Mechanisms underlying inflammation-induced alloimmunization to RBC antigens in lupus

狼疮中炎症诱导的红细胞抗原同种免疫的机制

• 批准号: 10458054
• 负责人: David R Gibb
• 金额: $ 8.35万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458054
• 关键词: Acute; Adult; Allogenic; Alloimmunization; Anemia; Animals; Antibody Formation; Antigens; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; Blood Transfusion; Cells; Child; Chronic; Chronic Disease; Clinical Research; Communities; Data; Dependence; Development; Disease; Erythrocyte Transfusion; Erythrocytes; Event; Future; Genes; Goals; Graft Rejection; High Prevalence; Human; IFNAR1 gene; Immune; Immune response; Immune signaling; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injections; Innate Immune Response; Interferon-alpha; Interferons; Investigation; Isoantibodies; Kidney Transplantation; Lead; Life; Lupus; Mediating; Mentorship; Modeling; Mus; Pathology; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Phenotype; Population; Pregnancy; Pristane; Production; Protocols documentation; Reporting; Risk; Role; Safety; Savings; Severity of illness; Signal Pathway; Signal Transduction; Stimulus; Stratification; Systemic Lupus Erythematosus; TLR7 gene; Testing; Toll-like receptors; Transfusion; United States; Viral; Virus Diseases; clinically significant; cytokine; genetic signature; improved; influenza infection; lupus-like; mimetics; molecular recognition; mouse model; novel; pre-clinical; receptor; response; transfusion medicine

Abstract Approximately 50% of patients with systemic lupus erythematosus (SLE) suffer from anemia, for which red blood cell (RBC) transfusion is a common therapy. While RBC transfusion can be life-saving, production of alloantibodies against non-self RBC antigens causes clinically significant hemolytic events during RBC transfusion, pregnancy, and renal transplant. Prior human and animal studies have demonstrated that inflammation in a transfusion recipient, including autoimmune-associated inflammation, can induce or enhance RBC alloantibody responses. For example, while 3-5% of hospitalized patients in the United States produce RBC alloantibodies, more than 20% of patients with SLE produce RBC alloantibodies, representing the second highest prevalence compared to all other studied disease populations. However, mechanisms underlying autoimmune- induced RBC alloimmunization are poorly understood. Using murine transfusion models, we previously reported that acute viral-like stimuli and influenza infection induce pro-inflammatory type 1 interferons (IFNα/β), which critically regulate alloimmunization to human RBC antigens expressed on mouse RBCs. Approximately two- thirds of adults and nearly all children with SLE express an IFNα/β gene signature, defined as the production of numerous interferon stimulated genes by innate immune cells. Thus, we hypothesized and recently reported that IFNα/β also promotes RBC alloimmunization during acute inflammation in a lupus mouse model, prior to development of autoimmunity. It is unclear, however, whether chronic inflammation, in the presence of autoantibodies and lupus-like pathology, promotes RBC alloimmunization. In addition, it is unclear whether the lupus phenotype or IFNα/β directly promotes alloimmunization in the chronic setting. In this application, we propose to utilize lupus models with chronic inflammation to generate preliminary data for a future R01. We will test the hypothesis that chronic inflammation in lupus promotes RBC alloantibody production by an IFNα/β-dependent mechanism by determining the role of the lupus phenotype and IFNα/β in regulating RBC alloantibody production (Aim1) and identifying innate immune signaling pathways that promote inflammation- induced alloimmunization in models of chronic lupus (Aim 2). While the K08 focused on basic mechanisms of IFNα/β production and IFNα/β-mediated alloimmunization in the absence of inflammation or disease, this application diverges by examining mechanisms of chronic inflammation-induced alloimmunization in lupus models. Findings will provide a potential mechanistic basis for past observations of autoimmunity-associated alloimmunization. In addition, results may uncover novel pathways underlying inflammation-induced alloimmunization and provide preclinical data to strengthen an R01 proposal that will include investigation of mechanisms underlying RBC alloimmunization in patients with SLE. With mentorship from experts in RBC alloimmunization, lupus, IFNα/β, and other innate immune responses, we are well-equipped to complete the proposed aims.

抽象的 大约50％的全身性红斑狼疮患者（SLE）患有贫血，为此红血 细胞（RBC）输血是一种常见的疗法。虽然RBC输血可以挽救生命，但生产 针对非自发RBC抗原的同种抗体在RBC期间引起临床上显着的溶血事件 输血，怀孕和肾移植。先前的人类和动物研究表明 输血接受者的炎症，包括自身免疫相关感染，可以诱导或增强 RBC同种抗体反应。例如，美国有3-5％的住院患者产生RBC 同种抗体，超过20％的SLE患者产生了RBC同抗体，代表第二高的患者 与所有其他研究疾病人群相比，患病率。但是，自身免疫性的机制 诱导的RBC同释免疫知识率很少。使用鼠输血模型，我们先前报道了 急性病毒样刺激和影响流感感染引起促炎的1型干扰素（IFNα/β），这 严重调节在小鼠RBC上表达的人RBC抗原的同种异体免疫。大约两个 三分之一的成年人和几乎所有患有SLE的儿童表达IFNα/β基因签名，定义为产生 许多干扰素通过先天免疫球刺激基因。那我们假设并最近报告说 在狼疮小鼠模型中，IFNα/β还促进急性炎症期间的RBC同种异体免疫。 自身免疫的发展。然而，尚不清楚是否存在慢性炎症 自身抗体和类似狼疮的病理学，促进RBC同种免疫化。此外，还不清楚是否 狼疮表型或IFNα/β直接促进慢性环境中的同种免疫化。在此应用程序中，我们 利用带有慢性感染的狼疮模型来生成未来R01的初步数据。我们将 检验狼疮中慢性炎症的假设可促进RBC同种抗体产生 通过确定狼疮表型和IFNα/β在调节RBC中的作用，IFNα/β依赖性机制 同种抗体产生（AIM1），并鉴定出促进炎症的先天免疫信号传导途径 在慢性狼疮模型中诱导的同种免疫化（AIM 2）。而K08的重点是 在没有感染或疾病的情况下，IFNα/β的产生和IFNα/β介导的同种异体免疫 通过检查慢性感染诱导的狼疮的同种异体免疫的机制来分歧 型号。调查结果将为自身免疫相关的过去观察提供潜在的机械基础 同种免疫。此外，结果可能会发现感染引起的基本的新途径 同种免疫并提供临床前数据以加强R01提案，其中包括投资 SLE患者的RBC同种免疫的机制。借助加拿大皇家银行的专家 同种免疫化，狼疮，IFNα/β和其他先天免疫调查员，我们都有能力完成 拟议的目标。