Mechanisms underlying inflammation-induced alloimmunization to RBC antigens in lupus

摘要 大约50%的系统性红斑狼疮(SLE)患者患有贫血，为此红血球 细胞(RBC)输注是一种常见的治疗方法。虽然输注红细胞可以挽救生命，但生产 抗非自身RBC抗原的同种异体抗体在RBC期间引起临床显著的溶血事件 输血、怀孕和肾移植。先前的人类和动物研究已经证明 输血受者的炎症，包括自身免疫相关的炎症，可以诱发或增强 红细胞同种异体抗体反应。例如，虽然美国3%-5%的住院患者会产生红细胞 同种异体抗体，超过20%的SLE患者产生RBC同种抗体，排在第二位 将患病率与所有其他研究的疾病人群进行比较。然而，自身免疫的潜在机制- 对诱导的红细胞同种异体免疫知之甚少。使用小鼠输血模型，我们之前报告了 急性病毒样刺激和流感感染诱导促炎性1型干扰素(α/β)，这是 严格控制对小鼠红细胞上表达的人红细胞抗原的同种免疫。大约两个人- 三分之一的成人和几乎所有的儿童系统性红斑狼疮患者都表达干扰素α/β基因签名，其定义为产生 大量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 干扰素α/β还促进狼疮小鼠模型急性炎症期间的红细胞同种免疫，在此之前 自身免疫的发展。然而，目前尚不清楚慢性炎症是否存在于 自身抗体和狼疮样病理，促进红细胞同种异体免疫。此外，目前还不清楚 狼疮表型或干扰素α/β在慢性环境中直接促进同种异体免疫。在此应用程序中，我们 建议利用狼疮慢性炎症模型来产生未来R01的初步数据。我们会 检验狼疮慢性炎症促进红细胞同种异体抗体产生的假说 狼疮表型干扰素α/β依赖机制及干扰素α/β在调节红细胞中的作用 同种异体抗体产生(Aim1)和识别促进炎症的先天免疫信号通路- 慢性狼疮模型诱导同种异体免疫(目标2)。而K08专注于以下基本机制 在没有炎症或疾病的情况下，干扰素α/β的产生和干扰素α/β介导的同种异体免疫 通过研究狼疮慢性炎症诱导的同种异体免疫的机制，应用存在分歧 模特们。这些发现将为过去观察到的自身免疫相关疾病提供潜在的机制基础。 同种异体免疫。此外，研究结果可能揭示炎症诱导的新途径。 并提供临床前数据以加强R01提案，该提案将包括对 红斑狼疮患者红细胞同种异体免疫的机制。在加拿大皇家银行专家的指导下 同种异体免疫、狼疮、干扰素α/β和其他先天免疫反应，我们完全有能力完成 建议的目标。

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.