Human immunoglobulin Fc receptor functions in sarcoidosis

描述(申请人提供)：结节病是一种病因不明的多系统肉芽肿性疾病。结节病经常影响肺部，并可能导致严重的发病率。环境因素被认为是该病的潜在触发因素，但尚未确定发生结节病的单一触发因素。基因因子在结节病病因学中的关键作用得到了双胞胎研究、家族疾病聚集性和发病率种族差异的有力支持。结节病可能涉及多个基因，但目前尚无基因在功能上对结节病产生影响。临床上，结节病患者循环中免疫球蛋白和免疫复合体升高，免疫细胞表面免疫球蛋白Fc受体(Fc？RS)表达发生改变，提示免疫球蛋白及其受体可能参与了结节病的发病机制。然而，到目前为止，结节病的生物标志物还没有确定。本课题组最近的研究表明，IgGFc受体(Fc？R)的功能变异影响肉芽肿性多发性血管炎，提示Fc？R基因可能在结节病肉芽肿性炎症中起一定作用。Fc？Rs是体液免疫和细胞免疫之间的重要纽带，在人体免疫反应中起着核心作用。从技术上讲，同源的人类Fc？R基因不适用于全基因组关联研究(GWAS)分析，因此，人类Fc？R基因簇中的遗传标记不包括在任何GWAS分析中。此外，Fc？R基因存在拷贝数变异(CNV、基因缺失或染色体上的重复)，导致Fc？R基因缺失或功能获得。在初步研究中，我们观察到Fc？RIIIA CNV与系统性红斑狼疮显著相关，提示Fc？R基因的结构变异可能在慢性炎症性疾病中起重要作用。候选基因方法已经在我们以前的遗传学研究中成功地用于展示Fc？R SNPs(单核苷酸多态)在自身免疫性疾病中的作用。然而，到目前为止，FC？RS在结节病中的作用尚不清楚。因此，在目前的建议中，我们假设Fc？R基因的遗传变异(CNvs和SNPs)在结节病的发病机制中起关键作用。利用NHLBI生物标本库在ACCESS(A Case Control病因学研究)项目中收集的标本和数据，我们将通过以下具体目标大力检验我们的假设：1)确定Fc？R CNV是否是结节病的危险因素；2)研究功能性Fc？R SNP是否与结节病相关。阐明Fc？R变异在结节病发生发展中的作用将对结节病的遗传学和结节病的免疫学机制提供重要的见解。此外，我们的研究可能会导致开发新的策略来预测和治疗其他免疫球蛋白介导的炎症性疾病。

DESCRIPTION (provided by applicant): Sarcoidosis is a multisystem granulomatous disorder of unknown etiology. Sarcoidosis frequently affects the lungs and may cause significant morbidity. Environmental factors are considered as potential triggers for the disease, but no single trigger for the development of sarcoidosis has been identified. The critical role for geneti factors contributing to sarcoidosis etiology is strongly supported by twin studies, disease clustering in families, and racial differences in incidence rates. Multiple genes may be involved in sarcoidosis, but no gene has been functionally demonstrated to influence sarcoidosis. Clinically, the elevated immunoglobulins and immune complexes in the circulation and the altered expressions of IgG Fc receptors (Fc?Rs) on the immune cells are observed in sarcoidosis patients, suggesting that IgG immune complexes and their receptors may be involved in the pathogenesis of sarcoidosis. However, up to now, biomarkers for sarcoidosis have not been identified. Recent data from our group demonstrated that the functional variants of IgG Fc receptor (Fc?R) influence granulomatosis with polyangiitis, suggesting that Fc?R genes may play a role in the granulomatous inflammation of sarcoidosis. Fc?Rs serve as the essential link between the humoral and cellular immunities and play a central role in human immune responses. Technically, homologous human Fc?R genes are not suitable for genome-wide association study (GWAS) assays and therefore, the genetic markers within the human Fc?R gene cluster are not included in any GWAS assays. Additionally, Fc?R genes have copy number variations (CNVs, gene deletions or duplications on the chromosome), which lead to Fc?R gene deficiency or gain-of-function. In the preliminary studies, we observed that Fc?RIIIA CNVs are significantly associated with systemic lupus erythematosus, suggesting that structural variations of Fc?R genes may have a significant impact on chronic inflammatory diseases. The candidate gene approach has been successfully used in our previous genetic studies in demonstrating the role of Fc?R SNPs (single nucleotide polymorphisms) in autoimmune diseases. However, the role of Fc?Rs in sarcoidosis is unknown thus far. Therefore, in the current proposal, we hypothesize that genetic variations (CNVs and SNPs) of Fc?R genes play a critical role in the pathogenesis of sarcoidosis. Taking advantage of specimens and data collected by NHLBI Biologic Specimen Repository in the ACCESS (A Case Control Etiologic Study of Sarcoidosis) program, we will vigorously test our hypothesis through the following specific aims: 1) To determine whether Fc?R CNVs are risk factors for sarcoidosis; and 2) to investigate whether functional Fc?R SNPs are associated with sarcoidosis. The delineation of the role of Fc?R variants in the development of sarcoidosis will provide significant insights into the genetics of sarcoidosis and the immunological mechanisms underlying sarcoidosis. In addition, our study may lead to the development of new strategies for the prediction and treatment of other immunoglobulin-mediated inflammatory diseases.