Clinical, Immunological and Genetic Analyses of ALPS

ALPS 的临床、免疫学和遗传分析

• 批准号: 8745347
• 负责人: michael j lenardo
• 金额: $ 47.7万
• 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/8745347
• 关键词: Adult; Affect; Algorithms; Apoptosis; Autoimmune Process; Autoimmunity; Biological; Biological Assay; Biological Markers; Biology; CASP10 Gene Mutation; CASP10 gene; Cell Death; Cells; Cellular biology; Chronic; Classification Scheme; Clinical; DNA Sequence Analysis; Databases; Defect; Development; Diagnostic; Discipline of Nursing; Disease; Dose; Dose-Limiting; Early Diagnosis; Early treatment; Etiology; Evaluation; Functional disorder; Gene Mutation; Genes; Genetic; Genomics; Goals; Hemophagocytic Lymphohistiocytoses; Hereditary Disease; Histopathology; Home environment; Homeostasis; Human Genetics; Hypersplenism; Immune; In Vitro; Indolent Clinical Course; Juvenile Myelomonocytic Leukemia; KRAS2 gene; Knowledge; Laboratories; Lymphatic Diseases; Lymphocyte Subset; Lymphoid; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Manuscripts; Mediating; Modeling; Molecular; Molecular Biology; Monocytosis; Mus; Mutation; Myelogenous; Natural History; Online Systems; Pathogenesis; Pathway interactions; Patient Monitoring; Patients; Population; Positron-Emission Tomography; Procedures; Process; Proteins; Publications; Research; Role; Schedule; Scientist; Somatic Cell; Somatic Mutation; Splenomegaly; Subgroup; Syndrome; System; T cell differentiation; T-Lymphocyte; TNFRSF6 gene; TNFSF6 gene; Techniques; Testing; Therapeutic Agents; Toxic effect; Tumor Necrosis Factor Ligand Superfamily Member 6; Tumor Necrosis Factor Receptor; United States National Institutes of Health; Validation; apoptosis in lymphocytes; autoimmune lymphoproliferative syndrome; base; bench to bedside; caspase-10; clinical phenotype; cohort; cytopenia; exome; extracellular; follow-up; genetic analysis; imaging modality; insight; lymph nodes; member; mutant; novel; prevent; protein function; research study; therapy duration; tool; web site

Research accomplishments of this project include: 1) This project allows us to study the largest cohort of patients with ALPS, one of the first genetic disorders of immunedysregulation. ALPS natural history study based on follow up of these patients over 18 yeas has been completed and a manuscript is being generated summarizing the critical features of the clinical and molecular pathogenesis in 150 patients with ALPS-FAS with a median followup of 13 years. This included the validation of new biomarkers as well as establishing new modes of treatment for the disorder. It elucidates the role of fas mediated apoptosis in lymphocyte homeostasis and lymphoma genesis. 2)This project has also led to identifying new genetic causes of ALPS like disorders by identification of mutations affecting RAS pathway in 14 patients, otherwise known as Ras Associated Leukoproliferative Disorder (RALD) : RALD: Patients with this ALPS like syndrome caused by somatic mutations in NRAS and KRAS are currently classified separately as ALPS related apoptosis disorders. These patients with somatic NRAS and KRAS mutations present with autoimmune phenomena, massive splenomegaly, modest lymphadenopathy and normal or only marginally elevated TCR alpha/beta+ DNT cells. Their lymph node histopathology is also not typical of ALPS-FAS. Additionally, these patients show abnormalities of the myeloid compartment, with chronic persistent monocytosis, mimicking juvenile myelomonocytic leukemia (JMML) in otherwise asymptomatic young patients. 3) Provided below is the current classification scheme that we have devised for ALPS patients based on the particular molecular defect present: ALPS-FAS : mutations in the TNFRSF6 (tumor necrosis factor receptor superfamily 6) gene, encodes the protein CD95 (Fas). ALPS-sFas: somatic mutant: TNFRSF6 gene defect in the double negative T (DNT) cell population. ALPS-FASLG: mutations in TNFSF6 gene, encodes the protein CD95 ligand (Fas ligand). ALPS-CASP10: mutations in CASP10 gene, encodes caspase-10. ALPS-U: associated mutation unidentified to date. 4) Recently we clarified that the cause of disordered FAS protein function leading to ALPS is based on haploinsuffiiciency caused by mutations affecting the extracellular portion of the protein in some patients. This is a newly emerging unique mechanism of genetic dysfunction. With support from NCBI we have implemented a web based publication of the existing databases of pathogenic FAS mutations, by far the commonest cause of ALPS, which is publicly available and can be used for diagnostic help by referring to NCBI NIH ALPS website <http://www.ncbi.nlm.nih.gov/lovd/home.php?select_db=FAS>. 5) Characterized the pathophysiology and clinical phenotype of the second largest subgroup of ALPS patients in our cohort with somatic mutations in the FAS gene mostly limited to their ALPS signature cells, also known as double negative T lymphocytes. 6) Extended the use of PET scans as an imaging modality in patients with ALPS associated lymphadenopathy as a tool to monitor patients with suspected ALPS associated cancer of the lymphoid system (lymphoma). We have identified lymphomas associated with ALPS-FAS in approximately 10% of our patients. Ongoing critical surveillance for lymphoma and its early diagnosis and treatment has been pursued over the last 20 years of longitudinal follow up of these patients. 7) Continued search for new genetic mutations in the subgroup of patients with ALPS and undetermined genetic defects using emerging genomic and cell biology tools. Currently a large group of patients with unknown molecular etiologies are being subjected to whole exome DNA sequencing and analysis. 8) More recently the ALPS Clinical group is being repositioned to tackle new classes of immunological disorders which has involved the recruitment of new members of the team as well as special inservices on genetics and molecular biology for the nursing and ancillary support staff. 9) Continued efforts to streamline the techniques of apoptosis assay by evaluating Fas mediated cell death in lymphocyte subsets so that this test procedure can be readily adapted in more clinical laboratories for patient evaluation. 10) Confounding factors in the clinical presentation of ALPS and another hematological condition called HLH (Hemophagocytic lymphohistiocytosis) have been identified and clinicians are being advised to be aware of the distinguishing biomarkers in both conditions.

该项目的研究成就包括： 1）该项目使我们能够研究最大的阿尔卑斯山患者队列，这是免疫疾病的第一批遗传疾病之一。阿尔卑斯山自然历史研究基于这些患者的随访，已经完成了18年以上，并且正在生成手稿，总结了150例ALPS-FAS患者的临床和分子发病机理的关键特征，中位随访的中位随访。这包括对新生物标志物的验证以及建立新的疾病治疗方式。它阐明了FAS介导的凋亡在淋巴细胞稳态和淋巴瘤起源中的作用。 2）该项目还导致通过鉴定影响14名患者的RAS途径的突变（也称为RAS相关的白细胞增生性疾病（RALD）），从而鉴定出阿尔卑斯山（例如疾病）的新遗传原因： RALD：该阿尔卑斯山（如NRA和KRAS中的体细胞突变引起的综合征）患者目前被分别分别为与ALPS相关的凋亡疾病。这些患有体细胞NRA和KRAS突变的患者具有自身免疫现象，大量的脾肿大，适度的淋巴结肿大和正常的TCRα/β+ DNT细胞。他们的淋巴结组织病理学也不是阿尔卑斯山-FA的典型代表。此外，这些患者表现出髓样区室的异常，慢性持续单核细胞增多症，模仿少年脊髓细胞性白血病（JMML），其他无症状的年轻患者。 3）下面提供的是我们根据当前特定分子缺陷为阿尔卑斯山患者设计的当前分类方案： Alps-FAS：TNFRSF6中的突变（肿瘤坏死因子受体超家族6）基因编码蛋白CD95（FAS）。 Alps-SFA：体细胞突变体：双（DNT）细胞群中的TNFRSF6基因缺陷。 Alps-FASLG：TNFSF6基因中的突变编码蛋白CD95配体（FAS配体）。 Alps-CASP10：CASP10基因中的突变编码caspase-10。 Alps-U：迄今为止相关的突变未识别。 4）最近，我们澄清说，导致阿尔卑斯山的FAS蛋白功能无序的原因是基于某些患者在蛋白质细胞外部分的突变引起的单倍弥补的。这是一种新出现的遗传功能障碍的独特机制。在NCBI的支持下，我们已经实施了基于网络的病原FAS突变数据库的出版物，这是迄今为止最常见的阿尔卑斯山原因，这是公开可用的，可以通过参考NCBI NIH ALPS网站<HTTP://wwwwwwwwwwwwwwwwwwww.ncbi.nlm.nlm.nih.gov/lovd/.fb = sighate ncbi nih alps网站来诊断帮助。 5）表征了我们队列中第二大阿尔卑斯山患者的病理生理学和临床表型，在FAS基因中具有体细胞突变，主要仅限于其Alps签名细胞，也称为双阴性T淋巴细胞。 6）扩大了对Alps相关淋巴结肿大患者的PET扫描作为成像方式的使用，以监测疑似阿尔卑斯山相关的淋巴机系统（淋巴瘤）患者的工具。我们已经确定了大约10％的患者中与Alps-FAS相关的淋巴瘤。在过去20年的这些患者的纵向随访中，对淋巴瘤的持续关键监测及其早期诊断和治疗进行了追求。 7）使用新兴的基因组和细胞生物学工具，继续在阿尔卑斯山患者的亚组中寻找新的基因突变。目前，一大群分子病因未知的患者正在接受整个外部DNA测序和分析。 8）最近，Alps临床组正在重新定位，以解决新的免疫疾病，这些疾病涉及招募新的团队成员，以及有关遗传学和分子生物学的特殊疾病，用于护理和辅助支持人员。 9）继续努力通过评估FAS介导的淋巴细胞亚群中FAS介导的细胞死亡来简化细胞凋亡测定的技术，从而可以很容易地在更临床实验室中适应该测试，以进行患者评估。 10）在阿尔卑斯山的临床表现和另一种称为HLH的血液学疾病中的混杂因素（淋巴细胞淋巴虫组织细胞增多症）已被鉴定出来，并建议临床医生意识到在这两种情况下的生物标志物。