Immune cell dysfunction in SJIA

描述（由申请方提供）：全身性幼年特发性关节炎（SJIA）是一种病因不明的疾病，其特征是全身特征和关节炎的结合，可导致严重残疾。我们先前的kPCR验证的微阵列结果显示单核细胞活化是SJIA的特征。我们假设单核细胞活化失调是SJIA病理学的一个关键方面。我们建议调查SJIA单核细胞是如何改变的，以及这种激活状态如何干扰调节性T细胞功能。T淋巴细胞群中的一些相关缺陷也将被研究。基于我们的初步数据，我们的具体目标是：目的1：研究干扰素3，GMCSF，IL-6和IL-1信号通路在循环免疫细胞在SJIA受试者，确定改变信号的机制基础，并研究这些发现的特异性SJIA细胞。目标二：确定免疫细胞的失调状态是否与单核细胞抵抗和淋巴细胞对凋亡的易感性相关，以及这些缺陷是否是SJIA特异性的。目的3：检测SJIA单核细胞是否下调Treg的抑制功能，以及这种特性是否是SJIA特异性的。通过与川崎（KD）和多关节型JIA（PolyJIA）的比较，我们将区分SJIA特有的因素和与全身炎症（常见于SJIA和KD）和关节炎（常见于SJIA和PolyJIA）相关的因素。了解这些疾病中单核细胞活化的调节可能会揭示其他炎症条件和自身免疫反应。叙述：全身性幼年特发性关节炎（SJIA）是一种儿童疾病，其原因目前尚不清楚。在我们以前的研究中，我们检查了SJIA儿童血液中的细胞，发现他们的单核细胞被激活，特别是在疾病活动期间，并抵抗细胞死亡的正常途径，而他们的T细胞对细胞死亡高度敏感。这些观察结果使我们提出，在SJIA中，免疫细胞活化没有得到适当的控制。我们建议研究SJIA单核细胞中哪些特定的细胞途径被激活，以及单核细胞活化是否以及如何干扰调节细胞活化的T细胞群的功能。

DESCRIPTION (provided by applicant): Systemic juvenile idiopathic arthritis (SJIA) is a disease of unknown etiology characterized by a combination of systemic features and arthritis that can result in severe disability. Our previous kpcr-validated microarray results show monocyte activation as a characteristic of SJIA. We hypothesize that dysregulation of monocyte activation represents a key aspect of the pathobiology of SJIA. We propose to investigate how SJIA monocytes are altered, and how this activated state may interfere with regulatory T cell function. Some related defects in T lymphocyte populations also will be investigated. Based on our preliminary data, our specific aims are: Aim 1: To investigate the interferon 3, GMCSF, IL-6 and IL-1 signaling pathways in circulating immune cells in SJIA subjects, determine the mechanistic basis of altered signaling and investigate the specificity of these findings for SJIA cells. Aim 2: To determine whether the dysregulated state of immune cells is associated with monocyte resistance and lymphocyte susceptibility to apoptosis and whether these defects are SJIA-specific. Aim 3: To test whether the SJIA monocytes down-regulate the inhibitory function of Treg and whether this property is SJIA-specific. By comparison with Kawasaki disease (KD) and polyarticular JIA (PolyJIA), we will differentiate between factors unique to SJIA and factors associated with systemic inflammation (common to SJIA and KD) and arthritis (common to SJIA and PolyJIA). Understanding regulation of monocyte activation in these diseases may shed light on other inflammatory conditions and autoimmune responses. Narrative: Systemic juvenile idiopathic arthritis (SJIA) is a childhood disease whose cause is presently unknown. In our previous studies examining cells from the blood of children with SJIA, we found that their monocytes are activated, especially during periods of disease activity, and resist normal pathways of cell death, whereas their T cells are highly susceptible to cell death. These observations led us to propose that in SJIA, immune cell activation is not properly controlled, We propose to investigate which specific cellular paths are activated in SJIA monocytes, and if and how monocyte activation may interfere with the function of T cell populations that regulate cell activation.