Abstract：
Cellular phenotype and function are altered in different microenvironments. For targeted therapies it is important to understand site-specific cellular adaptations. Juvenile Idiopathic Arthritis (JIA) is characterised by autoimmune joint inflammation, with frequent inadequate treatment responses. To comprehensively assess the inflammatory immune landscape, we designed a 37-parameter spectral flow cytometry panel delineating mononuclear cells from JIA synovial fluid (SF) of autoimmune inflamed joints, compared to JIA and healthy control blood. Synovial monocytes and NK cells (CD56bright) lack Fc-receptor CD16, suggesting antibody-mediated targeting may be ineffective. B cells and DCs, both in small frequencies in SF, undergo maturation with high 4-1BB, CD71, CD39 expression, supporting T cell activation. SF effector and regulatory T cells were highly active with newly described co-receptor combinations that may alter function, and suggestion of metabolic reprogramming via CD71, TNFR2 and PD-1. Most SF effector phenotypes, as well as an identified CD4-Foxp3+ T cell population, were restricted to the inflamed joint, yet specific SF-predominant CD4+Foxp3+ Treg subpopulations were increased in blood of active but not inactive JIA, suggesting possible recirculation and loss of immunoregulation at distal sites. This first comprehensive dataset of the site-specific inflammatory landscape at protein level will inform functional studies and the development of targeted therapeutics to restore immunoregulatory balance and achieve remission in JIA.
摘要：
细胞表型和功能在不同的微环境中发生改变。对于靶向治疗,重要的是理解位点特异性细胞适应。幼年特发性关节炎（JIA）的特点是自身免疫性关节炎症，频繁的治疗反应不足。为了全面评估炎症免疫景观，我们设计了一个37参数的光谱流式细胞术小组，描绘了来自自身免疫性发炎关节的JIA滑液（SF）的单核细胞，与JIA和健康对照血液相比。滑膜单核细胞和NK细胞（CD56bright）缺乏Fc受体CD16，表明抗体介导的靶向可能无效。B细胞和DC，在SF的小频率中，经历成熟与高4-1BB，CD71，CD39表达，支持T细胞激活。SF效应和调节性T细胞具有高度活性，新描述的共受体组合可能会改变功能，并建议通过CD71，TNFR2和PD-1进行代谢重编程。大多数SF效应表型，以及确定的CD4-Foxp3+T细胞群，仅限于发炎的关节，然而，在活跃而非不活跃的JIA血液中，特异性SF主导的CD4+Foxp3+Treg亚群增加，提示远端部位可能的再循环和免疫调节丧失。蛋白质水平的位点特异性炎症景观的第一个综合数据集将为功能研究和靶向疗法的开发提供信息，以恢复免疫调节平衡并在JIA中实现缓解。
