Does age substantially affect the emergence of human immune-mediated arthritis? Children do not usually develop immune-mediated articular inflammation during their first year of life. In patients with juvenile idiopathic arthritis, this apparent ‘immune privilege’ disintegrates, and chronic inflammation is associated with variable autoantibody signatures and patterns of disease that resemble adult arthritis phenotypes. Numerous mechanisms might be involved in this shift, including genetic and epigenetic predisposing factors, maturation of the immune system with a progressive modulation of putative tolerogenic controls, parallel development of microbial dysbiosis, accumulation of a pro-inflammatory burden driven by environmental exposures (the exposome) and comorbidity-related drivers. By exploring these mechanisms, we expand the discussion of three (not mutually exclusive) hypotheses on how these factors can contribute to the differences and similarities between the loss of immune tolerance in children and the development of established immune-mediated arthritis in adults. These three hypotheses relate to a critical window in genetics and epigenetics, immune maturation, and the accumulation of burden. The varied manifestation of the underlying mechanisms among individuals is only beginning to be clarified, but the establishment of a framework can facilitate the development of an integrated understanding of the pathogenesis of arthritis across all ages.

年龄是否会显着影响人类免疫介导性关节炎的出现？儿童在出生后的第一年通常不会出现免疫介导的关节炎症。在幼年特发性关节炎患者中，这种明显的“免疫特权”瓦解，慢性炎症与可变的自身抗体特征和类似于成人关节炎表型的疾病模式相关。这种转变可能涉及许多机制，包括遗传和表观遗传易感因素、免疫系统的成熟以及假定的耐受性控制的逐步调节、微生物失调的平行发展、环境暴露驱动的促炎负担的积累（暴露体) 和合并症相关的驱动因素。通过探索这些机制，我们扩大了对三个（不相互排斥）假设的讨论，这些假设是关于这些因素如何导致儿童免疫耐受性丧失与成人免疫介导性关节炎发展之间的差异和相似之处。这三个假设与遗传学和表观遗传学、免疫成熟和负担累积的关键窗口有关。个体之间潜在机制的不同表现才刚刚开始被阐明，但框架的建立可以促进对各个年龄段关节炎发病机制的综合理解。