TNIP1 risk haplotypes and immune endophenotypes

描述(由申请人提供)：这项建议旨在开展初步的探索性研究，以确定由TNIP1调控的免疫数量性状或内表型，该基因与各种自身免疫性疾病有关，包括系统性红斑狼疮(SLE)、系统性硬化症、牛皮癣，以及最近的类风湿性关节炎。我们最近报道了与重症肌无力(OR，1.91；p=3.2x10-10)的显著关联，这意味着第151密码子上Pro到Ala的氨基酸变化可能是一个致病变异。虽然TNIP1已被明确地表明参与了NFkB信号的负调控(6)，但最近的研究还涉及其他途径，包括通过C/EBPB的转录调控以及与核受体如PPAR/RAR的相互作用(7-9)。至少，受TNIP1调控的B细胞和髓系表型都可能与自身免疫的风险有关。这项建议将利用独特的人口资源来探索自身免疫性疾病相关的TNIP1风险单倍型的功能效应，重点是B细胞中的免疫数量性状。具体目标1.我们将研究风险单倍型对免疫系统的一系列原代人类外周血细胞亚群中TNIP1表达的影响，特别是过渡性、幼稚和记忆性B细胞，以及单核细胞和体外单核细胞来源的巨噬细胞和树突状细胞。还将研究主要T细胞亚群的等位基因特异性表达。这些研究将利用基因和表型注册表(GAP)中的5,000名正常个体的基因分型的内部资源。具体目的2.我们将检测TNIP1风险单倍型对免疫细胞亚群功能参数的影响。我们的主要关注点将是B细胞，因为初步数据表明它对记忆B细胞的功能有影响。将检查增殖反应、激活标记、分化、细胞因子和免疫球蛋白的产生，以建立基因型表型与TNIP1风险单倍型的相关性。具体目标3.我们将研究可能调节B细胞或其他免疫内表型的候选调节途径。我们将重点研究TNIP1对PPAR/RAR家族核受体功能的调节作用。

DESCRIPTION (provided by applicant): This proposal is directed at carrying out the initial exploratory studies to define the immune quantitative traits, or endophenotypes, that are regulated by TNIP1, a gene which has been associated with a variety of autoimmune diseases, including systemic lupus erythematosus (SLE), systemic sclerosis, and psoriasis, and more recently rheumatoid arthritis. We have recently reported a remarkably strong association with Myasthenia Gravis (OR, 1.91; p =3.2x10-10) that implicates an amino acid change of Pro to Ala at codon 151 as a possible causative variant. While TNIP1 has been clearly shown to be involved in the negative regulation of NFkB signaling(6), more recent studies have implicated other pathways, involving transcriptional regulation through C/EBPb as well as interactions with nuclear receptors such as PPAR/RAR(7-9). At a minimum, both B cell and myeloid phenotypes regulated by TNIP1 are likely to be relevant to risk for autoimmunity. This proposal will take advantage of unique population resources to explore the functional effects of autoimmune disease associated TNIP1 risk haplotypes, with an emphasis on immune quantitative traits in B cells. Specific aim 1. We will examine the effects of risk haplotypes on TNIP1 expression in a range of primary human peripheral blood cell subsets of the immune system, with a particular emphasis on transitional, naive and memory B cells, as well as monocytes and in vitro monocyte derived macrophages and dendritic cells. Allele specific expression will also be investigated in major T cell subsets. An internal resource of 5,000 genotyped normal individuals in the Genotype and Phenotype Registry (GaP) will be utilized for these studies. Specific aim 2. We will examine the influence of TNIP1 risk haplotypes on functional parameters in immune cell subsets. Our major focus will be on B cells, since preliminary data suggest an influence on memory B cell function. Proliferative responses, activation markers, differentiation and cytokine and immunoglobulin production will be examined in order to establish genotype phenotype correlations with TNIP1 risk haplotypes. Specific aim 3. We will examine candidate regulatory pathways that may regulate B cell or other immune endophenotypes. We will focus our studies particularly on the potential involvement of TNIP1 regulation of nuclear receptor function in the PPAR/RAR family.