Human immunoglobulin Fc receptor functions in sarcoidosis

人免疫球蛋白 Fc 受体在结节病中的作用

• 批准号: 8465356
• 负责人: JIANMING WU
• 金额: $ 11.4万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-19 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465356
• 关键词: Affect; African American; Alleles; Antigen-Antibody Complex; Autoimmune Diseases; Biological Assay; Biological Markers; Blood Circulation; Candidate Disease Gene; Cells; Cellular Immunity; Characteristics; Chromosome Deletion; Chromosomes; Chronic; Clinical; Clinical Data; Code; Copy Number Polymorphism; Custom; DNA Sequence; Data; Development; Discrimination; Disease; Disease Clusterings; Environmental Risk Factor; Etiology; FCGR2A gene; FCGR2B gene; FCGR2C gene; FCGR3A gene; FCGR3B gene; Family; Fc Receptor; Gene Cluster; Gene Deletion; Gene Duplication; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Granuloma; Granulomatous; Human; Humoral Immunities; Immune; Immune response; Immunoglobulin G; Immunoglobulins; Incidence; Inflammation; Inflammatory; Laboratories; Lead; Link; Lung; Mediating; Molecular; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Nested PCR; Nodule; Organ; Outcome; Pathogenesis; Patients; Platelet Factor 4; Play; Prognostic Marker; Pulmonary Sarcoidosis; Restriction fragment length polymorphism; Risk; Risk Factors; Role; Sarcoidosis; Single Nucleotide Polymorphism; Specimen; Structure; Systemic Lupus Erythematosus; Techniques; Testing; Therapeutic; Time; Tissues; Twin Studies; Variant; base; case control; caucasian American; cohort; design; gain of function; genetic analysis; genetic risk factor; genome wide association study; insight; novel; programs; pulmonary function; pyrosequencing; racial difference; receptor; receptor function; repository; therapeutic target; vpr Genes

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.

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疾病的潜在诱因，但尚未发现结节病发生的单一诱因。双胞胎研究、家庭疾病聚集性以及发病率的种族差异有力地支持了遗传因素对结节病病因的关键作用。结节病可能涉及多个基因，但尚未在功能上证明基因可影响结节病。临床上发现结节病患者循环中免疫球蛋白和免疫复合物升高，免疫细胞上IgG Fc受体（Fc?Rs）表达改变，提示IgG免疫复合物及其受体可能参与结节病的发病机制。然而，到目前为止，尚未确定结节病的生物标志物。我们小组的最新数据表明，IgG Fc 受体 (Fc?R) 的功能变异影响肉芽肿性多血管炎，表明 Fc?R 基因可能在结节病肉芽肿性炎症中发挥作用。 Fc?R 是体液免疫和细胞免疫之间的重要纽带，在人体免疫反应中发挥着核心作用。从技术上讲，同源人 Fc?R 基因不适合全基因组关联研究 (GWAS) 测定，因此，人 Fc?R 基因簇内的遗传标记不包括在任何 GWAS 测定中。此外，Fc?R 基因具有拷贝数变异（CNV、染色体上的基因缺失或重复），这会导致 Fc?R 基因缺陷或功能获得。在初步研究中，我们观察到Fc?RIIIA CNV与系统性红斑狼疮显着相关，这表明Fc?R基因的结构变异可能对慢性炎症性疾病产生显着影响。候选基因方法已成功用于我们之前的遗传学研究，证明了 Fc?R SNP（单核苷酸多态性）在自身免疫性疾病中的作用。然而，Fc?Rs 在结节病中的作用迄今为止尚不清楚。因此，在当前的提议中，我们假设Fc?R基因的遗传变异（CNV和SNP）在结节病的发病机制中发挥着关键作用。利用NHLBI生物样本库在ACCESS（结节病病例对照病因研究）计划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。描述 Fc?R 变异在结节病发展中的作用将为结节病的遗传学和结节病背后的免疫机制提供重要的见解。此外，我们的研究可能会导致开发预测和治疗其他免疫球蛋白介导的炎症性疾病的新策略。