干扰素-γ在自身免疫多分泌综合征1型中的作用
Vasileios Oikonomou1, Grace Smith1, Gregory M Constantine1
1From the Fungal Pathogenesis (V.O., G.M.C., M.M.S., E.M.N.F., L.D.S.D., J.P., Y.H., T.W., B.D.S., S.D., T.D., P.B., T.J.B., M.S.L.), the Immunopathogenesis (L.B.R., A.C., S.M.H.), and Immune Deficiency Genetics (L.D.N.) Sections, Laboratory of Clinical Immunology and Microbiology, the Centralized Sequencing Program, Division of Intramural Research (B.A.S., R.G., M.W.), and the Translational Autoinflammatory Disease Section (A.R., A.A.J., R.G.-M.), National Institute of Allergy and Infectious Diseases, the Laboratory of Pathology, Center for Cancer Research (J.L.D.), National Cancer Institute (G.S., J.C.A., D.R., C.R.L., D.E.K., M.M.Q., S.P.), the Immunoregulation Section, Kidney Diseases Branch (D.K., B.A.), and the Translational Hepatology Section, Liver Diseases Branch (T.H.), National Institute of Diabetes and Digestive and Kidney Diseases, the Genomics and Computational Biology Core (D.M.), the Salivary Disorders Unit (B.M.W.), and the Oral Immunity and Inflammation Section (N.M.M.), National Institute of Dental and Craniofacial Research, the Immunology Service, Department of Laboratory Medicine (J.S., H.S.K., S.D.R.), the Pharmacy Department (B.C.), and the Critical Care Medicine Department (A.F.S.), Clinical Center, the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., L.C.-S.), the Pulmonary Branch, National Heart, Lung, and Blood Institute (K.P.F., K.N.O.), and Eunice Kennedy Shriver National Institute of Child Health and Human Development (K.K.W.) - all at the National Institutes of Health, Bethesda, MD; Nantes Université, Centre Hospitalier Universitaire Nantes, INSERM, Centre de Recherche en Transplantation et Immunologie, Unité Mixte de Recherche 1064, Institut de Transplantation Urologie-Néphrologie, Nantes, France (M.B., C.G.); the Diabetes Center, University of California at San Francisco, San Francisco (M.S.A.), the Division of Infectious Diseases and the Lundquist Institute for Biomedical Innovation, Harbor-University of California, Los Angeles (UCLA), Medical Center, Torrance (M.S.), and the David Geffen School of Medicine, UCLA, Los Angeles (M.S.); Pediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla/Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Red de Investigación Translacional en Infectología Pediátrica (O.N., P.O.), and Departamento de Dermatología (M.T.M.-G.), Sección de Gastroenterología, Hepatología y Nutrición Pediatrica (J.V.-F.), Sección de Inmunología (J.M.L.), Sección de Endocrinología Pediátrica (A.L.G.-G.), and Sección de Nefrología Pediátrica (A.G.R.), Hospital Infantil Universitario Virgen del Rocío, and Departamento de Farmacología, Pediatría, y Radiología, Facultad de Medicina, Universidad de Sevilla (P.O.) - all in Seville, Spain; the University of Helsinki and Helsinki University Hospital, New Children's Hospital, Pediatric Research Center, Helsinki (M.R.J.S., J.L., M.H., S.L., P.K.); and the Department of Pediatrics, Institute of Clinical Sciences, and the Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (V.L., O.E.).
自免疫多分泌综合征1型 (APS-1) 是由过度的干扰素-反应驱动的. 鲁克索利提尼布有效地治疗了患者的Janus激酶 (JAK) 抑制,减少了自身免疫症状和T细胞活性.
科学领域:
- 免疫学 免疫学 免疫学
- 内分泌学 在内分泌学.
- 遗传学 是一个遗传学.
背景情况:
- 自免疫多分泌综合征1型 (APS-1) 是一种严重的遗传疾病,由自身免疫调节剂 (AIRE) 缺乏引起.
- 在APS-1中,自我反应的T细胞逃离了胆髓,导致对各种器官的自身免疫性攻击.
- 在APS-1中T细胞中介损伤的精确机制尚未完全理解.
研究的目的:
- 调查APS-1是否以干扰素- (IFN-γ) 介导的自身免疫反应为特征.
- 评估针对 APS-1 中的 Janus 激酶 (JAK) - STAT 途径的治疗潜力.
主要方法:
- 在APS-1患者和Aire-/-小鼠中评估IFN-γ水平和相关信号分子 (pSTAT1,CXCL9).
- 在Aire-/-小鼠中利用Ifng-/-小鼠和JAK抑制剂ruxolitinib来阻止IFN-γ信号传递.
- 用ruxolitinib治疗了5名APS-1患者,并监测了临床,免疫和转录变化.
主要成果:
- 患者和Aire-/-小鼠在血液和受影响的组织中表现出高的IFN-γ反应.
- 在Aire-/-小鼠中的JAK抑制使IFN-γ信号正常化,并防止器官损伤.
- 在APS-1患者中,鲁克索利提尼布治疗导致了多种自身免疫性疾病的临床缓解,没有严重的不良反应.
结论:
- 由于AIRE缺乏,APS-1的特征是过度的多器官IFN-γ介导的自身免疫反应.
- 正如鲁克索利提尼布治疗所证明的那样,JAK抑制代表了对APS-1的有希望的治疗策略.
- 针对IFN-γ通路为APS-1患者提供了潜在的治疗途径.
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