Impact of smoking on immune response and arthritis in humanized mice

吸烟对人源化小鼠免疫反应和关节炎的影响

基本信息

批准号：
7950248
负责人：
Veena Taneja
金额：
$ 20.9万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-18 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7950248
关键词：
Affect Alleles Animals Antibodies Antigen Presentation Antigens Arthritis Autoantibodies Autoantigens Autoimmunity B-Lymphocytes CD3 Antigens Citrulline Clinical Clinical Research Collagen Arthritis Collagen Type II Data Deformity Development Diagnosis Disease Early treatment Environmental Risk Factor Enzymes Epidemiologic Studies Epitopes Equilibrium Etiology Europe Exposure to Family Study Genes Genetic Genetic Predisposition to Disease HLA-DQ8 antigen HLA-DR Antigens Human Immune Immune response Immunization Individual Inherited Joints Kinetics Lead Literature Lung Measures Mediating Modeling Monitor Mus Other Genetics Pathogenesis Pathology Patients Peptide antibodies Peripheral Pilot Projects Population Study Precipitation Predisposition Process Production Protein-arginine deiminase Proteins Publishing Quality of life Reaction Regulatory T-Lymphocyte Resistance Rheumatoid Arthritis Rheumatoid Factor Risk Factors Role Severities Severity of illness Sex Bias Signal Transduction Smoke Smoker Smoking Spleen Symptoms Synovial Membrane T cell response T-Lymphocyte TNFRSF10A gene Time Transgenes Transgenic Mice Vimentin autoreactivity base cigarette smoking cohort cyclic citrullinated peptide cytokine disabling disease early onset genetic risk factor human disease human leukocyte antigen gene human study immunoregulation joint destruction macrophage public health relevance response

项目摘要

DESCRIPTION (provided by applicant): HLA-DQ8 and DRB1*0401 molecules render humans and transgenic mice susceptible to develop arthritis while DRB1*0402 provide protection. Collagen-induced arthritis (CIA) susceptible HLA transgenic mice produce rheumatoid factor and anti-cyclic citrullinated peptide antibodies (ACPA) similar to that in patients.. However, not 100% of humans and mice inheriting DR4 develop arthritis suggesting other genetic and environmental factors that may be involved in precipitation of disease. Epidemiological studies in humans have suggested smoking as a major environmental risk factor for seropositive RA. Smoking has been suggested to increase severity and extra-articular features of RA in the presence of *0401 molecules. However, the mechanism by which smoking modulates immune response leading to increased severity and higher production of ACPA is unknown. Clinical studies have suggested that ACPA precede onset of clinical symptoms of RA suggesting autoimmunity starts much earlier that the actual onset of clinical disease. Smoking has been shown to increase peptidylarginine deiminase (PAD) enzymes in lungs. PADs are required for citrullination process. These observations suggest that immune response that leads to citrullination of self- proteins in arthritis may not necessarily start in synovium. However, this effect of smoking has not been observed in all studies suggesting another mechanism by which smoking can impact immune response. Smokers show an increased number of activated T cells expressing HLA-DR with suppressed function of DCs. The transgenic mice proposed in this model express HLA class II molecules in a subset of CD3+T cells unlike mice but similar to that of humans. Our pilot studies using transgenic mice showed that DQ8 mice develop arthritis with earlier onset and increased severity in mice exposed to cigarette smoke compared to controls, although this effect was not observed in DR4 mice. These studies may rationalize the differences observed in human study cohorts from Europe and USA. We hypothesize that smoking may increase disease severity by modulating immune response in lungs leading to presentation of a self protein like Vimentin ensuing autoreactive response. In this proposal, we have 2 aims. In aim 1 we will study the Impact of smoking on pathogenesis of arthritis using transgenic mice, DRB1*0401, DQ8 and DR4/DQ, to determine interaction between MHC genes and environmental factors. We will study T cell response to self protein, Vimentin an autoantigen in RA, to understand if smoking leads to break in tolerance to self-protein. In aim2,we will study the mechanism of modulation of immune response after exposure to smoking in context of RA susceptible and resistant HLA allele and arthritis. The model described here develops arthritis with similarities to human disease in sex-bias, autoantibody profile and pathology. There are no animal studies in literature on the interaction of HLA genes and environmental factors in arthritis. The human studies suggest a role of smoking and arthritis but are controversial and lack mechanism by which environmental factors associate with genetics due to linkage of DR and DQ alleles in humans. Definition of environmental factors in context of certain genetic factors may lead to earlier intervention and educating patients resulting in a better quality of life. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis is a disabling disease that leads to joint destruction. Family studies have suggested role of genetic factors in predisposition to develop arthritis. Human studies suggest that it is a multifactorial disease requiring interaction between both genetic and environmental factors. To date there is no specific environmental factor that has been associated with arthritis. Recent studies suggest smoking as a risk factor for arthritis. In this study we will use mice that express human arthritis associated genes to delineate the role of smoking in arthritis. These humanized mice mimic rheumatoid arthritis in pathology and autoantibodies. Arthritic mice produce autoantibodies like rheumatoid factor and anti-cyclic citrullinated peptide antibodies that are used for diagnosis of rheumatoid arthritis. These studies will identify if certain genes make individuals more susceptible to the effects of smoking so that an earlier intervention can be done to avoid joint deformities.

描述（由申请人提供）： HLA-DQ8 和 DRB1*0401 分子使人类和转基因小鼠容易患关节炎，而 DRB1*0402 则提供保护。胶原诱导关节炎 (CIA) 敏感的 HLA 转基因小鼠产生与患者相似的类风湿因子和抗环瓜氨酸肽抗体 (ACPA)。然而，并非 100% 继承 DR4 的人类和小鼠都会发展关节炎，这表明还有其他遗传和环境因素这可能与疾病的沉淀有关。人类流行病学研究表明吸烟是血清阳性 RA 的主要环境危险因素。有人建议，在 *0401 分子存在的情况下，吸烟会增加 RA 的严重程度和关节外特征。然而，吸烟调节免疫反应导致严重程度增加和 ACPA 产生增加的机制尚不清楚。临床研究表明，ACPA 先于 RA 临床症状出现，表明自身免疫的开始时间比临床疾病的实际发病时间早得多。吸烟已被证明会增加肺部的肽基精氨酸脱亚胺酶 (PAD)。瓜氨酸化过程需要 PAD。这些观察结果表明，导致关节炎中自身蛋白瓜氨酸化的免疫反应可能不一定始于滑膜。然而，并非所有研究都观察到吸烟的这种影响，这表明吸烟影响免疫反应的另一种机制。吸烟者表现出表达 HLA-DR 的活化 T 细胞数量增加，而 DC 功能受到抑制。该模型中提出的转基因小鼠在 CD3+T 细胞子集中表达 HLA II 类分子，这与小鼠不同，但与人类相似。我们使用转基因小鼠进行的初步研究表明，与对照组相比，接触香烟烟雾的小鼠 DQ8 小鼠患关节炎的时间更早，并且严重程度更高，尽管在 DR4 小鼠中没有观察到这种效应。这些研究可能合理化欧洲和美国人类研究队列中观察到的差异。我们假设吸烟可能会通过调节肺部的免疫反应来增加疾病的严重程度，从而导致出现波形蛋白等自身蛋白，从而引发自身反应。在这个提案中，我们有两个目标。在目标 1 中，我们将使用转基因小鼠 DRB1*0401、DQ8 和 DR4/DQ 研究吸烟对关节炎发病机制的影响，以确定 MHC 基因与环境因素之间的相互作用。我们将研究 T 细胞对自身蛋白（RA 中的一种自身抗原波形蛋白）的反应，以了解吸烟是否会导致对自身蛋白的耐受性破坏。在目标 2 中，我们将研究在 RA 易感性和耐药性 HLA 等位基因和关节炎的背景下吸烟后免疫反应的调节机制。这里描述的模型开发的关节炎在性别偏见、自身抗体谱和病理学方面与人类疾病相似。文献中没有关于关节炎中 HLA 基因和环境因素相互作用的动物研究。人类研究表明吸烟和关节炎有关，但存在争议，并且由于人类 DR 和 DQ 等位基因的连锁，缺乏环境因素与遗传学相关的机制。在某些遗传因素的背景下定义环境因素可能会导致早期干预和教育患者，从而提高生活质量。公共卫生相关性：类风湿性关节炎是一种导致关节破坏的致残性疾病。家庭研究表明遗传因素在关节炎易感性中发挥作用。人类研究表明，这是一种多因素疾病，需要遗传因素和环境因素之间的相互作用。迄今为止，还没有与关节炎相关的特定环境因素。最近的研究表明吸烟是关节炎的危险因素。在这项研究中，我们将使用表达人类关节炎相关基因的小鼠来描述吸烟在关节炎中的作用。这些人源化小鼠在病理学和自身抗体方面模仿类风湿性关节炎。关节炎小鼠产生类风湿因子和抗环瓜氨酸肽抗体等自身抗体，用于诊断类风湿性关节炎。这些研究将确定某些基因是否使个体更容易受到吸烟的影响，以便尽早进行干预以避免关节畸形。