The etiology of sporadic human chronic inflammatory diseases remains mostly unknown. To fill this gap, we developed a strategy that simultaneously integrates blood leukocyte responses to innate stimuli at the transcriptional, cellular, and secreted protein levels. When applied to systemic juvenile idiopathic arthritis (sJIA), an autoinflammatory disease of unknown etiology, this approach identified gene sets associated with specific cytokine environments and activated leukocyte subsets. During disease remission and off treatment, sJIA patients displayed dysregulated responses to TLR4, TLR8, and TLR7 stimulation. Isolated sJIA monocytes underexpressed the IL-1 inhibitor aryl hydrocarbon receptor (AHR) at baseline and accumulated higher levels of intracellular IL-1β after stimulation. Supporting the demonstration that AHR down-regulation skews monocytes toward macrophage differentiation, sJIA monocytes differentiated in vitro toward macrophages, away from the dendritic cell phenotype. This might contribute to the increased incidence of macrophage activation syndrome in these patients. Integrated analysis of high-dimensional data can thus unravel immune alterations predisposing to complex inflammatory diseases.

零星的人类慢性炎性疾病的病因学仍然是未知的。为了填补这一空白，我们开发了一种策略，该策略在转录，细胞和分泌蛋白水平上同时整合血液白细胞对先天刺激的反应。当应用于病因不明的自身炎症性疾病系统性幼年特发性关节炎（sJIA）时，此方法可鉴定与特定细胞因子环境和活化的白细胞亚群相关的基因集。在疾病缓解和停止治疗期间，sJIA患者显示出对TLR4，TLR8和TLR7刺激的反应失调。分离的sJIA单核细胞在基线时低表达IL-1抑制剂芳烃受体（AHR），并在刺激后积累更高水平的细胞内IL-1β。支持AHR下调使单核细胞偏向巨噬细胞分化的证明，sJIA单核细胞在体外向巨噬细胞分化，远离树突状细胞表型。这可能导致这些患者中巨噬细胞活化综合征的发生率增加。因此，对高维数据的综合分析可以揭示易患复杂炎症性疾病的免疫变化。