Immune dysregulation by the rheumatoid arthritis shared epitope

类风湿关节炎共享表位引起的免疫失调

• 批准号: 7531665
• 负责人: Joseph Holoshitz
• 金额: $ 20.03万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531665
• 关键词: Address; Affect; Alleles; American; Amino Acid Sequence; Autoimmunity; Binding; Bone Marrow; CD19 gene; CD8B1 gene; CTLA4-Ig; Cell Separation; Cell Surface Proteins; Cell surface; Cells; Chronic; Condition; DBA/1 Mouse; Dendritic Cells; Depth; Dioxygenases; Disease; Disease Association; Enzymes; Epitopes; Fibroblasts; Frequencies; Future; Genes; HLA-DR2 Antigen; HLA-DRB1; HLA-DRB1*0401; Histocompatibility Antigens; Immune; Immune Tolerance; Immune response; In Vitro; Interferon Type II; Investigation; Ligands; Mediating; Modeling; Mus; Natural Immunity; Nitric Oxide; Pathway interactions; Peripheral; Phenotype; Play; Positioning Attribute; Predisposition; Production; Proteins; Public Health; Regulation; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Structure; T cell regulation; T-Lymphocyte; Techniques; Testing; Tissue Transplantation; Transgenic Mice; Transgenic Organisms; base; calreticulin; cytokine; genetic association; in vivo; indoleamine; lymph nodes; novel; prevent; receptor; research study

DESCRIPTION (provided by applicant): Immune Dysregulation by the Rheumatoid Arthritis Shared Epitope Susceptibility to rheumatoid arthritis is strongly associated with HLA-DRB1 alleles encoding a five-amino acid sequence motif in positions 70-74 of the HLA-DR2 chain, called the shared epitope (SE). The mechanistic basis for this association is presently unknown. We have recently found that the SE functions as an allele-specific signal transducing ligand that activates a nitric oxide (NO)-mediated pathway in opposite cells. We further found that SE-triggered NO signaling inhibits the enzymatic activity of indoleamine 2,3 dioxygenase (IDO), a key enzyme in dendritic cell (DC)-mediated immune tolerance and T cell regulation. Given the critical role of IDO in maintaining peripheral tolerance, we hypothesize that the SE may contribute to immune dysregulation in RA by inhibiting IDO. In this exploratory project, we propose to examine the effect of the SE in murine DC with three specific aims: 1) To better establish the inhibitory effect of exogenously added SE ligands on IDO activation in subsets of DC isolated from SE-negative mice and to determine whether this effect is mediated by NO. 2) To determine the effect of SE ligand-triggered signaling on the phenotype of - and production of cytokines and induction of in vitro T cell tolerance by - DC subsets isolated from SE-negative mice. 3) To determine IDO expression level and enzymatic activity in-, phenotype of- and in vitro T cell tolerance induction and cytokine production by - subsets of DC derived from transgenic mice constitutively carrying SE-positive HLA-DRB1 alleles. Collectively, these studies offer an examination of a highly novel paradigm in HLA-disease association. The results of the proposed studies will strengthen the rationale for future in-depth investigation of role of the SE in RA and possibly other conditions. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is a chronic debilitating disease that affects over 2,000,000 Americans. The cause of the disease is unknown but it has been previously shown that there is a strong genetic association with certain genes that determine tissue transplantation antigens. The mechanism for this association is unknown. The hypothesis of this project is that those genes determine the structure of cell surface proteins that activate other cells upon contact and interfere with normal regulation of the immune response. In prior studies in our group, an aberrant signaling pathway that is directly caused by the RA-associated transplantation antigens has been identified. In the studies proposed here, the effect of that pathway on certain intra-cellular enzymes that play a role in immune regulation will be investigated. These studies examine a highly novel paradigm for the cause of RA and could discover ways to prevent or treat the disease.

描述(申请人提供)：类风湿性关节炎共同表位的免疫调节失调类风湿性关节炎的易感性与人类白细胞抗原DRB1等位基因密切相关，该等位基因编码人类白细胞抗原DR2链第70-74位的五个氨基酸序列基序，称为共同表位(SE)。这种联系的机制基础目前尚不清楚。我们最近发现，SE作为等位基因特异性的信号转导配体，在相对细胞中激活一氧化氮(NO)介导的途径。我们进一步发现，SE触发的NO信号抑制吲哚胺2，3双加氧酶(IDO)的活性，IDO是树突状细胞(DC)介导的免疫耐受和T细胞调节的关键酶。鉴于IDO在维持外周耐受中的关键作用，我们推测SE可能通过抑制IDO而导致RA的免疫失调。在这个探索性项目中，我们建议研究SE对小鼠DC的影响，具体有三个目的： 1)为了更好地确定外源性添加的SE配体对SE阴性小鼠DC亚群IDO激活的抑制作用，并确定这一作用是否由NO介导。 2)研究SE配体触发的信号转导对SE阴性小鼠T细胞表型、细胞因子产生及诱导T细胞耐受的影响。 3)检测携带SE-HLADRB1等位基因的转基因小鼠树突状细胞的IDO表达水平和体外T细胞耐受诱导表型及细胞因子产生亚群的酶活性。 总而言之，这些研究提供了对人类白细胞抗原-疾病关联中一种非常新的范式的检验。建议的研究结果将加强未来深入研究SE在RA中的作用以及可能的其他情况的理论基础。 公共卫生相关性：类风湿性关节炎(RA)是一种慢性衰弱疾病，影响着200多万美国人。这种疾病的原因尚不清楚，但以前已经表明，与决定组织移植抗原的某些基因有很强的遗传关联。这种联系的机制尚不清楚。该项目的假设是，这些基因决定了细胞表面蛋白的结构，这些蛋白在接触时激活其他细胞，并干扰免疫反应的正常调节。在我们小组以前的研究中，已经发现了一条由RA相关移植抗原直接引起的异常信号通路。在这里提出的研究中，将研究该途径对某些在免疫调节中发挥作用的细胞内酶的影响。这些研究检验了一种关于类风湿性关节炎病因的高度新颖的范例，并可能发现预防或治疗这种疾病的方法。