Autoantibody-induced type 1 interferons and RBC alloimmunization in sickle cell disease

镰状细胞病中自身抗体诱导的 1 型干扰素和红细胞同种免疫

• 批准号: 10504262
• 负责人: David R Gibb
• 金额: $ 41.75万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10504262
• 关键词: Address; Allogenic; Alloimmunization; Antibodies; Antigens; Autoantibodies; Autoimmunity; Blocking Antibodies; Blood; Blood Transfusion; Cell Culture Techniques; Cells; Coculture Techniques; Cytokine Activation; Data; Disease; Erythrocyte Transfusion; Erythrocytes; Erythrophagocytosis; Evaluation; Event; Exposure to; Flow Cytometry; Frequencies; Genes; Goals; Human; Immune response; Incidence; Inflammation; Inflammatory; Interferon-alpha; Interferons; Intervention; Investigation; Isoantibodies; Kinetics; Lead; Leukocytes; Life; Ligands; Liver; Measures; Mediating; Mediator of activation protein; Modeling; Mus; Nucleic Acid Binding; Nucleic Acids; Pathway interactions; Patients; Phagocytosis; Play; Population; Pre-Clinical Model; Process; Production; Protocols documentation; Reporter; Reporting; Reticulocyte count; Reticulocytes; Reticulocytosis; Risk; Role; Safety; Savings; Serum; Sickle Cell Anemia; Signal Pathway; Signal Transduction; Spleen; Testing; Transfusion; Virus Diseases; antiviral immunity; cytokine; disorder control; genetic signature; improved; insight; macrophage; mouse model; pre-clinical; receptor; receptor binding; response; risk stratification

Project Summary RBC alloimmunization in patients with sickle cell disease (SCD) can lead to potentially fatal hemolytic events. Patients with SCD have the highest incidence of RBC alloimmunization, compared to all other disease populations including those with similar transfusion burdens. Factors explaining this high incidence are poorly understood. Identifying such factors would allow for identification of patients with SCD who may benefit from personalized transfusion protocols and rare antigen-matched units. Inflammation in the transfusion recipient has been shown to promote RBC alloantibody responses. We previously reported that proinflammatory type 1 interferons (IFNα/β) induced by viral infection or autoimmunity promote RBC alloimmunization in pre-clinical transfusion models. Recent studies, including preliminary data included in this application, have revealed that many patients with SCD have an IFNα/β gene signature, defined by leukocyte expression of IFNα/β stimulated genes. However, mechanisms leading to IFNα/β activation, including signaling pathways, receptors, and ligands, are poorly understood. Nearly all IFNα/β-inducing receptors are intracellular receptors for nucleic acids. Thus, phagocytosis of nucleic acid containing cells, including reticulocytes which are elevated in SCD, has the potential to activate IFNα/β pathways. Anti-RBC autoantibodies facilitate erythrophagocytosis, with alloimmunized patients with SCD having an increased incidence of such autoantibodies. While the RBC alloantibody/RBC autoantibody association is poorly understood, our preliminary data indicate that reticulocyte counts correlate with IFNα/β gene scores and erythrophagocytosis of autoantibody-opsonized reticulocytes from patients with SCD induces IFNα/β activation in human macrophages. Preliminary data also show that anti-RBC autoantibodies induce IFNα/β activation and RBC alloimmunization in a pre-clinical transfusion model. In this proposal, we aim to test the hypothesis that RBC autoantibodies promote IFNα/β-mediated RBC alloimmunization in SCD by identifying inflammatory pathways that induce IFNα/β (Aim 1) and determining the effects of autoantibody-induced IFNα/β inflammation on RBC alloimmunization in SCD mice (Aim 2). In Aim 1, IFNα/β pathways induced by autoantibodies will be identified in co-cultures of human macrophages and reticulocytes from patients with and without SCD, and the extension of findings will be tested in pre-clinical murine models. Identified pathways and receptors will inform ligands that induce IFNα/β in SCD. Aim 2 represents the first investigation of IFNα/β-regulated RBC alloimmunization in pre-clinical models of SCD and has the potential to reveal a mechanism that may contribute to the elevated incidence of RBC alloimmunization. Long term goals of this project include improved understanding of proinflammatory interferons in SCD, with the possibility that targeted IFNα/β-modulated therapy may be beneficial. Findings may also have applicability beyond SCD, with inflammatory interferons playing a critical role in autoimmunity and other disease processes.

项目概要 镰状细胞病 (SCD) 患者的红细胞同种免疫可能导致潜在致命的溶血事件。 与所有其他疾病相比，SCD 患者的红细胞同种免疫发生率最高 包括那些具有类似输血负担的人群，解释这种高发病率的因素很差。 了解这些因素将有助于识别可能受益的 SCD 患者。 个性化输血方案和稀有抗原匹配单位已导致输血受者出现炎症。 已被证明可促进 RBC 同种抗体反应 我们之前报道过促炎 1 型。 病毒感染或自身免疫诱导的干扰素（IFNα/β）在临床前促进红细胞同种免疫 最近的研究，包括本申请中包含的初步数据，表明： 许多 SCD 患者具有 IFNα/β 基因特征，定义为受 IFNα/β 刺激的白细胞表达 然而，导致 IFNα/β 激活的机制，包括信号通路、受体和配体， 几乎所有的 IFNα/β 诱导受体都是细胞内核酸受体。 含有核酸的细胞（包括 SCD 中升高的网织红细胞）的吞噬作用具有潜力 激活 IFNα/β 途径，抗红细胞自身抗体促进红细胞吞噬作用，并进行同种免疫。 SCD 患者此类自身抗体的发生率增加，而 RBC 同种抗体/RBC 的发生率增加。 自身抗体关联知之甚少，我们的初步数据表明网织红细胞计数相关 IFNα/β基因评分和来自患有以下疾病的患者的自身抗体调理后的网织红细胞的噬红细胞作用 初步数据还表明，SCD 会诱导人巨噬细胞中的 IFNα/β 激活，从而产生抗红细胞自身抗体。 在临床前输血模型中诱导 IFNα/β 激活和红细胞同种免疫。 在本提案中，我们旨在检验红细胞自身抗体促进 IFNα/β 介导的红细胞的假设 通过识别诱导 IFNα/β 的炎症途径（目标 1）并确定 SCD 中的同种免疫 自身抗体诱导的 IFNα/β 炎症对 SCD 小鼠红细胞同种免疫的影响（目标 1）。 由自身抗体诱导的 IFNα/β 途径将在人类巨噬细胞和 来自患有和不患有 SCD 的患者的网织红细胞，研究结果的扩展将在临床前小鼠中进行测试 已确定的途径和受体将告知在 SCD 中诱导 IFNα/β 的配体。 首次在 SCD 临床前模型中研究 IFNα/β 调节的红细胞同种免疫，并具有潜力 揭示可能导致红细胞同种免疫发生率升高的机制。 该项目的长期目标包括提高对 SCD 中促炎干扰素的了解， 靶向 IFNα/β 调节疗法的可能性也可能具有适用性。 除了 SCD 之外，炎症干扰素在自身免疫和其他疾病过程中发挥着关键作用。