Discovery of novel autoantigens in patients with inclusion body myositis

包涵体肌炎患者新型自身抗原的发现

• 批准号: 8316289
• 负责人: Kevin C O'connor
• 金额: $ 8.3万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316289
• 关键词: Address; Age; Antibodies; Antigen Targeting; Antigens; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmune Responses; Autoimmunity; Automobile Driving; B-Lymphocytes; Biological Markers; Biopsy; Cell Line; Cells; Characteristics; Chronic; Clinical; Collection; Data; Deposition; Dermatomyositis; Desmin; Diagnostic; Disease; Frequencies; Gender; Immune; Immune response; Immune system; Immunoglobulin G; Immunoglobulin Variable Region; Immunoglobulins; Inclusion Body Myositis; Individual; Inflammation; Inflammation Mediators; Inflammatory Response; Intermediate Filament Proteins; Intramuscular; Lasers; Lead; Light; Location; Mass Spectrum Analysis; Measures; Mediating; Methods; Microdissection; Modeling; Molecular; Muscle; Muscle Fibers; Muscle Proteins; Muscle Weakness; Myopathy; Myositis; Outcome Study; Pathology; Patients; Peripheral; Plasma Cells; Prevalence; Proteins; Recombinants; Research; Role; Sampling; Scheme; Screening procedure; Series; Serum; Skeletal Muscle; Source; Specificity; Sporadic Inclusion Body Myopathy; T-Lymphocyte; Testing; Therapeutic; Tissues; Vacuole; Work; cohort; design; differentiated B cell; experience; immunopathology; injured; innovation; insight; laser capture microdissection; macrophage; novel; novel strategies; prognostic; research study; response; tool

DESCRIPTION (provided by applicant): Inclusion body myositis (IBM) is one of a group of muscle diseases known as the inflammatory myopathies, which are characterized by chronic muscle inflammation accompanied by muscle weakness. There is no cure for IBM, nor is there a standard course of treatment. We have determined that previously unappreciated components of the immune system, namely antibody-secreting plasma cells, infiltrate the muscle tissue in this disease. Both the role of these cells and the target(s) of the antibody they produce are not known, yet their identification is a critical first step to understanding the mechanisms of IBM immunopathology. We set out to identify the targets of the autoimmune response in both the tissue and periphery of patients with IBM. To determine the identity of the antigen target, single tissue-associated plasma cells were micro-dissected from IBM muscle tissue acquired through biopsy. Single cell PCR was then used to amplify the immunoglobulin heavy and light chain from a series of single cells. Recombinant immunoglobulin was then prepared and used to isolated muscle antigens. We discovered that a muscle intermediate filament protein was recognized by IBM tissue-derived immunoglobulin. Our proposed research is designed to examine both the prevalence and relevance of this newly identified autoimmune target in the disease. First, single plasma cells, will be isolated, using laser-assisted microdissection, from a large set of IBM muscle biopsy tissues. Then, recombinant immunoglobulin derived from these single cells will be tested for reactivity to muscle intermediate filament proteins and other candidate autoantigens. In the second part of the project, the sero-prevalence of IBM autoantibodies will be determined. Here we will identify targets of IBM serum autoantibodies using high throughput antigen arrays. The presence of serum autoantibodies will be correlated with disease features as a prerequisite for identifying these molecules as useful clinical diagnostic or prognostic biomarkers.

描述（由申请人提供）：包涵体肌炎（IBM）是一组被称为炎性肌病的肌肉疾病之一，其特征在于慢性肌肉炎症伴随肌无力。IBM没有治愈的方法，也没有标准的治疗过程。我们已经确定，以前不受重视的免疫系统的组成部分，即抗体分泌浆细胞，浸润在这种疾病的肌肉组织。这些细胞的作用和它们产生的抗体的靶点都是未知的，但它们的鉴定是理解IBM免疫病理学机制的关键第一步。我们着手确定IBM患者组织和外周中自身免疫反应的靶点。为了确定抗原靶标的身份，从通过活检获得的IBM肌肉组织显微解剖单个组织相关浆细胞。然后使用单细胞PCR从一系列单细胞扩增免疫球蛋白重链和轻链。然后制备重组免疫球蛋白并用于分离肌肉抗原。我们发现肌肉中间丝蛋白被IBM组织来源的免疫球蛋白识别。我们提出的研究旨在检查这种新发现的自身免疫靶点在疾病中的流行率和相关性。首先，使用激光辅助显微切割从大量IBM肌肉活检组织中分离单个浆细胞。然后，将测试源自这些单细胞的重组免疫球蛋白对肌肉中间丝蛋白和其他候选自身抗原的反应性。在项目的第二部分，将确定IBM自身抗体的血清流行率。在这里，我们将确定IBM血清自身抗体的目标，使用高通量抗原阵列。血清自身抗体的存在将与疾病特征相关，作为鉴定这些分子作为有用的临床诊断或预后生物标志物的先决条件。