Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, NSW, Australia.
Autoimmun Rev. 2014 Oct;13(10):1013-9. doi: 10.1016/j.autrev.2014.08.030. Epub 2014 Aug 27.
The viruses are salient in the roles of environmental factors that trigger autoimmunity. The virus realizes its effects by the power of its induction of heat shock proteins (HSPs) as well as by the viral IE-axis-mediated conversion of organ epithelial cells into virgin de novo professional antigen-presenting cells (APCs). The HSP is the accomplished operator in homeostasis by the logic of it being the regulator of apoptosis. That HSP which regulates and controls different points in the pathways of apoptosis is rationally propitious as both HSP and apoptosis are highly conserved in multicellular organisms. By virtue of its regulation of apoptosis, the HSP is also involved in human autoimmunity and this involvement is tripartite: (i) adornment of viral IE-axis-generated virgin de novo professional APCs with HSP-induced co-stimulatory molecules which transform these otherwise epithelial cells to achieve the status of fledged competent antigen-presenters, the operatus APCs, which are liable to apoptosis that becomes the initiator of organ damages that can culminate in the autoimmune syndrome(s); apoptosis is a routine fate that befalls all APCs following their antigen presentation; (ii) molecular mimicry mechanism: epitopes on the HSP may be mistaken for viral peptides and be presented by operatus APCs to autoreactive TCRs resulting in the apoptosis of the operatus APCs; and (iii) regulation of MHC class II-DR-mediated apoptosis of operatus APCs which can ultimately consequent in organ-specific autoimmune syndromes. We should remember, however, that Nature's intended purpose for the apoptosis of the professional APCs is benevolence: as a principal regulator of homeostasis. It is only from the apoptosis of our postulated operatus APCs that the apoptotic consequence can be deleterious, an autoimmune syndrome(s). The transformation of virgin de novo professional APCs to operatus APCs mirrors the maturation of DCs, through their acquisition of HSP-induced co-stimulatory molecules; and what happens to mature DCs as antigen-presenters that ends in homeostasis is replicated by what happens to operatus APCs that ends instead in autoimmune syndromes (Fig. 1).
病毒在触发自身免疫的环境因素中起着重要作用。病毒通过诱导热休克蛋白（HSPs）的能力以及病毒 IE 轴介导的将器官上皮细胞转化为新的初现的专业抗原呈递细胞（APCs）的能力来实现其作用。HSP 是通过调节细胞凋亡的逻辑来实现体内平衡的完成者。调节和控制细胞凋亡途径中不同点的 HSP 是合理的，因为 HSP 和细胞凋亡在多细胞生物中高度保守。由于其对细胞凋亡的调节，HSP 也参与了人类自身免疫，这种参与是三方面的：（i）用 HSP 诱导的共刺激分子对病毒 IE 轴产生的新的初现的专业 APC 进行修饰，将这些原本的上皮细胞转化为成熟的有能力的抗原呈递者，即 operatus APCs，它们易于凋亡，成为器官损伤的启动子，最终导致自身免疫综合征；细胞凋亡是所有 APC 在抗原呈递后都会经历的常规命运；（ii）分子模拟机制：HSP 上的表位可能被误认为是病毒肽，并由 operatus APC 呈递给自身反应性 TCR，导致 operatus APC 的凋亡；（iii）调节 MHC Ⅱ类-DR 介导的 operatus APC 的凋亡，最终导致器官特异性自身免疫综合征。然而，我们应该记住，专业 APC 凋亡的自然目的是善意的：作为体内平衡的主要调节剂。只有在我们假设的 operatus APC 的凋亡中，凋亡的后果才可能是有害的，即自身免疫综合征。从初现的新专业 APC 向 operatus APC 的转化反映了 DC 的成熟，通过它们获得 HSP 诱导的共刺激分子；作为抗原呈递者的成熟 DC 最终在体内平衡中发生的事情，被 operatus APC 所复制，而 operatus APC 最终导致自身免疫综合征（图 1）。
