Role of B cells in pathogenesis of Collagen-induced Arthritis in Humanized Mice

B 细胞在人源化小鼠胶原诱导的关节炎发病机制中的作用

基本信息

批准号：
7727199
负责人：
Veena Taneja
金额：
$ 26.44万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7727199
关键词：
Address Adoptive Transfer Affect Alleles Animal Model Antibodies Antibody Formation Antigen Presentation Antigen-Presenting Cells Antigens Apoptosis Apoptotic Arthritis Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Responses Autoimmunity B cell differentiation B-Cell Activation B-Lymphocyte Epitopes B-Lymphocytes Biological Cell Count Cell Survival Cell physiology Cells Collagen Arthritis Collagen Type II Cyclic Peptides Data Defect Dendritic Cells Development Diagnosis Disease Epitope Mapping Epitopes Family Female Fibrinogen Freund&apos s Adjuvant Genes Goals HLA-DQ8 antigen Heat-Shock Proteins 70 Human Hybridomas Hyperactive behavior Immune response Immunization In Vitro Incidence Individual Knock-out Knockout Mice Lead Ligands Light MS4A1 gene Maps Measures Mediating Modeling Mus Pathogenesis Pathology Patients Peptide antibodies Peptides Peripheral Phenotype Plasma Cells Preventive Process Production Proteins Receptors, Antigen, B-Cell Regulation Resistance Rheumatoid Arthritis Rheumatoid Factor Role Serum Severities Sex Bias Symptoms Synovial Fluid T memory cell T-Cell Activation T-Lymphocyte T-Lymphocyte Epitopes TALL-1 protein TLR4 gene TLR5 gene TNF gene TNFRSF10A gene Testing Toll-like receptors Transgenic Mice Transgenic Organisms Woman Work autoreactive B cell autoreactive T cell chemokine chemokine receptor cyclic citrullinated peptide cytokine disabling disease human leukocyte antigen gene in vivo macrophage men microbial public health relevance receptor receptor expression research study resistant strain response rituximab synthetic peptide trafficking

项目摘要

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) and its animal model collagen-induced arthritis (CIA) are known to be T and B cell dependent diseases. HLA-DQ8 and DRB1*0401 molecules render humans and mice susceptible to develop arthritis while DQ6 and DRB1*0402 provide protection. CIA susceptible HLA transgenic mice produce rheumatoid factor and anti-cyclic citrullinated peptide (CCP) antibodies similar to that in patients. Absence of CIA and low cellular responses in B cell knockout mice suggests that the autoreactive B cells, in addition to producing antibodies may also be involved in presenting auto antigens to T cells. Improvement in ACR response criteria after depletion of B cells in patients further underscores the role of B cells in arthritis. However, the exact role of B cells in antigen presentation and their regulation in susceptible versus resistant strains of transgenic mice remains unclear. B cell function is regulated by B cell receptor, BCR, as well as other B cell specific receptors like BAFF-R. Our hypothesis is that B cells in transgenic mice carrying RA susceptible HLA gene have a defect in regulation which occurs through B cell receptor leading to hyperactivity and increased survival of autoreactive B cells. Females have hyperactive B cells which contribute towards the development of autoantibodies and presentation of antigens to T cells leading to increased incidence in females. Our preliminary data is consistent with this notion. Recent studies have shown that B cell responses are controlled by TLRs. In this study we will address the mechanism by which B cells contribute towards pathogenesis of collagen-induced arthritis in transgenic mice using mice expressing both CIA-susceptible and resistant HLA genes. In aim1, we will define the requirement of B cells as antigen presenting cells in pathogenesis of CIA. In aim 2 we will test our hypothesis if hyperactivity of B cell responses and epitope spreading in genetically susceptible mice leads to pathogenic response. Also, since not all transgenic mice positive for RA susceptible allele develop arthritis, potential differences in B cell activation status in those that develop arthritis versus that do not will be determined. In aim 3, we will determine the control of B cell responses by Toll like receptors, especially, TLR4 in this model. These transgenic mice and experiments proposed here should provide a mechanism of pathogenesis in context of B cells and narrow the focus of B cell-directed therapy. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis is a disabling disease, affecting women more often than men. B cells produce rheumatoid factor and other autoantibodies. In this study we will use mice that express human arthritis associated genes to delineate the role of B cells in rheumatoid arthritis patients. These humanized mice mimic rheumatoid arthritis in pathology and sex-bias. Arthritic mice produce autoantibodies like rheumatoid factor and anti-cyclic citrullinated peptide antibodies that are used for diagnosis of rheumatoid arthritis. We will determine if B cells can present pathogenic antigen and if there is a defect in regulation of B cells in arthritis susceptible mice. The information gained using this unique model may be instructive in developing preventive immunointervention for ongoing arthritis especially in women.

描述（由申请人提供）：已知类风湿关节炎（RA）及其动物模型胶原蛋白诱导的关节炎（CIA）是T和B细胞依赖性疾病。 HLA-DQ8和DRB1*0401分子使人类和小鼠易受性关节炎，而DQ6和DRB1*0402提供了保护。 CIA易感的HLA转基因小鼠产生类风湿因子和抗偶然的瓜氨酸肽（CCP）抗体，类似于患者的抗体。 B细胞基因敲除小鼠中CIA和低细胞反应的缺乏表明，除产生抗体外，自动反应性B细胞还可能参与向T细胞呈现自身抗原。 B细胞在患者中耗尽后ACR反应标准的改善进一步强调了B细胞在关节炎中的作用。然而，B细胞在抗原表现中的确切作用及其在转基因小鼠的易感性和抗性菌株中的调节尚不清楚。 B细胞功能由B细胞受体，BCR以及其他B细胞特异性受体（如BAFF-R）调节。我们的假设是，携带RA易感HLA基因的转基因小鼠中的B细胞在调节方面存在缺陷，该缺陷通过B细胞受体导致过度活跃和自身反应性B细胞的存活增加。雌性具有多动的B细胞，有助于自身抗体的发展，并将抗原呈递给T细胞，从而导致女性发病率增加。我们的初步数据与此概念一致。最近的研究表明，B细胞反应由TLR控制。在这项研究中，我们将使用表达CIA敏感和抗性HLA基因的小鼠胶原蛋白诱导的转基因小鼠胶原蛋白诱导关节炎的发病机理的机制。在AIM1中，我们将在CIA发病机理中定义B细胞作为抗原呈现细胞的需求。在AIM 2中，如果B细胞反应的多动症和表位传播在遗传易感小鼠中的过度活性会导致致病反应，我们将检验我们的假设。同样，由于并非所有对RA易感性等位基因呈阳性的转基因小鼠都会出现关节炎，因此在患有关节炎的患者中，B细胞激活状态的潜在差异与未确定的患者。在AIM 3中，我们将确定像受体一样通过TOLL（尤其是TLR4）在此模型中控制B细胞反应的控制。这些转基因小鼠和这里提出的实验应在B细胞的背景下提供发病机理，并缩小B细胞指导治疗的重点。公共卫生相关性：类风湿关节炎是一种致命的疾病，比男性更频繁地影响女性。 B细胞产生类风湿因子和其他自身抗体。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B细胞在类风湿关节炎患者中的作用。这些人源化的小鼠模仿了病理和性偏见中的类风湿关节炎。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。我们将确定B细胞是否可以呈现致病性抗原，以及关节炎易感小鼠的B细胞调节缺陷。使用这种独特模型获得的信息可能具有启发性，以开发针对持续关节炎的预防性免疫介入，尤其是在女性中。