Investigating monocyte dysfunction in Down Syndrome

项目总结 我们请求R01 AR076242“IRF5和Include项目的行政补充 系统性幼年特发性关节炎的巨噬细胞激活综合征“。在这方面的拟议研究 补贴在积极的父母资助范围内，重点是唐氏综合症(DS)，并且是一致的 总体目标包括项目-组成部分1：有针对性的高风险-高回报基础科学 与DS高度相关的研究。我们的研究利用了不断增长的DS注册和生物信息库 由Bernard Khor博士和Jane博士在Benaroya研究所建立的个人 巴克纳。这一行政补充的目标是更好地了解先天免疫改变。 DS.患有DS的个体免疫功能障碍的证据是疫苗应答减少，增加 病毒感染的严重性和某些自身免疫性疾病，包括自身免疫性疾病的发病率增加 甲状腺炎、1型糖尿病和幼年特发性关节炎(JIA)。DS患者的1型干扰素也增加了 一些炎性细胞因子的反应和数量增加以及T和B细胞的特异性改变。 然而，这些改变如何导致DS患者免疫力的整体变化尚不清楚。重要的是 DS的获得性免疫反应一直是人们关注的焦点，而对先天免疫细胞的关注较少。 系统，包括单核细胞和巨噬细胞，在许多自身免疫性疾病的发病机制中起重要作用， 包括(JIA)。 本附录属于亲本R01的范围，因为它：1)研究单核细胞和TLR 这些细胞中的反应，是父母R01，2)的焦点，与所见的一种形式的青少年关节炎有关 更常见的是患有DS的个人，因为父母的赠款侧重于另一种形式的青少年关节炎(系统性 幼年特发性关节炎(SJIA)，以及3)将利用我们现有的单细胞RNA-Seq(scRNA-Seq)数据 由母公司R01提供资金。从本补充中生成的数据将通过向我们提供更多 将单核细胞scRNA-Seq数据集与我们已经从儿童中生成的scRNA-Seq数据集进行比较 SJIA相关的MAS和匹配的对照。本补充内容包含在NIAMS的计划优先级范围内 通过整个生命周期更好地了解DS中的关节炎疾病。因为单核细胞和巨噬细胞是关键 在所有形式的关节炎的发病机制中发挥作用，了解这些细胞及其反应是否 DS的失调将使人们更好地理解它们在关节炎发病率增加中的作用 对于患有DS的儿童。

PROJECT SUMMARY We are requesting an Administrative Supplement for the INCLUDE Project for R01 AR076242 “IRF5 and Macrophage Activation Syndrome in systemic Juvenile Idiopathic Arthritis”. The proposed studies for the in this Supplement are within the scope of the active parent grant, focused on Down syndrome (DS) and are aligned with the goals of the overall INCLUDE Project—Component 1: Targeted high risk – high reward basic science studies highly relevant to DS. Our studies take advantage of a growing registry and biorepository of DS individuals that has been established at the Benaroya Research Institute by Drs. Bernard Khor and Jane Buckner. The objectives of this administrative supplement are to better understand innate immune alterations in DS. Individuals with DS have immune dysfunction evidenced by decreased vaccine responses, increased severity of viral infections and increased incidence of certain autoimmune diseases, including autoimmune thyroiditis, type 1 diabetes and juvenile idiopathic arthritis (JIA). DS individuals also have increased type 1 IFN responses and increased amounts of some inflammatory cytokines and specific alterations in T and B cells. However, how these alterations lead to the overall changes in immunity in DS is not well-understood. Importantly, there has been much focus on adaptive immune responses in DS, with less focus on cells of the innate immune system, including monocytes and macrophages, important in the pathogenesis of many autoimmune diseases, including (JIA). This supplement is within the scope of the Parent R01 as it: 1) investigates monocytes and TLR responses in these cells, which are the focus of the parent R01, 2) relates to a form of juvenile arthritis seen more frequently in individuals with DS, as the parent grant focuses on another form of juvenile arthritis (systemic juvenile idiopathic arthritis (SJIA)), and 3) will leverage our existing single cell RNA-Seq (scRNA-Seq) data funded by the parent R01. Data generated from this supplement will inform our parent R01 by giving us additional monocyte scRNA-Seq datasets to compare with our already generated scRNA-Seq datasets from children with SJIA-associated MAS and matched controls. This supplement is within NIAMS INCLUDE Program priorities to better understand arthritic disorders in DS across the lifepan. Because monocytes and macrophages are key players in pathogenesis of all forms of arthritis, understanding whether these cells and their responses are dysregulated in DS will lead to a better understanding of their contributions to the increased incidence of arthritis in children with DS.