在自身炎症综合征中,STAT4变异和对鲁克索利提尼布的反应
Hratch Baghdassarian1, Sarah A Blackstone1, Owen S Clay1
1From the Bioinformatics and Systems Biology Program (H.B.), the Department of Pediatrics (H.B., O.S.C., V.K.H., N.E.L.), the Center for Computational Biology and Bioinformatics, Department of Medicine (A.M., R.S., K.M.F.), the Institute for Genomic Medicine (K.J.), the Department of Bioengineering (N.E.L.), the Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics (J.C., L.B.), and the Department of Medicine (C.D.P.), University of California, San Diego, Sanford Burnham Prebys Medical Discovery Institute (R.M., Y.L.), and the San Diego Branch, Ludwig Institute for Cancer Research (C.D.P.), La Jolla, and the Department of Pathology (S.M.T.), Rady Children's Institute for Genomic Medicine (S.C., D.D.), and Rady Children's Hospital Foundation (J.C., L.B.), Rady Children's Hospital, San Diego - all in California; the Inflammatory Disease Section (S.A.B., B.M., M.N., S.R., P.P.C., N.H., E.F.R., D.L.K., H.O.), the Oncogenesis and Development Section (N.D.), and the Undiagnosed Diseases Program, Medical Genetics Branch (D.R.M., W.A.G.), National Human Genome Research Institute, the Molecular Immunology and Inflammation Branch (R.P., J.J.O.), the Light Imaging Section (D.R.) and the Translational Immunology Section (M.G.), Office of Science and Technology, and the Protein Expression Laboratory (E.E., N.R.W.), National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Genetics and Pathogenesis of Allergy Section, Laboratory of Allergic Diseases (C.A.M.), and the Translational Autoinflammatory Disease Section (R.G.-M.), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, and the Department of Cell Biology and Molecular Genetics, University of Maryland, College Park (B.M.) - all in Maryland; Sanford School of Medicine, University of South Dakota, Sioux Falls (S.A.B.); the Division of Rheumatology and Clinical Immunology, University of Pittsburgh (D.M.S.), University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh (A.S., G.W., K.T.), and the University of Pittsburgh Scleroderma Center (A.S., G.W., K.T.) - all in Pittsburgh; the Division of Pediatric Allergy, Immunology, and Rheumatology, Columbia University, New York (J.D.M.); and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases and the Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany (H.O.).
致残的松硬性形态 (DPM) 与新型STAT4基因变异有关. 简氏激酶 (JAK) 抑制剂鲁克索利提尼布通过改善皮肤和炎症症状,在治疗这种罕见的炎症性疾病方面表现有前途.
科学领域:
- 遗传学 是一个遗传学.
- 免疫学 免疫学 免疫学
- 皮肤病学 皮肤病学
背景情况:
- 致残性松硬性形态 (DPM) 是一种罕见的,严重的系统性炎症疾病,死亡率高.
- 它的特点是伤口愈合不良,纤维化,细胞衰竭,低血糖球蛋白血症和状细胞癌.
- 目前尚不清楚DPM的根本原因.
研究的目的:
- 在具有自体主导遗传模式的家庭中调查DPM的遗传基础.
- 定义已识别的遗传变异的功能后果.
- 确定DPM的潜在治疗点.
主要方法:
- 来自三个不相关家庭的患者的基因组测序.
- 在体外测试中使用初级皮肤纤维细胞和细胞系.
- 周围血液单核细胞的单细胞RNA测序.
- 抑制雅努斯酶 (JAK) -STAT信号通路.
主要成果:
- 在信号传感器和转录4 (STAT4) 基因激活器中发现了三种新型异质合体功能增益变异.
- 试验室研究显示,纤维细胞中增强的联素-6分泌和受损的伤口愈合.
- 卢克索利提尼布治疗在体外改善了高炎性纤维细胞表型,并解决了患者的临床症状.
- 单细胞RNA测序证实了一种通过JAK抑制修饰的免疫失调表型.
结论:
- 功能增益的STAT4变体是研究家族中DPM的原因.
- 鲁克索利提尼布有效地向JAK-STAT通路,减弱DPM的皮肤和炎症表型.
- 这项研究为DPM提供了潜在的治疗策略.
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