Pathogenesis, and Outcome of Autoinflammatory Diseases, NOMID/CAPS, DIRA, CANDLE, SAVI, NLRC4-MAS, Still's-like Diseases, and other Undifferentiated Autoinflammatory Diseases

自身炎症性疾病、NOMID/CAPS、DIRA、CANDLE、SAVI、NLRC4-MAS、斯蒂尔样疾病和其他未分化自身炎症性疾病的发病机制和结果

• 批准号: 10697673
• 负责人: Raphaela Goldbach-Mansky
• 金额: $ 213.57万
• 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/10697673
• 关键词: Adult; Affect; Amyloidosis; Animal Model; Area; Arthralgia; Biological; Biological Markers; Biopsy; Blood; CDC42 gene; COVID-19 pandemic; COVID-19 patient; Cell Culture System; Cell Differentiation process; Cell Line; Central Nervous System; Chronic; Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; Clinic; Clinical; Collaborations; Collection; Complex; Cytokine Signaling; DNA; DNA Sequence Alteration; Data; Defect; Development; Diagnosis; Disease; Disease model; Disease remission; Dose; Early treatment; Endothelial Cells; Enrollment; Evaluation; Exanthema; Eye; Fatty acid glycerol esters; Fever; Fibroblasts; Frequencies; Gene Expression Profiling; Genes; Genetic; Glucocorticoids; Goals; Growth and Development function; Image; Immune; Immunologics; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injections; Interferons; Interleukin-1; Interleukin-1 Receptors; Interleukin-18; Interstitial Lung Diseases; LYN gene; Laboratories; Labyrinth; Left; Life; Macrophage activation syndrome; Maintenance; Mediating; Medical Genetics; Mendelian disorder; Modeling; Molecular; Monitor; Muscle; Mutation; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; Natural History; Neonatal Onset Multisystem Inflammatory Disease; Organ; Organ Model; Outcome; Parents; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Perinatal mortality demographics; Phenotype; Phosphotransferases; Pilot Projects; Plasma Cells; Procedures; Production; Protocols documentation; Pulmonary Alveolar Proteinosis; Pulmonary Fibrosis; RNA; RNA Splicing; Radiology Specialty; Research; Risk; Role; Safety; Saliva; Sampling; Serum; Signal Transduction; Site; Skin; Source; Swab; Syndrome; Tissues; Treatment Protocols; Undifferentiated; United States National Institutes of Health; Urine; Validation; Variant; Vascular Diseases; Vasculitis; Viremia; Visit; Weaning; anakinra; antagonist; autoinflammatory; base; biomarker validation; bone; clinical phenotype; cohort; cytokine; de novo mutation; design; disability; early onset; follow-up; genetic analysis; genetic signature; genome sequencing; healthy volunteer; human model; improved; induced pluripotent stem cell; infancy; inhibitor; macrophage; microbiome analysis; molecular imaging; monocyte; mortality; next generation sequencing; novel; participant enrollment; patient subsets; pediatric patients; perinatal morbidity; peripheral blood; prevent; programs; response; side effect; small molecule; src-Family Kinases; stool sample; systemic inflammatory response; targeted treatment; tool; whole genome

A. CHARACERIZATION OF THE NATURAL HISTORY OF SAIDs: 1. CANDLE, SAVI: We have assessed geno-phenotype correlations in CANDLE and SAVI patients using data pre-JAK inhibitor treatment to characterize the spectrum of inflammatory disease manifestations, the impact of untreated inflammation on accumulating organ damage, the rate of perinatal morbidity and mortality and assessed cytokine and other biomarker dysregulation. 2. We have clinically characterized the disease manifestations of a novel disease Lyn associated autoinflammatory disease. B. DEVELOPMENT AND VALIDATION OF OUTCOME CRITERIA: We have developed outcome parameters for several autoinflammatory diseases and have validated the outcomes in the following areas for patients with DIRA and CANDLE: 1. parents/ patient outcomes, 2. remission, and 3. low disease activity. 4. Maintenance of a outcome inclusion of 5. growth and development parameters and 6. Ability to wean systemic glucocorticoids. C. LONG-TERM OUTCOME AND SAFETY EVALUATION ON TARGETED TREAT-MENTS ON PATIENTS ENROLLED IN PREVIOUS TREATMENT PROTOCOLS. 1. SAVI and CANDLE/PRAAS patients require long-term treatment and currently JAK inhibitors (JAKi) provide the most consistent benefit. Our studies with the small molecule JAKi, baricitinib, identified that BK reactivation in urine in most patients and in blood (3). We follow patients long-term on the natural history study and developed guidance to monitor BK viruria and viremia in patients requiring higher doses of JAK inhibitors. 2. Follow-up of a cohort of NOMID patients we characterized a long-term efficacy and side effects and identified the development of amyloidosis in a subset of patients who are receiving long-term high dose anakinra at the injections site. We evaluating the extend of this side effect. D. GENETIC DISCOVERY AND CHARACTERIZATION OF NOVEL AUTO-INFLAMMATORY DISEASES AND CLINICAL AND GENETIC EVALUATION OF PATIENTS WITH NOT YET CHARACTERIZED EARLY-ONSET AUTOINFLAMMATORY DISEASES 1. We characterized 2 novel autoinflammatory diseases, one that clinically mimics CANDLE, NEMO exon5 deleted autoinflammatory syndrome (NEMO-NDAS) (4, 5) and another disease caused by GOF mutations in Lyn kinase. We continue to evaluate and treat patients with severe inflammatory diseases that present early in infancy particularly those with interferonopathies but yet unknown genetic mutations. All patients undergo a detailed immune evaluation that includes assessment of their assessed their IFN response gene signature, genetic analyses using next generation sequencing, (currently whole genome sequencing (WGS)). E. DEVELOPMENT AND VALIDATION OF BIOMARKERS AND FOCUS ON UNDERSTANDING MONOCYTE AND MACROPHAGE DIFFERENTIATION TO IMPROVE DIAGNOSIS AND MONITORING OF AUTOINFLMAMMTORY DISEASES. 1. We are comparing IFN production, the source of IFN and of the IFN response gene signature in peripheral blood and tissues. We are validating the IFN signature in other monogenic and complex diseases including in adult and pediatric patients with COVID-19. 2. We collaborated with Dr. Scott Canna and a wider group to characterize biomarkers that allow the identification of patients with IL-18 PAP-MAS (4) now referred to as SOJIA-LD who develop pulmonary alveolar proteinosis and are at risk for the development of macrophage activation syndrome. F. EXPLORE MONOCYTE AND MACROPHAGE DIFFERENTIATION TO IMPROVE DIAGNOSIS AND UNDERSTAND PATHOGENIC IMPACT 1. We established that monocyte differentiation in the IL-1 mediated disease and compared monocyte differentiation in NEMO-NDAS and CANDLE patients. We are describing the immunological impact of the disease-causing NEMO-NDAS mutations on monocyte and macrophage differentiation and function. G. USE OF IN VITRO CELL CULTURE SYSTEMS TO MODEL ORGAN-SPECIFIC IMMUNE DYSREGULATION AND ORGAN DAMAGE IN SELECTED AUTOINFLAMMATORY DISEASES. We modeled aspects of organ inflammation and damage in two diseases, SAVI and LYN kinase mediated disease. 1. The interstitial lung disease in patients with SAVI with predominantly p.V155M mutations in STING1 are severe, and the predominant cause for mortality in SAVI. Complications and progression of lung fibrosis occur despite JAKis. In collaboration with the Boehm laboratory (NHLBI) we developed iPSC model to assess endothelial cells differentiation. 2. We developed iPScells from a patient with a GOF mutation in Lyn kinase to investigate small vessel vasculitis THE NATURAL HISTORY PROTOCOL was developed for initial and follow-up evaluations of patients with autoinflammatory diseases. Affected participants (enrollment ceiling of n = 1000) are clinically evaluated and phenotyped at the NIH CC which includes state of the art radiologic molecular imaging. Research samples are collected and include blood, skin, saliva, urine, and CSF as well as skin swabs and stool samples for microbiome analyses. Unaffected relatives and unrelated healthy volunteers (n = 500 of each) are enrolled for the collection of control biological samples. All affected patients and their parents undergo genetic evaluation. The frequency of the follow-up visits is based on the participants clinical status and the scientific objective related to the patient's disease. We collect and store samples including DNA for comprehensive genetic analyses, RNA for gene expression profiling, serum, plasma and cells for biomarker analysis and biopsy material if left over from clinically indicated procedures. We generate fibroblast cells lines from selected patients, and in selective patients we may generate iPSCs to model disease pathogenesis in organs and tissues. We obtain imaging to evaluate organs that are inflamed or damaged. During the COVID pandemic we closed a compassionate use program and we follow patients with CANDLE, SAVI and with other autoinflammatory interferonopathies on the natural history protocol.

A. SAID自然史的特征： 1. CANDLE，SAVI：我们使用JAK抑制剂治疗前的数据评估了CANDLE和SAVI患者的基因-表型相关性，以表征炎性疾病表现的谱、未治疗的炎症对累积器官损伤的影响、围产期发病率和死亡率，并评估了细胞因子和其他生物标志物失调。 2.我们对一种新的疾病--林恩相关的自身炎症性疾病的临床表现进行了表征。 B。结果标准的制定和验证：我们已经制定了几种自身炎症性疾病的结果参数，并验证了DIRA和CANDLE患者在以下领域的结果：1.父母/患者结局，2.缓解，以及3.疾病活动性低。4.保持5项结果入选。生长发育参数和6.能够停用全身性糖皮质激素。 C.既往治疗方案入组患者靶向治疗的长期结局和安全性评价。1. SAVI和CANDLE/PRAAS患者需要长期治疗，目前JAK抑制剂（JAKi）提供最一致的益处。我们对小分子JAKi baricitinib的研究发现，大多数患者的尿液和血液中BK重新激活（3）。我们在自然史研究中对患者进行了长期随访，并制定了监测需要更高剂量JAK抑制剂的患者的BK病毒尿和病毒血症的指南。 2.对NOMID患者队列的随访，我们表征了长期疗效和副作用，并确定了在注射部位接受长期高剂量阿那白滞素的患者亚组中淀粉样变性的发展。 我们评估这种副作用的程度。 D.新的自身炎性疾病的遗传学发现和特征以及尚未特征化的早发性自身炎性疾病患者的临床和遗传学评价 1.我们描述了2种新的自身炎性疾病，一种临床上类似于CANDLE，NEMO外显子5缺失的自身炎性综合征（NEMO-NDAS）（4，5），另一种疾病由林恩激酶的GOF突变引起。 我们继续评估和治疗婴儿早期出现的严重炎症性疾病患者，特别是那些患有干扰素病但基因突变未知的患者。所有患者均接受详细的免疫评估，包括评估其IFN应答基因特征，使用下一代测序进行遗传分析（目前为全基因组测序（WGS））。 E.生物标志物的开发和验证，重点是了解单核细胞和巨噬细胞分化，以改善自身感染性疾病的诊断和监测。 1.我们正在比较IFN的产生、IFN的来源以及外周血和组织中IFN应答基因特征。 我们正在验证其他单基因和复杂疾病中的IFN特征，包括成人和儿童COVID-19患者。 2.我们与Scott Canna博士和一个更广泛的小组合作，对生物标志物进行了表征，这些生物标志物允许识别患有IL-18 PAP-MAS（4）的患者，现在称为SOJIA-LD，这些患者发生肺泡蛋白沉积症，并有发生巨噬细胞活化综合征的风险。 F.探索单核细胞和巨噬细胞分化以提高诊断水平并了解致病影响 1.我们确定了IL-1介导的疾病中的单核细胞分化，并比较了NEMO-NDAS和CANDLE患者中的单核细胞分化。我们正在描述致病NEMO-NDAS突变对单核细胞和巨噬细胞分化和功能的免疫学影响。 G.使用体外细胞培养系统模拟选定的自身炎症性疾病中的器官特异性免疫调节障碍和器官损伤。我们对两种疾病（SAVI和林恩激酶介导的疾病）中的器官炎症和损伤方面进行了建模。1. STING 1中主要具有p.V155M突变的SAVI患者的间质性肺病是严重的，并且是SAVI中死亡的主要原因。 尽管有JAK，但仍会发生肺纤维化的并发症和进展。我们与Boehm实验室（NHLBI）合作开发了iPSC模型来评估内皮细胞分化。2.我们从一名林恩激酶GOF突变的患者身上开发了iPS细胞，以研究小血管炎 自然病史方案是为自身炎症性疾病患者的初始和随访评估而开发的。受影响的参与者（入组上限n = 1000）在NIH CC进行临床评价和表型分析，包括最先进的放射分子成像。 收集研究样本，包括血液，皮肤，唾液，尿液和CSF以及皮肤拭子和粪便样本用于微生物组分析。招募未受影响的亲属和无关的健康志愿者（各n = 500）用于收集对照生物样品。所有受影响的患者及其父母都接受了遗传评估。随访访视的频率基于参与者的临床状态和与患者疾病相关的科学目标。我们收集和储存样本，包括用于综合遗传分析的DNA，用于基因表达谱分析的RNA，用于生物标志物分析的血清，血浆和细胞以及活检材料（如果是临床手术遗留的）。我们从选定的患者中产生成纤维细胞系，并且在选定的患者中，我们可以产生iPSC来模拟器官和组织中的疾病发病机制。我们获取成像来评估发炎或受损的器官。在COVID大流行期间，我们关闭了一个同情使用项目，我们按照自然史方案跟踪CANDLE、SAVI和其他自身炎症性干扰素病患者。