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: 10642866
• 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/10642866
• 关键词: Address; Allogenic; Alloimmunization; Antibodies; Antigens; Autoantibodies; Autoimmunity; Binding; 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; Leukocytes; Life; Ligands; Liver; Macrophage; Measures; Mediating; Mediator; 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; Serum; Sickle Cell Anemia; Signal Pathway; Signal Transduction; Spleen; Testing; Transfusion; Virus Diseases; antiviral immunity; cytokine; genetic signature; improved; insight; 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.

项目摘要 镰状细胞病(SCD)患者的红细胞免疫可导致潜在的致命性溶血事件。 与所有其他疾病相比，SCD患者的红细胞异体免疫发生率最高。 人口，包括那些有类似输血负担的人。解释这种高发病率的因素很少。 明白了。确定这些因素将有助于确定哪些SCD患者可能受益于 个性化的输血方案和稀有的抗原匹配单位。受血者体内的炎症已经 已被证明能促进红细胞同种异体抗体反应。我们之前报道过促炎性1型 病毒感染或自身免疫诱导的干扰素α/β促进临床前红细胞同种异体免疫 输血模型。最近的研究，包括本申请中包含的初步数据，表明 许多系统性红斑狼疮患者都有干扰素α/β基因特征，由干扰素α/β刺激的白细胞表达来定义 基因。然而，导致干扰素α/β激活的机制，包括信号通路、受体和配体， 人们对此了解甚少。几乎所有干扰素α/β诱导的受体都是细胞内的核酸受体。因此， 吞噬含有核酸的细胞，包括在SCD中升高的网织红细胞，具有潜在的 激活干扰素α/β通路。抗RBC自身抗体促进红细胞吞噬功能 SCD患者此类自身抗体的发生率增加。而RBC同种抗体/RBC 我们的初步数据表明，网织红细胞计数与自身抗体的相关性知之甚少。 自身抗体调理的网织红细胞干扰素α/β基因积分和吞噬功能的研究 SCD诱导人巨噬细胞干扰素α/β活化。初步数据还显示，抗红细胞自身抗体 在临床前输血模型中诱导干扰素α/β激活和红细胞同种异体免疫。 在这项提议中，我们的目标是检验红细胞自身抗体促进干扰素α/β介导的红细胞的假设。 通过识别诱导干扰素α/β的炎症途径(目标1)和确定 自身抗体诱导的干扰素α/β炎症对小鼠红细胞同种异体免疫的影响(目标2)。在目标1中， 由自身抗体诱导的干扰素α/β通路将在人巨噬细胞和 来自SCD患者和非SCD患者的网织红细胞以及研究结果的延伸将在临床前小鼠身上进行测试 模特们。识别的途径和受体将告知在SCD中诱导干扰素α/β的配体。目标2代表 首次在SCD临床前模型中研究干扰素α/β调节的红细胞同种异体免疫 揭示红细胞同种异体免疫发生率升高的可能机制。 该项目的长期目标包括改善对SCD中促炎症干扰素的理解， 靶向干扰素α/β调节治疗可能是有益的。这些发现也可能具有适用性 在SCD之外，炎性干扰素在自身免疫和其他疾病过程中发挥关键作用。