Environmental factors determine DAP12 deficiency to either enhance or suppress immunopathogenic processes.
Environmental factors determine DAP12 deficiency to either enhance or suppress immunopathogenic processes.
复制标题
环境因素决定了 DAP12 缺乏会增强或抑制免疫致病过程。
作者：
Montalvo V;Quigley L;Vistica BP;Boelte KC;Nugent LF;Takai T;McVicar DW;Gery I.
DNAX活化蛋白12（DAP 12）是一种跨膜衔接子，在自然杀伤细胞和各种骨髓细胞中转导活化信号中发挥重要作用。定量RT-PCR在正常小鼠眼中检测到相当水平的DAP 12和多种DAP 12偶联受体，特别是TREM-1，Clec 5a和SIRPb 1。DAP 12及其受体在实验性自身免疫性疾病中的作用一直存在争议。在这里，我们分析了DAP 12缺乏对小鼠对致葡萄膜炎眼抗原和感光细胞间类维生素A结合蛋白（IRBP）产生免疫病理细胞反应的能力以及发展实验性自身免疫性葡萄膜炎（EAU）的影响。令人惊讶的是，在两个不同的动物设施中，对缺乏DAP 12的小鼠的EAU的连续分析首先显示与野生型小鼠相比疾病增强，但是当这些小鼠重新衍生到第二个更清洁的动物设施中时，对照小鼠的反应基本上没有变化，而DAP 12缺失小鼠相对于新设施中的对照明显反应低下。因此，当用IRBP体外刺激时，与对照组相比，两个设施中饲养的DAP 12缺陷小鼠的淋巴细胞增殖并产生相反的促炎和抗炎细胞因子谱。因此，这些发现表明，DAP 12缺乏对自身免疫性疾病发展的影响受到环境因素的显著影响。
DNAX‐activation protein 12 (DAP12), a transmembrane adapter, plays a major role in transducing activation signals in natural killer cells and various myeloid cells. Quantitative RT‐PCR detected in normal mouse eyes considerable levels of DAP12 and multiple DAP12‐coupled receptors, in particular TREM‐1, Clec5a and SIRPb1. The role of DAP12 and its receptors in experimental autoimmune diseases has been controversial. Here, we analysed the effect of DAP12 deficiency on the capacity of mice to mount immunopathogenic cellular responses to the uveitogenic ocular antigen and interphotoreceptor retinoid‐binding protein (IRBP), and to develop experimental autoimmune uveitis (EAU). Surprisingly, sequential analysis of EAU in mice deficient in DAP12 in two different animal facilities at first revealed enhanced disease as compared with wild‐type mice, but when these mice were re‐derived into a second, cleaner, animal facility, the response of control mice was essentially unchanged, whereas the DAP12 null mice were markedly hyporesponsive relative to controls in the new facility. Accordingly, when stimulatedin vitrowith IRBP, lymphocytes from the DAP12‐deficient mice housed in the two facilities proliferated and produced opposite profiles of pro‐inflammatory and anti‐inflammatory cytokines, compared with their controls. These findings therefore demonstrate that the effects of DAP12 deficiency on development of autoimmune disease are dramatically affected by environmental factors.