Studies on the Immunology of IgG4-related diseases

IgG4相关疾病的免疫学研究

基本信息

批准号：
8732923
负责人：
SHIV Subramaniam PILLAI
金额：
$ 36.12万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8732923
关键词：
Alleles Antibodies Antigen Receptors Antigens Autoimmune Diseases Autoimmune Process B-Lymphocytes CD11 Antigens CD4 Positive T Lymphocytes Cells Cessation of life Cicatrix Clinical Clonal Expansion Clone Cells Color Cytometry Data Disease Epigenetic Process Expression Library Fibrosis Flow Cytometry Gene Expression Genetic Predisposition to Disease Genotype Hamman-Rich syndrome Human IgG4 Immunoglobulin Genes Immunoglobulins Immunology In Vitro Inflammatory Lesion Light MHC Class II Genes Maintenance Molecular Mononuclear Nature Organ Pathogenesis Pathway interactions Patients Peptides Phenotype Phlebitis Pilot Projects Plasmablast Population Predisposition Process Production Proteins Proteomics Quality of life Reagent Receptor Gene Recombinant Proteins Recombinants Role Serum Source Steroids Subgroup Surface Survivors Syndrome System T memory cell T-Cell Activation T-Cell Development T-Lymphocyte Therapeutic Therapeutic Intervention Tissues base cytokine exome exome sequencing liquid chromatography mass spectrometry memory CD4 T lymphocyte microbiome next generation sequencing novel premature protein expression protein metabolite response transcriptomics

项目摘要

lgG4-Related Disease is a multi-system disorder encompassing a host of previously described syndromes, all now recognized to be characterized by tumescent lesions, storiform fibrosis, obliterative phlebitis and large amounts of serum lgG4. Clinical improvement is seen with steroids in many subjects and B cell depletion is also clinically effective. Very little is known about the pathogenesis of this disorder or about the molecular and cellular basis for fibrosis in a host of apparently unrelated disorders. Studies will be performed to define T cell clonal expansions observed by Next Gen Sequencing approaches in subjects with this disease but with distinct organ involvements. Novel surface markers expressed only on effector T cell clones will be investigated as potential targets for therapy. Detailed interrogation of gene expression protein expression and metabolites will be performed by global as well as single cell RNAseq, multi color flow cytometry, by Cytof mass cytometry, and liquid chromatography-mass spectrometry on clonally expanded T cells and will be conducted in order to understand pathways of potential therapeutic significance that contribute to the development of these T cells as well as to their effector functions in this fibrotic inflammatory disease. A possible role for lgG4 antibodies in this disorder will also be examined. Next Gen Sequencing as well as single cell cloning and sequencing strategies will be used to define plasmablast expansions and to establish specific antibody heavy-light chain pairs that may contribute to the disease. Reagents will be thus generated to identify specific antigens using human ORFeome expression libraries as source of antigen. Determining the B cell specific protein antigen and the use of recombinant proteins will be used to assist the identification of T cell specific peptides. Studies will also be performed on genetic susceptibility to lgG4-RD using Fluidigm based MHC class II genotyping and if indicated from the Immunochip analyses by Exome sequencing. Global comparisons of gene and protein expression will inform the need for epigenetic profiling studies.

IgG4 相关疾病是一种多系统疾病，包括许多先前描述的综合征，现在所有这些疾病都被认为以肿胀病变、席纹状纤维化、闭塞性静脉炎和血清中存在大量 IgG4。在许多受试者中使用类固醇和 B 细胞可以看到临床改善临床上，排毒也有一定效果。人们对这种疾病的发病机制或相关疾病知之甚少。许多明显不相关的疾病中纤维化的分子和细胞基础。将进行研究以确定下一代测序方法观察到的 T 细胞克隆扩增患有这种疾病但有不同器官受累的受试者。新颖的表面标记仅表达于效应T细胞克隆将作为潜在的治疗靶点进行研究。基因的详细询问表达蛋白表达和代谢物将通过全局和单细胞 RNAseq 进行，多色流式细胞仪、Cytof 质谱仪和液相色谱-质谱联用仪克隆扩增 T 细胞，并将进行该研究以了解潜在治疗途径有助于这些 T 细胞的发育及其效应功能的重要性纤维化炎症性疾病。还将研究 IgG4 抗体在这种疾病中的可能作用。下一代测序以及单细胞克隆和测序策略将用于定义浆母细胞扩增并建立可能导致疾病的特定抗体重轻链对。试剂将由此产生使用人 ORFeome 表达文库作为抗原来源来鉴定特定抗原。确定 B细胞特异性蛋白抗原和重组蛋白的使用将用于辅助鉴定 T细胞特异性肽。还将使用基于 Fluidigm 的 MHC II 类对 lgG4-RD 的遗传易感性进行研究基因分型，以及外显子组测序的免疫芯片分析是否表明。全球比较基因和蛋白质表达将告知表观遗传分析研究的需要。