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

A.艾滋病自然病史的分类： 1.DirA、Candle、SAVI：我们总结了未经治疗的DirA、Candle和SAVI的自然病史，以表征炎症性疾病的表现谱、未经治疗的炎症对器官损害累积的影响、对围产儿发病率和死亡率的影响以及对总死亡率的影响，并建立基因-表型相关性。2.对CCD42-AID、NEMO-NDAS、SAMD9L-SAAD、IL-18PAP-MAS等新疾病的临床表现进行了分析。3.我们为确定干扰素介导的自身炎症性疾病的临床标准做出了贡献(4)。 B.制定和验证结果标准：我们评估了各种参数作为自体炎症性疾病的结果，并制定和验证了以下方面的结果：1.父母/患者的结果，2.缓解，以及3.疾病活动性低。4.维持结果，包括5.生长和发育参数和6.全身糖皮质激素的断奶能力。 C.JAK INHIBITROR巴利替尼靶向治疗的长期结果和安全性评估。1.SAVI和CANTLE/PRAAS是基因上定义的罕见的自身炎症性干扰素病，由STING1和编码蛋白酶体成分或蛋白酶体组装基因(PSMB8、PSMB4、PSMA3、PSMB9、PSMB10、PSMG2和POMP)的功能获得突变引起。我们已经描述了小分子巴利西尼抑制JAK对蜡烛和SAVI患者的好处，以及患者需要终身治疗(13，14)。我们对患者进行长期跟踪观察，以确定巴利替尼长期治疗的安全性。正如我们之前描述的BK病毒尿症和病毒血症的发展，我们监测肾功能和血液学参数以及感染。 D.新的自体炎症性疾病的基因发现和特征，以及尚未表现为早发性自体炎症性疾病特征的患者的临床和遗传学评估 1.我们鉴定了两种新的自身炎症性疾病，它们是临床上类似蜡烛的疾病，包括Nemo外显子5缺失的自体炎综合征(Nemo-NDAS)和SAMD9L相关的自炎性疾病(SAMD9L-SAAD)(13例)。致病途径比蜡烛更广泛，涉及外周血中增加的干扰素和核因子-kB信号。2.我们还在CDC42中发现了一种新的突变，它导致了高IL-18状态，在应激和感染的背景下，这种状态会导致MAS的发展(5)。我们还发现并鉴定了一种新的疾病，IL-18 PAPMAS，这种疾病还不是遗传性的疾病，表现为高IL-18血清水平和肺泡蛋白沉积症，并易发生MAS(13，3)。 我们继续评估和治疗早期出现严重炎症性疾病的患者，特别是那些患有干扰素疾病但未知基因突变的患者所有患者都要接受详细的免疫评估，包括评估他们的干扰素反应基因签名，使用下一代测序进行基因分析(全外显子测序(WES)和/或全基因组测序(WGS))。 E.生物标志物的开发和验证，并侧重于了解单核细胞和巨噬细胞的分化，以改进对自身免疫性疾病的诊断和监测。 1.我们正在评估干扰素产生的来源以及外周血液和组织中干扰素反应的来源。我们正在验证干扰素签名在其他单基因和复杂疾病中的有效性，包括新冠肺炎患者。 F.了解单核细胞和巨噬细胞分化，以提高诊断水平和对疾病发病机制的影响 1.我们建立了单核细胞分化在IL-1介导的疾病Majeed综合征中的作用，并发现M2分化细胞产生促炎细胞因子和趋化因子，这些细胞因子也可以驱动破骨细胞的形成，为自身炎症性骨病患者的骨炎症提供了一个模型。 使用体外细胞培养系统在选定的自体炎症性疾病中模拟器官特异性免疫失调和器官损伤。1.SAVI患者间质性肺疾病的严重程度从无到重度不等。间质性肺病的并发症是SAVI儿童死亡的主要原因。我们评估了SAVI患者的胸部计算机断层扫描(CT)和肺功能测试(PFT)以及肺组织，发现一个基因修饰区域与肺部疾病的严重程度相关。我们确定了导致SAVI的疾病严重程度的遗传标记。

A. CHARACERIZATION OF THE NATURAL HISTROY OF AIDS: 1. DIRA, CANDLE, SAVI: We have summarized the natural history of untreated DIRA, CANDLE and SAVI to characterize the spectrum of inflammatory disease manifestations, the impact of untreated inflammation on accumulating organ damage, the impact on perinatal morbidity and mortality as well as on overall mortality and to establish genotype-phenotype correlations. 2. We have clinically characterized the disease manifestations of novel diseases including CCD42-AID, NEMO-NDAS, SAMD9L-SAAD and IL-18PAP-MAS. 3. We contributed to the development of clinical criteria to identify patients with IFN mediated autoinflammatory diseases (4). B. DEVELOPMENT AND VALIDATION OF OUTCOME CRITERIA: We have assessed various parameters as outcome in autoinflammatory diseases and have developed and 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 TREATMENT WITH JAK INHIBITROR BARICITINIB. 1. SAVI and CANDLE/PRAAS are genetically defined rare autoinflammatory interferonopathies that are caused by gain-of-function mutations in STING1 and in genes encoding proteasome components or proteasome assembly genes (PSMB8, PSMB4, PSMA3, PSMB9, PSMB10, PSMG2 and POMP). We have described the benefit of JAK inhibition with the small molecule baricitinib in patients with CANDLE and SAVI and that patients require life-long treatment (13,14). We follow patients long-term to characterize the safety profile on long-term treatment with baricitinib. As we previously described the development of BK viruria and viremia we monitor kidney function and hematologic parameters and infections. D. GENETIC DISCOVERY AND CHARACTERIZATION OF NOVEL AUTOINFLAMMATORY DISEASES AND CLINICAL AND GENETIC EVALUATION OF PATIENTS WITH NOT YET CHARACTERIZED EARLY-ONSET AUTOINFLAMMATORY DISEASES 1. We characterized 2 novel autoinflammatory diseases that are clinical mimics of CANDLE and include NEMO exon5 deleted autoinflammatory syndrome (NEMO-NDAS) and SAMD9L associated autoinflammatory disease (SAMD9L-SAAD) (13). The pathogenic pathways are broader than in CANDLE and involve increased IFN and NF-kB signaling as assessed in the peripheral blood. 2. We also identified a novel mutation in CDC42 that causes a high IL-18 state that in the context of stress and infections leads to the development of MAS (5). We have also identified and characterized a novel disease, IL-18 PAPMAS, which is not yet genetically characterized disease that presents with high IL-18 serum levels and with pulmonary alveolar proteinosis and predisposition to the development of MAS (13, 3). 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, (whole exome sequencing (WES) and/or 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 assessing the source of IFN production and the source of the IFN response in peripheral blood and tissues. We are validating the IFN signature in other monogenic and complex diseases including in patients with COVID-19. F. UNDERSTAND MONOCYTE AND MACROPHAGE DIFFERENTIATION TO IMPROVE DIAGNOSIS AND IMPACT ON DISEASE PATHOGENESIS 1. We established that monocyte differentiation in the IL-1 mediated disease, Majeed syndrome and found that M2 differentiated cells produce pro-inflammatory cytokines and chemokines that can also drive osteoclastogenesis and provide a model for bone inflammation in patients with autoinflammatory bone diseases. G. USE OF IN VITRO CELL CULTURE SYSTEMS TO MODEL ORGAN-SPECIFIC IMMUNE DYSREGULATION AND ORGAN DAMAGE IN SELECTED AUTOINFLAMMATORY DISEASES. 1. The severity of interstitial lung disease varies in patients with SAVI from being absent to being severe. Complications from interstitial lung disease are the major cause of childhood mortality in SAVI. We assess chest computed tomography (CT) and pulmonary function tests (PFTs) and lung tissue in SAVI patients and found a genetic modifying region to be associated with the severity of lung disease. We identified genetic markers of disease severity that causes SAVI.