Human immunoglobulin Fc receptor functions in sarcoidosis

描述（由申请人提供）：结节病是一种病因不明的多系统肉芽肿性疾病。结节病常累及肺部，可引起显著的发病率。环境因素被认为是该病的潜在诱因，但尚未确定结节病发展的单一诱因。双胞胎研究、家族疾病聚集性和发病率的种族差异有力地支持了遗传因素在结节病病因学中的关键作用。结节病可能涉及多个基因，但没有基因在功能上被证明影响结节病。临床表现为循环中免疫球蛋白和免疫复合物的升高以及IgG Fc受体(Fc？在结节病患者的免疫细胞上观察到IgG免疫复合物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尚未确定。我们小组最近的数据表明，IgG Fc受体(Fc？R)影响肉芽肿伴多血管炎，提示Fc？R基因可能在结节病肉芽肿性炎症中起作用。Fc ?Rs是体液免疫和细胞免疫之间的重要纽带，在人体免疫应答中起着核心作用。从技术上讲，同源的人类Fc？R基因不适合用于全基因组关联研究（GWAS）分析，因此，人类Fc？R基因簇不包括在任何GWAS检测中。此外,俱乐部吗?R基因具有拷贝数变异（CNVs，染色体上的基因缺失或重复），从而导致Fc？R基因缺失或功能获得。在初步研究中，我们观察到Fc？RIIIA CNVs与系统性红斑狼疮显著相关，提示Fc？R基因可能对慢性炎症性疾病有重要影响。候选基因方法在我们之前的遗传学研究中已经成功地用于证明Fc？自身免疫性疾病中的R snp（单核苷酸多态性）然而，Fc？结节病中的Rs目前尚不清楚。因此，在目前的建议中，我们假设Fc？R基因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of Sarcoidosis）项目中收集的标本和数据，我们将通过以下具体目的大力检验我们的假设：1)确定Fc？rcnvs是结节病的危险因素；2)研究功能性Fc？R snp与结节病有关。对Fc角色的描述？R变异在结节病的发展将为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其他免疫球蛋白介导的炎症性疾病的预测和治疗的新策略的发展。

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.