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）：已知类风湿性关节炎（RA）及其动物模型胶原诱导的关节炎（CIA）是T和B细胞依赖性疾病。 HLA-DQ8 和 DRB1*0401 分子使人类和小鼠容易患关节炎，而 DQ6 和 DRB1*0402 则提供保护。 CIA 易感 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 (CCP) 抗体。 B 细胞敲除小鼠中 CIA 的缺失和低细胞反应表明，自身反应性 B 细胞除了产生抗体外，还可能参与向 T 细胞呈递自身抗原。患者 B 细胞耗尽后 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 细胞在抗原呈递中的确切作用及其在转基因小鼠的易感品系和耐药品系中的调节仍不清楚。 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 细胞存在调节缺陷，这种缺陷通过 B 细胞受体发生，导致自身反应性 B 细胞过度活跃和存活率增加。女性的 B 细胞异常活跃，有助于自身抗体的产生以及向 T 细胞呈递抗原，从而导致女性发病率增加。我们的初步数据与这个想法是一致的。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 基因的小鼠来探讨 B 细胞在转基因小鼠中促进胶原诱导的关节炎发病机制的机制。在目标1中，我们将定义B细胞作为抗原呈递细胞在CIA发病机制中的需求。在目标 2 中，我们将检验我们的假设：遗传易感小鼠中 B 细胞反应过度活跃和表位扩散是否会导致致病反应。此外，由于并非所有 RA 易感等位基因呈阳性的转基因小鼠都会发生关节炎，因此将确定发生关节炎的小鼠与未发生关节炎的小鼠的 B 细胞激活状态的潜在差异。在目标 3 中，我们将确定 Toll 样受体（尤其是该模型中的 TLR4）对 B 细胞反应的控制。这里提出的这些转基因小鼠和实验应该提供 B 细胞背景下的发病机制，并缩小 B 细胞导向治疗的焦点。公众健康相关性：类风湿性关节炎是一种致残性疾病，女性比男性更容易受到影响。 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 细胞在类风湿性关节炎患者中的作用。这些人源化小鼠在病理学和性别偏见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。我们将确定关节炎易感小鼠中 B 细胞是否可以呈递致病抗原以及 B 细胞的调节是否存在缺陷。使用这种独特模型获得的信息可能对开发针对持续性关节炎（尤其是女性关节炎）的预防性免疫干预措施具有指导意义。