Pathogenesis and treatment of autoinflammatory diseases i.e.NOMID,DIRA,CANDLE, SAVI and others

NOMID、DIRA、CANDLE、SAVI等自身炎症性疾病的发病机制和治疗

• 批准号: 9155466
• 负责人: Raphaela Goldbach-Mansky
• 金额: $ 139.19万
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN 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/9155466
• 关键词: Agonist; Apoptosis; Arthralgia; Biological Markers; CCL2 gene; Cells; Cerebrospinal Fluid; Child; Chronic; Clinic; Clinical; Clinical Research; Collaborations; Contracture; Data; Defect; Deficiency Diseases; Development; Diagnosis; Disease; Disease model; Effectiveness; Endothelial Cells; Enrollment; Evaluation; Exanthema; Eye; FDA approved; Fatty acid glycerol esters; Fever; Fibroblasts; Flare; Functional disorder; Gatekeeping; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; HIV-Associated Lipodystrophy Syndrome; Hematopoietic; Hyperlipidemia; Immune; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interferon Type II; Interferon-beta; Interferons; Interleukin-1; Interleukin-18; Interstitial Lung Diseases; Intervention; JAK1 gene; Joints; Laboratories; Labyrinth; Lead; Life; Light; Link; Lipodystrophy; Lung diseases; Lymphocyte; Macrophage Activation; Mediating; Mendelian disorder; Metabolic; Metabolic syndrome; Modeling; Molecular Target; Muscle; Muscular Atrophy; Mutation; Myositis; Names; Neonatal; Neuraxis; Neurologic; Organ; Outcome; Panniculitis; Parents; Pathogenesis; Pathway interactions; Patients; Perinatal; Peripheral; Phenotype; Prevention; Primary Prevention; Production; Proteins; Pulmonary Hypertension; Rare Diseases; Recruitment Activity; Recurrence; Research; Role; STAT1 gene; Safety; Secondary Prevention; Severities; Signal Transduction; Skin; Somatic Mutation; Sting Injury; Study Section; Syndrome; Temperature; Therapeutic Effect; Tissues; Undifferentiated; Variant; Vascular Diseases; Vasculitis; Work; anakinra; base; bone; chemokine; clinical efficacy; clinical phenotype; cytokine; disability; disease phenotype; disease-causing mutation; effective therapy; exome sequencing; gain of function mutation; genetic analysis; genetic variant; human disease; infancy; inhibitor/antagonist; insight; macrophage; multicatalytic endopeptidase complex; next generation sequencing; novel; prevent; primary pulmonary hypertension; receptor; response; sensor; skin disorder; targeted treatment; therapeutic target; treatment effect

RESEARCH ACCOMPLISHMENTS A. CHARACTIZATION OF THE NOVEL INTERFERON-MEDIATED AUTOINFLAMMATORY DISEASE CAUSED BY GAIN OF FUNCITON MUTATIONS IN STING, SAVI. We recently identified that gain of function mutations in TMEM173, the gene that encodes a key adaptor molecule in the interferon pathway, STING, causes a novel autoinflammatory disease that we named STING-associated vasculopathy with onset in infancy (SAVI). These patients have constitutive activation of the interferon-beta pathway. Patients present with vasculitis and a severity spectrum of interstitial lung disease, and several patients have developed pulmonary hypertension. STING is expressed in endothelial cells, and activation of the STING pathways in these cells results in endothelial activation and apoptosis, a feature that may explain the predominant manifestation as peripheral vasculitis and vasculopathy. However the severity of interstitial lung disease is variable in patients with SAVI ranging from being absent to severe. We observed that activated/phosphorylated STAT1 in SAVI patients lymphocytes and the exaggerated responses to STING agonists including cGAMP in patient fibroblasts are reduced by treatment with JAK inhibitors, we are treating SAVI patients in a compassionate use study with the JAK inhibitor baricitinib and evaluate the effect of treatment on the clinical manifestations including vasculitis, interstitial lung disease and pulmonary hypertension. We are characterizing genetic variants that modify the severity of the IFN dysregulation and are hypothesizing that these variants may determine the severity of the lung disease in SAVI patients. B. GAIN OF FUNCTION MUTATION IN NLRC4 CAUSE AN AUTOINFLAMMATORY SYNDROME WITH RECURRENT FEVER FLARES AND MACROPHAGE ACTIVATION (NLRC4-MAS) The identification of a de novo mutation T337S in the intracellular innate immune sensor, NLRC4 identified a monogenic defect that can lead to the development of macrophage activation syndrome. Functional analyses pf the mutation demonstrate spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1beta and IL-18. In contrast to NOMID patients with an inflammasome defect in NLRP3, NLRC4-MAS patients have very high elevation of IL-18 produced in macrophages, thus providing us with a disease model to study macrophage activation. High IL-18 levels are also seen in patients with other inflammatory conditions that are prone to the development of macrophage activation syndrome i.e Stills disease and our data suggest a critical role for IL-18 in the development of macrophage activation syndrome. This project is being developed in collaboration with the Metzger Scholar, Dr. Canna. C. NOVEL INSIGHTS INTO THE INTERFERON MEDIATED DISEASE CANDLE. The majority of patients with CANDLE (Chronic atypical neutrophilic dermatosis with lipodystrophy, and elevated temperature) have mutations in the proteasome subunit PSMB8 which led to the unifying concept that a group of rare diseases referred to as JMP (joint contractures, muscle atrophy and panniculitis-induced lipodystrophy) syndrome, and Nakajo-Nishimura syndrome (NNS) form one disease spectrum of proteasome-associated autoinflammatory syndromes. We have recently discovered that CANDLE patients who were negative for PSMB8 mutations have mutations in other proteasome components that lead to proteasome dysfunction indicating that CANDLE can be caused by digenic and monogenic inheritance. All patients expressed high IP-10 (Interferon gamma-induced protein 10), MCP-1, and other chemokines and cytokines associated with interferon induced diseases and a strong interferon (IFN) response signature (IRS) confirming that IFN dysregulation is linked to global proteasome dysfunction not related to mutations in one component. An ongoing compassionate use study with the JAK inhibitor, baricitinib (Eli Lilly) that can inhibit interferon signaling, is recruiting patients with CANDLE and SAVI and other interferonopathies who are unresponsive to IL-1 blocking agents. We are studying the inflammatory phenotype and metabolic changes in CANDLE, including hyperlipidemias, metabolic syndrome, myositis and primary pulmonary hypertension, a serious disease manifestation we recently identified in CANDLE patients. D. STUDIES ON THE IL-1-MEDIATED DISEASES, NOMID AND DIRA: 1. FDA submission of our long-term outcome data using the short-acting IL-1 inhibitor anakinra (SOBI) in patients with neonatal-onset multisystem inflammatory disease (NOMID) led to FDA approval of anakinra for the treatment of NOMID in December 2012. 2. We previously found that IL-1 blocking treatment adjustments need to be made to control central nervous system (CNS) inflammation in NOMID patients. We thus evaluated biomarkers in the cerebrospinal fluid (CSF) that correlate with CNS inflammation and suggest a contribution on non hematopoietic cells to the inflammatory response in the CNS. We validated these markers in patients treated with a short-acting and long-acting IL-1 inhibitor. 3. Dr. Montealegre in our group conducts a study with the long-acting IL-1 blocking agent rilonacept in patients with DIRA. Preliminary data suggest good inflammatory control and prevention of progression of organ damage in six patients enrolled. E. ONGING STUDY OF PATIENTS WITH UNDIFFERENTIATED AUTOINFLAMMTORY DISEASES We evaluate and treat patients with severe inflammatory diseases that present early in infancy. In addition to a detailed immune evaluation that includes gene expression studies, patients and their parents if indicated undergo genetic analyses including evaluation through next generation sequencing, including whole exome sequencing (WES). We have identified likely disease causing mutations that are being evaluated and we attempt to identify molecular targets that allow us to better treat patients with AIDs. CONCLUSIONS AND SIGNIFICANCE We developed an integrative approach using immune evaluation, whole exome sequencing and targeted therapeutics to assess patients with autoinflammatory disorders, with the goal to better diagnose, understand disease pathogenesis and identify novel targets for therapy. Our studies have resulted in the discovery of the genetic causes of novel diseases that provided insights into the disease pathogenesis and targets for novel treatment interventions. 1. Two novel recently identified autoinflammatory diseases, SAVI and NLRC4-MAS shed light on basic disease mechanisms that cause autoinflammatory disease phenotypes. 2. Our pathogenesis data in CANDLE and our findings that gain-of-function mutations in STING, a gatekeeper for IFN beta transcription cause SAVI, suggest a causative role of IFN signaling in a new group of autoinflammatory diseases and suggest novel targets for treatment. 3. Our studies in CANDL and SAVI provide a rational for a compassionate use study with the JAK1/2 inhibitor baricitinib that inhibits IFN signaling. We are assessing the clinical efficacy and safety in patients with CANDLE and SAVI and in patients with clinical and laboratory evidence of IFN mediated disease. 4. The identification mutations in NLRC4 causing macrophage activation, lead to the exploration of the role of IL-18 in macrophage activation and suggest IL-18 as a potential target for treatment. 5. IL-1-blocking therapies are FDA-approved for the use in CAPS including NOMID based on work performed under this study. Our biomarker analyses aim to define markers that help us determine appropriate control of systemic and organ inflammation in NOMID and to identify potential differences in the effectiveness in controlling organ inflammation that may exist between different IL-1 blocking agents. 6. A clinical study in patients with DIRA using the long-acting IL-1 inhibitor rilonacept (Regeneron) is being completed.

研究成果 A. 由于 Sting、Savi 中功能突变的获得而引起的新型干扰素介导的自身炎症性疾病的特征。我们最近发现，TMEM173（编码干扰素途径 STING 中关键接头分子的基因）的功能获得突变会导致一种新型自身炎症性疾病，我们将其命名为婴儿期发病的 STING 相关血管病 (SAVI)。这些患者具有干扰素-β途径的组成性激活。患者出现血管炎和一系列严重的间质性肺疾病，一些患者出现肺动脉高压。 STING 在内皮细胞中表达，这些细胞中 STING 通路的激活会导致内皮细胞活化和细胞凋亡，这一特征可以解释外周血管炎和血管病变的主要表现。 然而，SAVI 患者间质性肺疾病的严重程度各不相同，从不存在到严重不等。我们观察到，通过 JAK 抑制剂治疗，SAVI 患者淋巴细胞中激活/磷酸化的 STAT1 以及患者成纤维细胞中对 STING 激动剂（包括 cGAMP）的过度反应减少，我们正在一项同情用药研究中使用 JAK 抑制剂 baricitinib 治疗 SAVI 患者，并评估治疗对临床表现的影响，包括血管炎、间质性肺疾病和 肺动脉高压。 我们正在表征改变 IFN 失调严重程度的遗传变异，并假设这些变异可能决定 SAVI 患者肺部疾病的严重程度。 B. NLRC4 中的功能突变导致伴有反复发烧和巨噬细胞激活的自身炎症综合征 (NLRC4-MAS) 在细胞内先天免疫传感器 NLRC4 中鉴定出新突变 T337S，鉴定出可导致巨噬细胞激活综合征发生的单基因缺陷。突变的功能分析表明自发炎症小体形成以及炎症小体依赖性细胞因子 IL-1β 和 IL-18 的产生。 与 NLRP3 炎症体缺陷的 NOMID 患者相比，NLRC4-MAS 患者巨噬细胞中产生的 IL-18 水平非常高，从而为我们提供了研究巨噬细胞激活的疾病模型。高 IL-18 水平也见于患有其他容易发生巨噬细胞活化综合征（即斯蒂尔病）的炎症性疾病的患者，我们的数据表明 IL-18 在巨噬细胞活化综合征的发生中发挥着关键作用。该项目是与 Metzger 学者 Canna 博士合作开发的。 C. 对干扰素介导疾病蜡烛的新见解。大多数 CANDLE（伴有脂肪营养不良和体温升高的慢性非典型中性粒细胞性皮肤病）患者的蛋白酶体亚基 PSMB8 发生突变，这导致了一个统一的概念，即一组称为 JMP（关节挛缩、肌肉萎缩和脂膜炎诱导的脂肪营养不良）综合征和 Nakajo-Nishimura 综合征的罕见疾病 (NNS) 形成蛋白酶体相关自身炎症综合征的一种疾病谱。我们最近发现 PSMB8 突变阴性的 CANDLE 患者的其他蛋白酶体成分发生突变，导致蛋白酶体功能障碍，表明 CANDLE 可能是由双基因和单基因遗传引起的。所有患者均表达高 IP-10（干扰素 γ 诱导蛋白 10）、MCP-1 和其他与干扰素诱发疾病相关的趋化因子和细胞因子，以及强干扰素 (IFN) 反应特征 (IRS)，证实 IFN 失调与整体蛋白酶体功能障碍有关，与某一成分的突变无关。 一项正在进行的同情使用 JAK 抑制剂 baricitinib (Eli Lilly) 的研究，该抑制剂可以抑制干扰素信号传导，正在招募对 IL-1 阻断剂无反应的 CANDLE 和 SAVI 以及其他干扰素病患者。我们正在研究 CANDLE 的炎症表型和代谢变化，包括高脂血症、代谢综合征、肌炎和原发性肺动脉高压，这是我们最近在 CANDLE 患者中发现的一种严重疾病表现。 D. IL-1 介导的疾病 NOMID 和 DIRA 的研究： 1. FDA 提交了我们使用短效 IL-1 抑制剂阿那白滞素 (SOBI) 治疗新生儿多系统炎症性疾病 (NOMID) 患者的长期结果数据，导致 FDA 于 2012 年 12 月批准阿那白滞素用于治疗 NOMID。 2.我们之前发现需要调整IL-1阻断治疗以控制NOMID患者的中枢神经系统（CNS）炎症。 因此，我们评估了脑脊液（CSF）中与中枢神经系统炎症相关的生物标志物，并提出非造血细胞对中枢神经系统炎症反应的贡献。 我们在接受短效和长效 IL-1 抑制剂治疗的患者中验证了这些标志物。 3.我们组的Montealegre博士对DIRA患者进行了一项长效IL-1阻断剂利洛那西普的研究。 初步数据表明，六名入组患者的炎症控制良好，并预防了器官损伤的进展。 E. 对未分化自身炎症性疾病患者的长期研究 我们评估和治疗婴儿早期患有严重炎症性疾病的患者。 除了包括基因表达研究的详细免疫评估外，患者及其父母（如果有需要）还需接受遗传分析，包括通过下一代测序（包括全外显子组测序（WES））进行评估。 我们已经确定了可能导致疾病的突变，正在对其进行评估，并尝试确定分子靶标，使我们能够更好地治疗艾滋病患者。 结论及意义 我们开发了一种综合方法，利用免疫评估、全外显子组测序和靶向治疗来评估患有自身炎症性疾病的患者，目的是更好地诊断、了解疾病发病机制并确定新的治疗靶点。我们的研究发现了新疾病的遗传原因，为了解疾病发病机制和新治疗干预的目标提供了见解。 1. 最近发现的两种新的自身炎症性疾病，SAVI 和 NLRC4-MAS，揭示了导致自身炎症性疾病表型的基本疾病机制。 2. 我们在 CANDLE 中的发病机制数据以及我们在 STING（IFN β 转录看门人）中的功能获得性突变导致 SAVI 的发现，表明 IFN 信号传导在一组新的自身炎症性疾病中具有致病作用，并提出了新的治疗靶点。 3. 我们在 CANDL 和 SAVI 中的研究为抑制 IFN 信号转导的 JAK1/2 抑制剂 baricitinib 的同情使用研究提供了合理依据。 我们正在评估 CANDLE 和 SAVI 患者以及有 IFN 介导疾病临床和实验室证据的患者的临床疗效和安全性。 4. NLRC4中引起巨噬细胞激活的突变的鉴定，引发了对IL-18在巨噬细胞激活中的作用的探索，并表明IL-18作为潜在的治疗靶点。 5. 根据本研究中进行的工作，IL-1 阻断疗法已获得 FDA 批准用于 CAPS，包括 NOMID。我们的生物标志物分析旨在定义标志物，帮助我们确定 NOMID 中全身和器官炎症的适当控制，并确定不同 IL-1 阻断剂之间可能存在的控制器官炎症有效性的潜在差异。 6. 一项使用长效 IL-1 抑制剂利洛那西普（Regeneron）对 DIRA 患者进行的临床研究正在进行中。