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: 10281785
• 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/10281785
• 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% 的系统性红斑狼疮 (SLE) 患者患有贫血，红血 细胞（红细胞）输注是一种常见的疗法。虽然红细胞输注可以挽救生命，但生产 针对非自身 RBC 抗原的同种抗体会在 RBC 期间引起临床上显着的溶血事件 输血、妊娠和肾移植。先前的人类和动物研究表明 输血受​​者的炎症，包括自身免疫相关炎症，可以诱发或增强 红细胞同种抗体反应。例如，在美国，3-5% 的住院患者会产生红细胞 同种抗体，超过20%的SLE患者产生红细胞同种抗体，位居第二 与所有其他研究的疾病人群相比的患病率。然而，自身免疫的潜在机制 诱导红细胞同种免疫尚不清楚。我们之前报道过使用小鼠输血模型 急性病毒样刺激和流感感染会诱导促炎 1 型干扰素 (IFNα/β)， 关键调节小鼠红细胞上表达的人红细胞抗原的同种免疫。大约两—— 三分之一的成人和几乎所有患有 SLE 的儿童都表达 IFNα/β 基因特征，定义为产生 许多干扰素通过先天免疫细胞刺激基因。因此，我们假设并最近报道了 在狼疮小鼠模型的急性炎症期间，IFNα/β 还可促进红细胞同种免疫 自身免疫的发展。然而，尚不清楚慢性炎症是否存在 自身抗体和狼疮样病理，促进红细胞同种免疫。此外，尚不清楚是否 狼疮表型或 IFNα/β 直接促进慢性环境中的同种免疫。在这个应用程序中，我们 建议利用具有慢性炎症的狼疮模型为未来的 R01 生成初步数据。我们将 检验以下假设：狼疮的慢性炎症通过一种促进红细胞同种抗体产生的方法 通过确定狼疮表型和 IFNα/β 在调节红细胞中的作用来确定 IFNα/β 依赖性机制 同种抗体的产生（Aim1）和识别促进炎症的先天免疫信号通路- 在慢性狼疮模型中诱导同种免疫（目标 2）。而K08则侧重于基本机制 在没有炎症或疾病的情况下，IFNα/β 的产生和 IFNα/β 介导的同种免疫，这 通过检查狼疮慢性炎症诱导的同种免疫机制，应用有所不同 模型。研究结果将为过去对自身免疫相关的观察提供潜在的机制基础 同种免疫。此外，结果可能揭示炎症诱导的新途径 同种免疫并提供临床前数据以加强 R01 提案，其中包括调查 SLE 患者红细胞同种免疫的机制。在 RBC 专家的指导下 同种免疫、狼疮、IFNα/β和其他先天免疫反应，我们有能力完成 拟议的目标。