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

自身炎症性疾病、NOMID/CAPS、DIRA、CANDLE、SAVI、NLRC4-MAS、Stills 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: 10014247
• 负责人: Raphaela Goldbach-Mansky
• 金额: $ 244.92万
• 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/10014247
• 关键词: Adrenal Cortex Hormones; Animal Model; Arthralgia; Autoimmune Diseases; Automobile Driving; Biological Markers; Blood Cells; CDC42 gene; Cell Culture System; Child; Childhood; Chronic; Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; Clinic; Clinical; Clinical assessments; Complement; Complex; Cytokine Signaling; DNA Sequence Alteration; Data; Defect; Development; Diagnosis; Disease; Disease Outcome; Disease remission; Dose; Drug Kinetics; Early treatment; Evaluation; Exanthema; Eye; Fatty acid glycerol esters; Fever; Genes; Genetic; Genetic Diseases; Genetic Markers; Goals; Immune; Immunologics; Impairment; In Vitro; Infection; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Interferon Type I; Interferons; Interleukin-1; Interleukin-1 Receptors; Interleukin-18; Interstitial Lung Diseases; JAK1 gene; Laboratories; Labyrinth; Lead; Life; Link; Longterm Follow-up; Lung diseases; Macrophage Activation; Macrophage activation syndrome; Majeed syndrome; Mediating; Medical Genetics; Mendelian disorder; Molecular; Monitor; Muscle; Mutation; NF-kappa B; Neonatal Onset Multisystem Inflammatory Disease; Neuraxis; Organ; Organ Model; Osteoclasts; Osteomyelitis; Outcome; Paper; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pilot Projects; Predisposition; Prevention; Process; Production; Pulmonary Alveolar Proteinosis; Pulmonary function tests; Regimen; Research; Risk; Role; Safety; Serum; Severities; Severity of illness; Signal Pathway; Signal Transduction; Source; Stress; Structure of parenchyma of lung; Syndrome; Testing; Undifferentiated; Vascular Diseases; anakinra; autoinflammatory; base; biomarker validation; bone; chest computed tomography; clinical efficacy; cytokine; cytokine release syndrome; cytotoxic; design; disability; disease phenotype; early onset; exome sequencing; familial hemophagocytic lymphohistiocytosis; gain of function mutation; genetic analysis; genetic signature; genome sequencing; human model; improved; infancy; inhibitor/antagonist; insight; interleukin-18 binding protein; macrophage; monocyte; mortality; multicatalytic endopeptidase complex; next generation sequencing; novel; partial response; peripheral blood; prevent; programs; response; sensor; small molecule; targeted treatment; treatment effect; whole genome; young adult

A. STUDIES ON THE IL-1-MEDIATED DISEASES, NOMID AND DIRA: 1. We have completed long-term follow up of 42 patients with NOMID and MWS/NOMID overlap who have been treated for over ten years in long-term follow or who were started on treatment early in life. The evaluation of the data are ongoing and will provide valuable insights it the long-term outcome of NOMID patients treated with IL-1 blocking agents including the prevention of organ damage, and the long-term safety of chronic IL-1 blockade in NOMID patients. 2. We have collected long-term outcome data on DIRA patients treated with anakinra and are in the process of summarizing these data. 3. We identified novel mutations causing the monogenic osteomyelitis syndrome, Majeed syndrome, and are completing studies on the impact of the mutation on osteoclast activation and differentiation. B. ASSESSMENT OF GENTIC CAUSE AND BENEFIT AND SAFETY OF TYPE I IFN BLOCKADE IN TYPE I IFN-MEDIATED AIDs THAT CLINICALLY MIMIC CANDLE, AND SAVI. 1. SAVI and CANDLE/PRAAS are genetically-defined rare autoinflammatory interferonopathies that are caused by gain-of-function mutations in TMEM173 encoding STING and genes encoding proteasome components or proteasome assembly genes (PSMB8, PSMB4, PSMA3, PSMB9 and POMP). We have identified that JAK inhibition with the small molecule baricitinib improved manifestations in patients with CANDLE and SAVI with 50% of CANDLE patients achieving inflammatory remission off corticosteroids (9,12). We have identified novel CANDLE-causing mutations (3) and validated our findings on the clinical efficacy of JAK inhibitors in additional CANDLE patients (2, 3, 15) and patients with the autoinflammatory interferonopathy AGS (5). 2. We characterized novel autoinflammatory diseases that are clinical mimics of CANDLE. Their pathogenic pathways in these conditions are not only due to increased IFN signaling, but also due to increased NF-kB signaling in the peripheral blood. C. IDENTIFY AND CHARACTERIZE THE GENETIC CAUSE OF CONDITIONS THAT CAUSE CHRONICALLY ELEVATED IL-18 LEVELS. The identification of gain-of-function mutations in the innate immune sensor, NLRC4 (2014) represents the first monogenic defect that may link high IL-18 levels and macrophage activation syndrome (1). 1. Collaborating with the Canna lab, which tested this association in hyperferritinemic and autoinflammatory patients, we found a high correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 Binding Protein, or free IL-18. This paper confirms a unique connection between MAS risk and chronic IL-18, which distinguishes thes syndromes from the familial hemophagocytic lymphohistiocytosis diseases (fHLH) that converge with MAS in the activation of hyperferritinemic inflammation and complements the cytotoxic impairment which is the cause of fHLH in driving the cytokine storm that escalates hyperferritinemic inflammation to the end-organ damage that ensues with a high mortality in these syndromes (14). 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 MAS and thus increase the number of genetic conditions caused by high IL-18 states beyond NLRC4 (7). We have identified a novel 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. D. CLINICAL AND GENETIC EVALUATION OF PATIENTS WITH NOT YET CHARACTERIZED EARLY-ONSET AUTOINFLAMMATORY DISEASES Our findings of genetic defects that cause autoinflammatory disease manifestations revealed mutations in genes that lead to the IFN- mediated conditions (SAVI and CANDLE) and our biomarker and treatment data suggest a role of IFN overproduction in driving autoinflammatory/ autoimmune disease phenotypes. 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)). We are in the process of characterizing novel interferon-mediated diseases with partial responses to JAK inhibition. E. DEVELOPMENT AND VALIDATION OF BIOMARKERS AND FOCUS ON UNDERSTANDING MONOCYTE AND MACROPHAGE DIFFERENTIATION TO IMPROVE DIAGNOSIS AND MONITORING OF AUTOINFLMAMMTORY DISEASES. 1. We screened 65 patients with undifferentiated autoinflammatory diseases using the IFN score and serum cytokine analyses and identified novel diseases. We identified 3 conditions that present with an elevated IFN signature and with high NFKB signaling in peripheral blood cells, the latter distinguishing them from CANDLE and SAVI. 2. We identified peripheral blood monocytes as the source for IFNB1 in SAVI but not in CANDLE patients and establish differences in the sources of IFN between the different autoinflammatory interferonopathies. F. 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 assessed chest computed tomography (CT) and pulmonary function tests (PFTs) and lung tissue where available in 12 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. CONCLUSIONS AND SIGNIFICANCE Our program provides an integrative approach to the clinical, genetic and immunologic evaluation of patients with autoinflammatory diseases that continues to provide insights into the disease pathogenesis and into the use of targeted therapeutics to better treat patients and improve disease outcomes. Our studies have resulted in the discovery of novel autoinflammatory diseases that provided insights into the disease pathogenesis and revealed targets for treatment. 1. We expanded the genetics of CANDLE by identifying mutations in PSMG2 a novel monogenic cause of CANDLE. 2. In an ongoing compassionate use study using the JAK1/2 inhibitor baricitinib that inhibits IFN signaling we showed clinical benefit and collected safety data in patients with CANDLE and SAVI and in patients with clinical and laboratory evidence of IFN mediated disease. In a pharmacokinetic/dynamic study, we assessed the pharmacokinetic profile in children and young adults and provided a dosing regimen for patients with autoinflammatory interferonopathies. 3. The identification of mutations in NLRC4 that cause macrophage activation syndrome led to the exploration of the role of IL-18 in macrophage activation and to the characterization of 2 novel diseases associated with high IL-18 levels, one caused by mutations in CDC42 and a complex disease IL-18 PAP-MAS that presents with highly elevated serum IL-18 levels, pulmonary alveolar proteinosis (PAP) and predisposition to MAS. We contributed to biomarker studies in patients who present with macrophage activation syndrome in the context of various other autoinflammatory diseases.

A. IL-1 介导的疾病 NOMID 和 DIRA 的研究： 1. 我们已经完成了 42 名 NOMID 和 MWS/NOMID 重叠患者的长期随访，这些患者在长期随访中已经接受了十年以上的治疗或在生命早期就开始了治疗。 数据评估正在进行中，将为使用 IL-1 阻断剂治疗的 NOMID 患者的长期结果提供有价值的见解，包括预防器官损伤，以及 NOMID 患者慢性 IL-1 阻断的长期安全性。 2. 我们收集了接受阿那白滞素治疗的 DIRA 患者的长期结果数据，并正在总结这些数据。 3. 我们发现了导致单基因骨髓炎综合征（Majeed 综合征）的新突变，并正在完成该突变对破骨细胞活化和分化影响的研究。 B. 临床模拟蜡烛和 SAVI 的 I 型 IFN 介导的辅助药物中 I 型 IFN 阻断的遗传原因、益处和安全性评估。 1. SAVI 和 CANDLE/PRAAS 是基因定义的罕见自身炎症干扰素病，由编码 STING 的 TMEM173 和编码蛋白酶体成分或蛋白酶体组装基因（PSMB8、PSMB4、PSMA3、PSMB9 和 POMP）的基因的功能获得性突变引起。我们已经发现，小分子 baricitinib 抑制 JAK 可改善 CANDLE 和 SAVI 患者的症状，其中 50% 的 CANDLE 患者在皮质类固醇治疗后实现炎症缓解 (9,12)。我们已经确定了新的 CANDLE 引起突变 (3)，并验证了 JAK 抑制剂在其他 CANDLE 患者 (2、3、15) 和自身炎症干扰素病 AGS 患者 (5) 中的临床疗效。 2. 我们描述了临床模拟 CANDLE 的新型自身炎症性疾病。 在这些情况下，它们的致病途径不仅是由于 IFN 信号传导增加，而且是由于外周血中 NF-kB 信号传导增加所致。 C. 识别并描述导致 IL-18 水平长期升高的遗传原因。先天免疫传感器 NLRC4 (2014) 中功能获得性突变的鉴定代表了第一个可能将高 IL-18 水平与巨噬细胞活化综合征联系起来的单基因缺陷 (1)。 1. 与 Canna 实验室合作，在高铁蛋白血症和自身炎症患者中测试了这种关联，我们发现 MAS 风险与成熟 IL-18 的慢性（有时是终生）升高高度相关，特别是与 IL-18 结合蛋白未结合的 IL-18 或游离 IL-18。本文证实了 MAS 风险与慢性 IL-18 之间的独特联系，该联系将这些综合征与家族性噬血细胞性淋巴组织细胞增多症 (fHLH) 区分开来，后者与 MAS 共同激活高铁蛋白血症炎症，并补充细胞毒性损伤，而细胞毒性损伤是 fHLH 驱动细胞因子风暴导致高铁蛋白血症炎症升级的原因 这些综合征会导致终末器官损伤并导致高死亡率 (14)。 2. 我们还发现了 CDC42 中的一种新突变，该突变会导致高 IL-18 状态，在压力和感染的情况下会导致 MAS，从而增加由高 IL-18 状态引起的遗传性疾病数量，超出 NLRC4 (7)。我们发现了一种尚未具有遗传特征的新型疾病，其表现为高 IL-18 血清水平、肺泡蛋白沉积症和发生 MAS 的倾向。 D. 尚未确定早发性自身炎症性疾病特征的患者的临床和基因评估 我们对导致自身炎症性疾病表现的遗传缺陷的发现揭示了导致 IFN 介导的病症（SAVI 和 CANDLE）的基因突变，并且我们的生物标志物和治疗数据表明 IFN 过量产生在驱动自身炎症/自身免疫性疾病表型中的作用。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，特别是患有干扰素病但基因突变未知的患者。所有患者都接受详细的免疫评估，包括评估其 IFN 反应基因特征、使用下一代测序（全外显子组测序 (WES) 和/或全基因组测序 (WGS)）进行遗传分析。 我们正在研究对 JAK 抑制有部分反应的新型干扰素介导疾病的特征。 E. 生物标志物的开发和验证，重点了解单核细胞和巨噬细胞的分化，以改善自身炎症性乳房疾病的诊断和监测。 1. 我们使用 IFN 评分和血清细胞因子分析筛选了 65 名未分化自身炎症性疾病患者，并发现了新疾病。 我们确定了 3 种在外周血细胞中存在 IFN 特征升高和 NFKB 信号传导升高的病症，后者将它们与 CANDLE 和 SAVI 区分开来。 2. 我们确定外周血单核细胞是 SAVI 患者的 IFNB1 来源，但在 CANDLE 患者中则不然，并确定了不同自身炎症干扰素病之间 IFN 来源的差异。 F. 使用体外细胞培养系统对选定的自身炎症性疾病中的器官特异性免疫失调和器官损伤进行建模。 1. SAVI 患者间质性肺疾病的严重程度各不相同，从不存在到严重。间质性肺病并发症是 SAVI 儿童死亡的主要原因。我们评估了 12 名 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。 结论及意义 我们的项目提供了一种对自身炎症性疾病患者进行临床、遗传和免疫学评估的综合方法，继续深入了解疾病发病机制以及使用靶向治疗来更好地治疗患者并改善疾病结果。我们的研究发现了新型自身炎症性疾病，为了解疾病发病机制提供了见解并揭示了治疗靶点。 1. 我们通过鉴定 PSMG2 的突变（CANDLE 的新单基因原因）扩展了 CANDLE 的遗传学。 2. 在一项正在进行的同情使用研究中，使用抑制 IFN 信号传导的 JAK1/2 抑制剂 baricitinib，我们在 CANDLE 和 SAVI 患者以及有 IFN 介导疾病的临床和实验室证据的患者中显示了临床益处并收集了安全性数据。在一项药代动力学/动力学研究中，我们评估了儿童和年轻人的药代动力学特征，并为患有自身炎症干扰素病的患者提供了给药方案。 3. NLRC4 中导致巨噬细胞活化综合征的突变的鉴定导致人们对 IL-18 在巨噬细胞活化中的作用进行了探索，并确定了 2 种与高 IL-18 水平相关的新疾病的特征，其中一种是由 CDC42 突变引起的，另一种是复杂疾病 IL-18 PAP-MAS，该疾病表现为血清 IL-18 水平高度升高、肺泡蛋白沉积症 (PAP) 和易感性 至新加坡金管局。我们为患有各种其他自身炎症性疾病的巨噬细胞活化综合征患者的生物标志物研究做出了贡献。