Dysregulation of CXCR5+ B Helper T Cell Subsets in Dermatamyositis

皮肌炎中 CXCR5 B 辅助 T 细胞亚群的失调

• 批准号: 7687208
• 负责人: Hideki Ueno
• 金额: $ 22.36万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687208
• 关键词: Address; Adolescent; Adult; Adult Dermatomyositis; Affect; Age; Allogenic; Antibodies; Antigen-Presenting Cells; Antinuclear Antibodies; Atrophic; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Autologous; Automobile Driving; B Cell Proliferation; B cell differentiation; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; BLR1 gene; Biological Markers; Blood; CCR6 gene; CD4 Positive T Lymphocytes; CXCR3 gene; Cell Separation; Cell physiology; Cells; Cellular Immunity; Child; Childhood; Clinical; Clinical Trials; Coculture Techniques; Complement; Data; Dendritic Cells; Deposition; Dermatomyositis; Development; Disease; Employee Strikes; Eye; Flow Cytometry; Frequencies; Gastrointestinal tract structure; Gene Expression; Growth; Heart; Helper-Inducer T-Lymphocyte; Immune; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Individual; Interferon Type I; Interleukin-1; Interleukin-12; Intervention; Kidney; Lung; Measures; Mediating; Memory B-Lymphocyte; Molecular Profiling; Muscle; Muscle Cells; Myelogenous; Myositis; Natural Immunity; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Plasma Cells; Play; Production; Psoriatic Arthritis; Role; Serum; Skeletal Muscle; Skin; Sorting - Cell Movement; Staphylococcal Enterotoxin B; Stimulus; Systemic Lupus Erythematosus; Systems Biology; T-Lymphocyte; T-Lymphocyte Subsets; Th1 Cells; Th2 Cells; Tissues; Vascular Diseases; autoreactive B cell; base; chemokine receptor; cytokine; disease phenotype; insight; interstitial; monocyte; novel; overexpression; pilot trial; response; rituximab

Juvenile dermatomyositis (JDM) is an autoimmune inflammatory myopathy disease. CD4+ T cells and B cells are most prevalent, and evidence of autoimmunity is frequent with high-titer autoantibodies observed in the sera of 60-80% of adult patients and up to 40% of pediatric patients. Results from clinical trials with anti-CD20 clearly suggest the role of B cells in the pathogenesis and clinical manifestations of DM. While autoantibody responses have been studied in DM, the CD4+ T cell subsets which might be associated with the differentiation of autoreactive B cells are not understood. In preliminary studies, we have found that the CXCR5+CD4+ T cell subsets in dermatomyositis are skewed towards CXCR3-CCR6- Th2 and CXCR3-CCR6+ Th17 cells when compared to age-matched healthy children, and other autoimmune diseases including psoriatic arthritis and systemic lupus erythematosus (SLE). These B-helper-T cells might be the main drivers of autoreactive B cells differentiation in DM thus contributing to disease pathogenesis. Therefore, their development and function in DM need to be established. We have further shown that differentiation of B-helper-T cells is mediated by a subset of myeloid dendritic cells (DCs) (interstitial DCs). IL-12 is the critical DC-derived factor that induces naTve CD4+ T cells to become IL-21-secreting B-helper-T cells. These results form the basis for our hypothesis: Alterations in CXCR5+ B helper T cells and IL-12 producing Antigen Presenting Cells contribute to autoreactive B cell development in juvenile/adult dermatomyositis. AIM 1 will determine the phenotype and frequency of CXCR5+ B-helper-T cells in juvenile/adult DM patients. AIM 2 will determine the function of blood CXCR5+CD4+ T cells from DM patients. AIM 3 will determine the cytokine secretion pattern of Antigen Presenting Cells (APCs) from patients with DM. We expect that this comprehensive analysis of the phenotype and function of B-helper-T cells, B cells and APCs in DM patients will bring insights into the DM pathogenesis as well as help us establish novel disease biomarkers. It will be particularly informative in the group of patients in Clinical Trial Concept 1 where DM patients will receive IL1 blockade.

青少年皮肌炎(JDM)是一种自身免疫性炎症性肌病。CD4+T细胞与B细胞 细胞是最常见的，自身免疫的证据经常与高滴度自身抗体观察到 60-80%的成人患者和高达40%的儿科患者的血清。临床试验的结果 抗CD20抗体提示B细胞在糖尿病的发病机制和临床表现中起重要作用。而当 已对糖尿病患者的自身抗体反应进行了研究，CD4+T细胞亚群可能与 自身反应性B细胞的分化尚不清楚。在初步研究中，我们发现 皮肌炎患者CXCR5+CD4+T细胞亚群向CXCR3-CCR6-Th2倾斜 CXCR3-CCR6+Th17细胞与年龄匹配的健康儿童和其他自身免疫的比较 疾病包括牛皮癣关节炎和系统性红斑狼疮(SLE)。这些B辅助T细胞可能 是糖尿病自身反应性B细胞分化的主要驱动力，从而参与疾病的发病机制。 因此，需要确定它们在DM中的发展和作用。我们已经进一步表明， B辅助T细胞的分化是由髓系树突状细胞(DC)亚群(间质DC)介导的。 IL-12是诱导NATve CD4+T细胞成为分泌IL-21的B辅助T细胞的关键DC衍生因子 细胞。这些结果构成了我们假设的基础：CXCR5+B辅助T细胞和IL-12的变化 产生抗原提呈细胞有助于青少年/成人自身反应性B细胞的发育 皮肌炎。目的1测定CXCR5+B辅助T细胞的表型和频率 青少年/成年糖尿病患者。目的2测定糖尿病患者外周血中CXCR5+CD4+T细胞的功能 病人。目的3将确定抗原提呈细胞(APC)的细胞因子分泌模式 糖尿病患者。我们期待对B-Helper-T表型和功能的全面分析 糖尿病患者外周血中的细胞、B细胞和APC有助于深入了解糖尿病的发病机制 建立新的疾病生物标志物。它将在临床试验中的患者组中特别有用 概念1，糖尿病患者将接受IL1阻断。