MUNC13-4 gene Polymorphisms in Macrophage Activation syndrome and Systemic Juveni

MUNC13-4 基因多态性与巨噬细胞激活综合征和全身性幼稚病的关系

• 批准号: 8900744
• 负责人: ALEXEI A GROM
• 金额: $ 34.43万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-08 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900744
• 关键词: Abnormal Cell; Address; Apoptosis; BIRC5 gene; Biological Assay; Biological Markers; Cell Cycle; Cell Polarity; Cell physiology; Cells; Chronic Childhood Arthritis; Complication; Cytoplasmic Granules; DNA; Data; Defect; Depressed mood; Development; Disease; Exocytosis; Frequencies; Functional disorder; Gene Expression; Gene Targeting; Genes; Genetic Markers; Genetic Polymorphism; Genotype; Goals; Haplotypes; Hereditary Disease; Immune; Immune response; Incidence; Inflammation; Inflammatory; Inflammatory Response; Inherited; Intracellular Transport; Lead; Link; Lymphocyte Function; Macrophage Activation; Molecular Profiling; Mutation; Natural Killer Cells; Patients; Peripheral Blood Mononuclear Cell; Play; Promoter Regions; Proteins; Publishing; Reaction; Regulation; Reporting; Research; Risk; Role; Sampling; Secondary to; Single Nucleotide Polymorphism; Syndrome; T-Lymphocyte; Tissue-Specific Gene Expression; UNC13B gene; Virus; clinical practice; cohort; cytotoxic; differential expression; familial hemophagocytic lymphohistiocytosis; interest; killings; macrophage; mast cell; neoplastic cell; neutrophil; perforin; uncontrolled T lymphocyte proliferation

DESCRIPTION (provided by applicant): Macrophage activation syndrome (MAS) is a serious, potentially fatal complication of Systemic Juvenile Idiopathic Arthritis. In clinical practice, there is a strong need for reliable biomarkers that would identify patients at risk for this complication. MAS is caused by the exaggerated inflammatory response involving mainly two types of immune cells - macrophages and T lymphocytes. In clinically similar genetic conditions the development of the exaggerated immune response has been linked to defective function of cytolytic cells. These cells typically kill abnormal cells such as tumor cells or cells infected with viruses. There is some evidence that cytolytic cells may also be involved in the elimination of overly activated immune cells. Therefore, if they do not function properly, the immune response may not be terminated in a timely manner. This would lead to uncontrolled inflammation seen in MAS. Previously, we have identified several genetic markers within the MUNC13-4 gene inherited as a single haplotype. Since MUNC13-4 protein is involved with the cytolytic function this observations is important. An important unanswered question is whether the presence of the haplotype in the MUNC 13-4 is associated with abnormal function of the MUNC13-4 protein and, thus, directly contributes to the development of cytolytic dysfunction seen in patients MAS. Another possibility is that the described haplotype may extend either upstream or downstream of the MUNC13-4 gene and involve additional polymorphisms in the neighboring immunologically relevant genes. These two possibilities will be explored in the proposed study.

描述（由申请人提供）：巨噬细胞激活综合征（MAS）是严重的，可能是全身性特发性关节炎的致命并发症。在临床实践中，非常需要可靠的生物标志物，这将确定有这种并发症风险的患者。 MAS是由夸张的炎症反应引起的，主要涉及两种类型的免疫细胞 - 巨噬细胞和T淋巴细胞。在临床上相似的遗传条件下，夸张的免疫反应的发展与细胞溶解细胞的缺陷功能有关。这些细胞通常杀死异常细胞，例如肿瘤细胞或感染病毒的细胞。有证据表明，细胞溶细胞也可能参与消除过度活化的免疫细胞。因此，如果它们无法正常运行，则可能不会及时终止免疫反应。这将导致MAS中看到的不受控制的炎症。以前，我们已经确定了遗传为单个单倍型的Munc13-4基因中的几个遗传标记。由于Munc13-4蛋白与细胞溶解功能有关，因此观察值很重要。一个重要的未解决的问题是，在MUNC 13-4中，单倍型是否与Munc13-4蛋白的异常功能有关，因此直接有助于患者MAS中细胞溶解功能障碍的发展。另一种可能性是，所描述的单倍型可以延伸Munc13-4基因的上游或下游，并涉及相邻的免疫学相关基因中的其他多态性。这两种可能性将在拟议的研究中探讨。

项目成果

An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.

激活的 NLRC4 炎性体突变会导致自身炎症，并伴有复发性巨噬细胞激活综合征。

• DOI: 10.1038/ng.3089
• 发表时间: 2014-10
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Canna, Scott W.;de Jesus, Adriana A.;Gounil, Sushanth;Brooks, Stephen R.;Marrero, Bernadette;Liu, Yin;DiMattia, Michael A.;Zaal, Kristien J. M.;Sanchez, Gina A. Montealegre;Kim, Hanna;Chapelle, Dawn;Plass, Nicole;Huang, Yan;Villarinol, Alejandro V.;Biancotto, Angelique;Fleisher, Thomas A.;Duncan, Joseph A.;O'Shea, John J.;Benseler, Susanne;Grom, Alexei;Deng, Zuoming;Laxer, Ronald M.;Goldbach-Mansky, Raphaela
• 通讯作者: Goldbach-Mansky, Raphaela

Biomarkers in systemic juvenile idiopathic arthritis: a comparison with biomarkers in cryopyrin-associated periodic syndromes.

• DOI: 10.1097/bor.0000000000000098
• 发表时间: 2014-09
• 期刊: Current opinion in rheumatology
• 影响因子: 5.1
• 作者: Nirmala N;Grom A;Gram H
• 通讯作者: Gram H