Pathogenic Role of Malondialdehyde-Acetaldehyde Adducts in Rheumatoid Arthritis

丙二醛-乙醛加合物在类风湿性关节炎中的致病作用

• 批准号: 10421254
• 负责人: TED RICHARD MIKULS
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10421254
• 关键词: Acetaldehyde; Adjuvant; Affect; Age; Aging; Antibodies; Antigens; Arginine deiminase; Arthritis; Attenuated; Autoantibodies; Autoimmune Responses; Autoimmunity; Binding; Biological; Bypass; Calcium; Carrier Proteins; Cell Line; Cells; Characteristics; Chinese Hamster Ovary Cell; Citrulline; Data; Development; Diagnosis; Dihydropyridines; Disease; Disease Progression; Epitopes; Event; Fibrosis; Frequencies; Future; General Population; Healthcare; Human; Immune; Immune response; Immunization; Immunologic Adjuvants; Immunologics; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Joints; Laboratories; Lead; Link; Lipid Peroxidation; MHC Class II Genes; Malondialdehyde; Mediating; Modification; Morbidity - disease rate; Mus; Outcome; Oxidative Stress; Pathogenesis; Pathogenicity; Patients; Peptides; Play; Post-Translational Protein Processing; Prevention; Process; Prognosis; Proteins; Reporting; Research; Rheumatoid Arthritis; Role; Sampling; Seminal; Signal Transduction; Structure; Synovial Cell; Synovial Membrane; T cell response; Time; Tissues; Veterans; Woman; Work; adaptive immune response; adduct; base; cell type; chelation; citrullinated protein; cytotoxic; design; disability; experience; experimental study; immunogenic; improved; in vivo; inhibitor; innovation; insight; joint destruction; mRNA Expression; male; men; military veteran; mortality; mortality risk; neoantigens; novel marker; novel strategies; receptor; receptor binding; response; rheumatologist; scavenger receptor; seropositive; societal costs; systemic autoimmune disease; uptake

It has been estimated that rheumatologist-diagnosed Rheumatoid arthritis (RA) is seen in up to 2% of the users of VA healthcare. Moreover, compared to RA in women, RA in men (the primary VA demographic) leads to greater morbidity, a higher frequency of extra-articular manifestations, and worse disease-related outcomes. With an aging and predominantly male veteran population, it is anticipated that the burden posed by RA will grow dramatically in the VA in coming years. This is highly relevant given the association of RA with; substantially higher mortality risk among veterans, in addition to high rates of work-related disability, and annual societal costs approaching $40 billion in the US alone. Over the past few years, there have been substantial advances in our understanding of RA pathogenesis. Anti-citrullinated protein antibody (ACPA) is highly specific to RA with recent studies suggesting that ACPA are pathogenic with seropositivity portending a poor prognosis including more rapid joint destruction. However, the mechanism(s) by which citrullinated proteins/ peptides are recognized and processed and presented in the context of co-stimulatory molecules is still not well understood. Studies have shown that a unique post-translational modification of proteins that occurs under oxidative stress by malondialdehyde (MDA) and acetaldehyde (AA), termed MAA, up- regulates MHC Class II, increases co-stimulatory molecules and generates cytotoxic and pro-inflammatory responses in the absence of exogenous adjuvant. For the first time, our group has shown that MAA modified proteins are detected in synovial tissues of RA patients and co-localize with citrullinated antigen. Additionally, anti-MAA antibody isotypes are independently associated with ACPA concentration (p < 0.0001) in patients with established RA. Therefore, our overarching hypothesis is that these two post-translational modifications (MAA modification and citrullination) act in concert to drive tolerance loss resulting in the anti-citrulline autoimmune responses characteristic of RA. To investigate this hypothesis, studies in Aim 1 will evaluate adaptive immune responses (autoantibody and T cell responses) to citrullinated and/or MAA-modified proteins. We anticipate that compared to antigens that are only citrullinated or only MAA modified, immune responses to co-modified proteins will be higher in mice following immunization and in RA patients. As prior data has demonstrated that SRs mediate the biological effects of MAA-modified proteins on APCs and other cells, Aim 2 is designed to identify the specific SRs that mediate the effects of citrullinated and/or MAA-modified proteins in RA. In Sub-Aim #1, studies will leverage Chinese Hamster Ovary (CHO) cell lines that are already available in our laboratory and that have been transfected with each of the various SRs. Results of initial experiments will inform the design of subsequent binding studies using human APCs (that simultaneously express multiple SRs) and cell types unique to synovial tissue. Using available SR inhibitors alone or in combination will aid in defining which receptors are found on each cell type. In Sub-Aim #2, will focus on the biological effects (fibrosis, inflammation, calcium influx, PAD expression and citrullination) of the binding of MAA modified and/or citrullinated proteins to the different cell types. Thus, the innovative aspect of this proposal is its focus on the melding of two naturally occurring biological events (citrullination and oxidative stress) that conspire to initiate highly specific autoimmune responses, promoting the development and progression of RA.

据估计，在多达2％ VA Healthcare的用户。此外，与女性RA相比，男性RA（主要VA人群） 导致更高的发病率，较高的关节外表现频率以及与疾病有关的较差 结果。随着老化和主要是男性退伍军人的人口，预计 在未来几年，RA将在VA中急剧增长。考虑到RA的关联，这是非常相关的； 退伍军人之间的死亡风险显着较高，除了与工作相关的残疾率高以及年度 仅在美国，社会成本就接近400亿美元。在过去的几年中，有很大的 我们对RA发病机理的理解的进步。抗硝化蛋白抗体（ACPA）是高度特异性的 对RA进行的最新研究表明，ACPA具有致病性，血清阳性延伸较差 预后包括更快的关节破坏。但是，瓜氨酸蛋白/的机制 在共同刺激分子的背景下，肽被识别，处理和加工和呈现 理解。研究表明，蛋白质的独特后翻译后修饰 发生在丙二醛（MDA）和乙醛（AA）的氧化应激下发生，称为MAA，UP- 调节MHC II类，增加共刺激分子并产生细胞毒性和促炎性 在没有外源佐剂的情况下的反应。我们的小组首次表明MAA修改了 在RA患者的滑膜组织中检测到蛋白质，并与柠檬酸抗原共定位。此外， 抗MAA抗体同型与患者的ACPA浓度独立相关（P <0.0001） 与既定的RA。因此，我们的总体假设是这两个翻译后 修改（MAA修改和柠檬化）协同行动以驱动公差损失，导致 RA的抗核心自身免疫反应的特征。为了研究这一假设，研究 AIM 1将评估适应性免疫反应（自身抗体和T细胞反应）和/或 MAA修饰的蛋白质。我们预计，与仅柠檬酸或仅MAA的抗原相比 在免疫后，在小鼠中，对共修饰蛋白的改良，对共修饰蛋白的免疫反应将更高 患者。由于先前的数据表明SRS介导MAA修饰蛋白的生物学作用 在APC和其他细胞上，AIM 2旨在识别介导的特定SRS RA中的柠檬粉和/或MAA改性蛋白。在Sub-aim＃1中，研究将利用中国仓鼠 我们的实验室中已经可用的卵巢（CHO）细胞系已转染 每个SR中的每个。初始实验的结果将为随后的结合研究的设计提供信息 使用人APC（同时表达多个SR）和滑膜组织独有的细胞类型。使用 可用的SR抑制剂或组合将有助于定义每个细胞上的哪些受体 类型。在Sub-aim＃2中，将重点关注生物学作用（纤维化，炎症，钙涌入，PAD MAA修饰和/或柠檬硫化蛋白与不同细胞的结合的表达和柠檬化） 类型。因此，该提案的创新方面是它的重点是融合两个天然生物学 共同发起高度特定自身免疫反应的事件（柠檬化和氧化应激）， 促进RA的发展和发展。