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：
8131699
负责人：
Veena Taneja
金额：
$ 17.03万
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/8131699
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易感性致电关节炎，而DRB1*0402提供了保护。胶原蛋白诱导的关节炎（CIA）易感性HLA转基因小鼠产生类风湿因子和类似于患者的抗奇异柑橘类肽抗体（ACPA）。但是，在患者中，遗传性疾病的其他遗传和环境因素含有100％的人，而不是100％的人，而遗传性的dr4则会引起其他遗传和环境因素，这些遗传和环境因素与疾病造成的疾病有关。人类的流行病学研究表明，吸烟是血清阳性RA的主要环境风险因素。有人建议在存在 *0401分子的情况下增加RA的严重程度和关节外特征。但是，吸烟调节免疫反应的机制导致严重程度增加和ACPA产生更高的生产。临床研究表明，ACPA先于RA的临床症状发作，这表明自身免疫开始早于临床疾病的实际发作。已证明吸烟可以增加肺中的肽基金氨氨酸葡萄氨酸酶（PAD）酶。灰粉过程需要垫子。这些观察结果表明，导致关节炎中自蛋白鞭打的免疫反应可能不一定从滑膜开始。但是，在所有研究中尚未观察到这种吸烟的影响，这表明吸烟会影响免疫反应的另一种机制。吸烟者显示出具有抑制DC功能的HLA-DR的活化的T细胞数量增加。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，与小鼠不同，但与人类相似。我们使用转基因小鼠的试点研究表明，与对照组相比，DQ8小鼠患有早期发作和暴露于香烟烟雾的小鼠的严重程度增加的关节炎，尽管在DR4小鼠中未观察到这种作用。这些研究可能会合理化在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，从而导致自动反应性反应如波形蛋白这样的自我蛋白质。在此提案中，我们有2个目标。在AIM 1中，我们将研究吸烟对使用转基因小鼠DRB1*0401，DQ8和DR4/DQ的影响的影响，以确定MHC基因与环境因素之间的相互作用。我们将研究T细胞对自蛋白的反应，RA中的自身抗原，以了解吸烟是否会破坏对自蛋白的耐受性。在AIM2中，我们将研究在易感和抗性HLA等位基因和关节炎的背景下暴露于吸烟后免疫反应调节的机理。此处描述的模型在性偏见，自身抗体概况和病理学中发展了与人类疾病相似的关节炎。关于HLA基因与关节炎中环境因素相互作用的文献中没有动物研究。人类研究表明吸烟和关节炎的作用是有争议的，缺乏机制，由于人类中DR和DQ等位基因的联系而导致的环境因素与遗传学相关。在某些遗传因素的背景下对环境因素的定义可能会导致较早的干预和教育患者，从而提高生活质量。公共卫生相关性：类风湿关节炎是一种致命的疾病，导致关节破坏。家庭研究表明，遗传因素在发生关节炎的易感性中的作用。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基因的小鼠来描述吸烟在关节炎中的作用。这些人源化的小鼠模仿了病理和自身抗体的类风湿关节炎。关节炎小鼠产生自身抗体，例如类风湿因子和抗奇异的柠檬粉肽抗体，用于诊断类风湿关节炎。这些研究将确定某些基因是否会使个体更容易受吸烟的影响，从而可以采取更早的干预措施以避免关节畸形。