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

描述（由申请人提供）： 巨噬细胞活化综合征（MAS）是全身性幼年特发性关节炎的一种严重的、潜在致命的并发症。在临床实践中，迫切需要可靠的生物标志物来识别有这种并发症风险的患者。MAS是由过度的炎症反应引起的，主要涉及两种类型的免疫细胞-巨噬细胞和T淋巴细胞。在临床上类似的遗传条件下，过度免疫应答的发展与溶细胞细胞功能缺陷有关。这些细胞通常杀死异常细胞，如肿瘤细胞或被病毒感染的细胞。有一些证据表明，溶细胞细胞也可能参与消除过度活化的免疫细胞。因此，如果它们不能正常发挥作用，免疫反应可能无法及时终止。这将导致在MAS中观察到的不受控制的炎症。以前，我们已经确定了MUNC 13 -4基因内的几个遗传标记作为一个单一的单倍型遗传。由于MUNC 13 -4蛋白参与细胞溶解功能，因此该观察结果是重要的。一个重要的未回答的问题是MUNC 13-4中单倍型的存在是否与MUNC 13 -4蛋白的异常功能相关，从而直接导致在MAS患者中观察到的细胞溶解功能障碍的发展。另一种可能性是所述单倍型可以延伸到MUNC 13 -4基因的上游或下游，并涉及邻近免疫相关基因中的额外多态性。拟议的研究将探讨这两种可能性。

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.