定义新的人类免疫缺陷和免疫失调疾病

• 批准号: 9161625
• 负责人: Helen Su
• 金额: $ 106.91万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9161625
• 关键词: Amino Acids; Apoptosis; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bacterial Infections; Biochemical; CTLA4 gene; Candidate Disease Gene; Clinical; Common Variable Immunodeficiency; Cytomegalovirus; Defect; Developmental Delay Disorders; Diagnosis; Disease; Enzymes; Epstein-Barr Virus Infections; Evaluation; Gene Chips; Genes; Genetic; Genomics; Glycolysis; Hexokinase 2; Homeostasis; Human; Hybridization Array; Hypersensitivity; Immune; Immune System Diseases; Immune system; Immunologic Deficiency Syndromes; In Vitro; Infection; Infiltration; Intake; Job' s Syndrome; Link; Lymphatic Diseases; Lymphocyte; Lymphocyte Activation; Lymphoid; Magnesium; Medical; Molecular; Molecular Diagnosis; Mutation; Mycoses; Neoplasms; Organ; Patients; Predisposition; Recurrence; Regulation; STAT3 gene; Syndrome; Systemic Lupus Erythematosus; T-Lymphocyte; Technology; Testing; Variant; Viremia; Virus; Virus Diseases; autoimmune lymphoproliferative syndrome; caspase-8; cohort; comparative genomic hybridization; cytopenia; exome sequencing; gain of function; genome sequencing; improved; insight; loss of function mutation; research study; screening; senescence; trafficking; tripeptidyl-peptidase II

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.

除了缺乏已知诊断的独特免疫缺陷和免疫失调疾病患者外，我们的接收对象还包括联合免疫缺陷、常见变异型免疫缺陷 (CVID)、高 IgE 综合征或自身免疫性淋巴增殖综合征 (ALPS) 变异、埃文斯综合征、半胱天冬酶 8 缺陷状态 (CEDS)、X 连锁镁缺陷与 EBV 感染和肿瘤 (XMEN) 以及 PASLI（p110 δ 激活突变导致 T 细胞衰老、淋巴结肿大和免疫缺陷）疾病。我们的评估包括功能筛查和基因测序，并且还使用生化分析、基因表达微阵列、流式细胞术分析、体外功能测试和其他技术对一部分患者进行深入研究。这些实验为先前与疾病无关的新候选基因的测序提供了线索。此外，我们还利用比较基因组杂交（CGH）阵列、全外显子组测序、全基因组测序等技术，以公正的方式确定新免疫疾病的遗传原因。 2015 财年，利用这些方法，我们从高免疫球蛋白血症 E 队列中发现了一种新的联合免疫缺陷病。三角病的特征是反复出现的鼻窦肺部感染、持续性巨细胞病毒血症和其他病毒问题，以及严重的自身免疫，包括血细胞减少症和系统性红斑狼疮。患者还存在发育迟缓。我们发现该疾病是由三肽基肽酶 II (TPP2) 基因的常染色体隐性突变引起的。 TPPII 的缺失会扰乱细胞内氨基酸稳态，导致补偿性溶酶体扩张，并导致一种称为己糖激酶-2 的关键糖酵解酶的溶酶体降解。糖酵解受损进而导致免疫效应功能缺陷。 2015财年，我们还参与了几项合作研究，涉及鉴定两种新的伴有淋巴细胞增殖和免疫缺陷的多器官自身免疫性疾病（CTLA4单倍体不足伴自身免疫浸润（CHAI）疾病和STAT3功能获得性疾病）和一种伴有淋巴细胞增殖的联合免疫缺陷（PASLI疾病） PIK3R1 功能丧失突变）。此外，我们还参与了一项合作研究，该研究阐明了 LRBA 缺陷干扰 CTLA4 细胞内运输的机制，以及为什么这种疾病对 CTLA4 靶向治疗有反应。 总的来说，这些发现现在为某些形式的复杂 CVID 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，我们阐明其致病机制也导致了针对每种分子诊断量身定制的新医学疗法。