Immune dysregulation by the rheumatoid arthritis shared epitope

类风湿关节炎的易感性与HLA-DRB1等位基因密切相关，这些等位基因编码HLA-DR2链70-74位的5个氨基酸序列基序，称为共享表位（SE）。这种关联的机制基础目前尚不清楚。我们最近发现，SE作为一种等位基因特异性信号转导配体，在对面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）的酶活性，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。考虑到IDO在维持外周耐受性中的关键作用，我们假设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，我们提出在小鼠DC中研究SE的作用，有三个具体目标：

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.