Mechanisms by which IL-10 limits Toll-like Receptor 9 mediated Macrophage Activat

描述（由申请人提供）：巨噬细胞激活综合征（MAS）是一种罕见但可能危及生命的并发症，发生在许多感染性、恶性和风湿病中。它的特点是发烧，凝血困难和多器官功能障碍的设置压倒性的炎症。MAS与其他细胞因子风暴综合征（包括败血症和噬血细胞性淋巴组织细胞增多症（HLH））具有相同的特征。原发性HLH患者在免疫细胞杀伤所必需的机制中存在遗传缺陷，除非接受有效的免疫抑制和骨髓移植，否则通常在年轻时死亡。然而，MAS患者没有这种遗传缺陷，对MAS的遗传、环境和/或免疫原因知之甚少。目前的HLH/MAS动物模型因使用基因突变和/或感染而混淆。先前的研究表明，通过toll样受体9 （TLR9）的反复刺激会导致野生型小鼠出现与MAS非常相似的综合征。tlr9驱动的MAS需要干扰素γ （IFN¿），在该模型中，B淋巴细胞和T淋巴细胞缺乏的小鼠肝炎更严重。通过TLR9反复刺激不能通过白细胞介素10 （IL-10）受体发出信号的小鼠会发生更严重的疾病，这强调了IL-10作为MAS负调节因子的关键作用。拟议研究的总体目的是确定IL-10限制严重MAS发展的机制。具体来说，本研究旨在扩展肝T细胞可能是IL-10的重要来源，从而是MAS的调节因子的发现。我们的目标是确定这些细胞对于预防严重疾病是否必要和/或充分。更好地了解tlr9驱动疾病的调控将有助于更多地了解患者如何发展为MAS，以及如何最好地诊断和治疗这种潜在的致命疾病。

DESCRIPTION (provided by applicant): Macrophage Activation Syndrome (MAS) is an uncommon but potentially life-threatening complication of many infectious, malignant and rheumatic diseases. It is characterized by fever, difficulty clotting and multiple organ dysfunctio in the setting of overwhelming inflammation. MAS shares features with other cytokine storm syndromes including sepsis and Hemophagocytic Lymphohistiocytosis (HLH). Patients with a primary form of HLH have genetic defects in the machinery necessary for killing by immune cells, and usually die at a young age unless they receive potent immunosuppression and bone marrow transplant. Patients with MAS, however, have no such genetic defects, and very little is known about the genetic, environmental, and/or immunologic causes of MAS. Current animal models of HLH/MAS are confounded by the use of genetic mutations and/or infection. Previous work has shown that repeated stimulation through Toll-like Receptor 9 (TLR9) leads to a syndrome very similar to MAS in wild-type mice. TLR9-driven MAS requires interferon gamma (IFN¿), and hepatitis in this model is worse in mice deficient in B and T lymphocytes. Mice repeatedly stimulated through TLR9 who are unable to signal through the interleukin 10 (IL-10) receptor develop much more severe disease, underscoring the critical role of IL-10 as a negative regulator of MAS. The overall purpose of the proposed research is to define the mechanisms by which IL-10 limits the development of severe MAS. Specifically, this study aims to expand on the finding that hepatic T cells may be important sources of IL-10, and thereby are regulators of MAS. We aim to determine whether these cells are necessary and/or sufficient for preventing severe disease. A better understanding of the regulation of TLR9-driven disease will be beneficial to knowing more about how patients develop MAS, and how best to diagnose and treat this potentially fatal condition. PUBLIC HEALTH RELEVANCE: Macrophage Activation Syndrome (MAS) is a potentially fatal complication of many inflammatory diseases that is characterized by fever, clotting problems, and multiple organ dysfunction. The current understanding of MAS is poor and thus its diagnosis and treatment are difficult and highly variable. The proposed study hopes to determine how the immune system protects itself against MAS by expanding on a newly-developed mouse model, with the goal of gaining a better understanding of how best to diagnose and treat this life-threatening disease.