Structure-function of HLA-DR, peptides, and T cells in autoimmune arthritis

HLA-DR、肽和 T 细胞在自身免疫性关节炎中的结构-功能

• 批准号: 8305422
• 负责人: Edward F Rosloniec
• 金额: --
• 依托单位: MEMPHIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305422
• 关键词: A Mouse; Address; Adverse effects; Affect; Affinity; Alleles; Amino Acids; Antigens; Arthritis; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cell Separation; Cells; Characteristics; Collagen Type II; Complex; DR1 gene; Data; Development; Disease; Disease model; Drug or chemical Tissue Distribution; Epitopes; Evolution; Exhibits; Flow Cytometry; Genes; Goals; HLA-DR Antigens; HLA-DR1 Antigen; HLA-DR4 Antigen; Hemagglutinin; Histocompatibility Antigens Class II; Immune Response Genes; Immunization; Immunodominant Epitopes; Immunotherapy; Individual; Kinetics; Lead; Ligands; MHC Class II Genes; Major Histocompatibility Complex; Measures; Mediating; Memory; Molecular Conformation; Mus; Mutation; Peptide T; Peptides; Phenotype; Play; Predisposition; Protein Array; Recombinants; Relative (related person); Rheumatoid Arthritis; Risk; Role; Sampling; Seminal; Shapes; Signal Transduction; Signaling Molecule; Sorting - Cell Movement; Source; Stretching; Structure; Structure-Activity Relationship; Study models; Surface; T cell response; T-Cell Receptor; T-Lymphocyte; TNFRSF10A gene; Testing; Time; autoimmune arthritis; base; chemokine; cytokine; mRNA Expression; microbial; mouse model; protein expression; public health relevance; research study; response

DESCRIPTION (provided by applicant): The overall goal of these studies is to advance our understanding of the function of a pathogenic T cell response in autoimmunity and to define the structural parameters of the HLA-DR: peptidelig and that stimulates the pathogenic T cell response. Toward this goal, we have made several significant observations regarding the structure and function of the RA associated alleles HLA-DR1 and DR4 in the presentation of auto antigenic peptides. Using a humanized mouse model we have developed for the study of the model auto antigen type IIcollagen (CII), we have identified the CII immunodominant determinants presented by the DR1and DR4 class II molecules, defined the molecular interactions that occur during both the binding of this peptide by these DR molecules and the recognition of this complex by the T cell receptor, solved the crystal structure of HLA-DR1 complexed with the immunodominant CIIpeptide, and developed a means of identifying CII-specific autoimmune T cells ex vivo for highly specific, functional studies of these cells. Based on these data, the focus of this proposal is to investigate the structure-function relationship between the binding affinity of theCII peptide by the DR molecules and the effect of this binding affinity on the stimulation and function of the CII-specific autoimmune T cells. The central hypothesis that we are testing in this proposal is that the low affinity interaction of self peptides with MHC class II molecules induces significant changes in the conformation of the class II: peptide complex, and that this altered structure plays a major role in the stimulation and function of autoimmune T cells. The impact of these studies will be significant to autoimmunity in general in that they address a seminal question - how do MHC molecules mediate susceptibility to autoimmunity? In addition, these studies will identify the phenotype of the autoimmune T cells and the mechanisms by which they function in mediating disease, and will determine how an MHC: peptide low affinity autoimmune response differs from a high affinity foreign anti genresponse. The long term prospect of these studies is that they will provide us with new structural/functional concepts that can be targeted for the development of highly specific immunotherapies for autoimmunity. PUBLIC HEALTH RELEVANCE: There are more than 40 autoimmune diseases in which we know the susceptibility isassociated with the expression of specific HLA-DR class II genes. In these studies we will usethe humanized HLA-DR1 autoimmune arthritis mouse model to study the a pathogenicautoimmune T cell response. This autoimmune disease model is the most widely studiedmodel of rheumatoid arthritis (RA). Through the experiments in this proposal we will gain newinsight into the evolution of an autoimmune T cell response and how the structure of an HLADRmolecule complexed with an autoantigen dictates the function of these pathogenic T cells.It is our long term goal that these studies lead to the development of new highly specific meansof intervening in autoimmune responses, to eliminate the undesirable side effects of currentless specific treatments, and provide direct means of regulating autoimmune responses.VA Public

描述（由申请人提供）： 这些研究的总体目标是促进我们对自身免疫中致病性T细胞应答的功能的理解，并确定刺激致病性T细胞应答的HLA-DR：peptidelig的结构参数。为了实现这一目标，我们对RA相关等位基因HLA-DR 1和DR 4在自身抗原肽呈递中的结构和功能进行了一些重要的观察。利用我们开发的用于研究模型自身抗原II型胶原（CII）的人源化小鼠模型，我们鉴定了由DR 1和DR 4 II类分子呈递的CII免疫显性决定簇，确定了在这些DR分子结合该肽和T细胞受体识别该复合物期间发生的分子相互作用，解决了与免疫显性CII肽复合的HLA-DR 1的晶体结构，并开发了一种离体鉴定CII特异性自身免疫T细胞的方法，用于这些细胞的高度特异性功能研究。基于这些数据，本建议的重点是研究DR分子与CII肽的结合亲和力之间的结构-功能关系以及这种结合亲和力对CII特异性自身免疫T细胞的刺激和功能的影响。中心假设，我们正在测试在这个建议是，低亲和力的相互作用的自身肽与MHC II类分子诱导显着变化的构象的II类：肽复合物，这种改变的结构中起着重要作用的刺激和自身免疫性T细胞的功能。这些研究的影响将是显着的自身免疫一般，因为他们解决了一个开创性的问题-MHC分子如何介导自身免疫的易感性？此外，这些研究将确定自身免疫性T细胞的表型及其介导疾病的机制，并将确定MHC：肽低亲和力自身免疫反应与高亲和力外源抗原反应的区别。这些研究的长期前景是，它们将为我们提供新的结构/功能概念，这些概念可用于开发针对自身免疫的高度特异性免疫疗法。 公共卫生关系： 目前已知有40多种自身免疫性疾病的易感性与HLA-DR II类基因的表达有关。在这些研究中，我们将使用人源化HLA-DR 1自身免疫性关节炎小鼠模型来研究致病性自身免疫性T细胞应答。这种自身免疫性疾病模型是类风湿性关节炎（RA）研究最广泛的模型。通过本提案中的实验，我们将获得对自身免疫性T细胞应答的演变以及与自身抗原复合的HLADR分子的结构如何决定这些致病性T细胞的功能的新认识。我们的长期目标是，这些研究导致开发新的高度特异性的干预自身免疫性应答的方法，以消除目前没有特异性治疗的不良副作用，并提供调节自身免疫反应的直接手段。VA公共