干扰素-γ 在自身免疫性多内分泌腺综合征 1 型中的作用。
The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.
机构信息
From 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.).
出版信息
N Engl J Med. 2024 May 30;390(20):1873-1884. doi: 10.1056/NEJMoa2312665.
BACKGROUND
Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood.
METHODS
We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using mice and mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses.
RESULTS
Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. ablation or ruxolitinib-induced JAK-STAT blockade in mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients.
CONCLUSIONS
Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
背景
自身免疫性多内分泌腺综合征 1 型（APS-1）是一种危及生命的常染色体隐性遗传病，由自身免疫调节因子（AIRE）缺陷引起。在 APS-1 中，自身反应性 T 细胞逃避了胸腺的阴性选择，浸润到各个器官并导致自身免疫损伤。导致 APS-1 中 T 细胞介导损伤的效应机制仍知之甚少。
方法
我们研究了 APS-1 是否可以归类为干扰素-γ 介导的疾病。我们首先评估了参与前瞻性自然病史研究的 APS-1 患者，并评估了血液和组织中的 mRNA 和蛋白表达。然后，我们使用干扰素-γ 处理 小鼠和 小鼠，并使用 Janus 激酶（JAK）抑制剂芦可替尼治疗。基于我们的发现，我们使用芦可替尼治疗了 5 例 APS-1 患者，并评估了临床、免疫、组织学、转录和自身抗体反应。
结果
APS-1 患者的血液和所有受自身免疫影响的组织中均存在增强的干扰素-γ 反应。小鼠选择性地增加了 T 细胞产生的干扰素-γ，并增强了多个器官中的干扰素-γ、磷酸化信号转导和转录激活因子 1（pSTAT1）和 CXCL9 信号。小鼠中的 缺失或 JAK-STAT 阻断可使干扰素-γ 反应正常化，并防止器官中的 T 细胞浸润和损伤。芦可替尼治疗 5 例 APS-1 患者可降低 T 细胞衍生的干扰素-γ水平，使干扰素-γ和 CXCL9 水平正常化，并使脱发、口腔念珠菌病、指甲营养不良、胃炎、肠炎、关节炎、类干燥综合征、荨麻疹和甲状腺炎缓解。这些患者未发现芦可替尼的严重不良反应。
结论
我们的研究结果表明，由 AIRE 缺陷引起的 APS-1 表现为过度的多器官干扰素-γ 介导的反应。在 5 例患者中使用芦可替尼进行 JAK 抑制显示出良好的效果。（由国家过敏和传染病研究所等资助）。
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