Identification of functional links between redox homeostasis and immunity

免疫系统对入侵微生物的识别需要被特殊的抗原提呈细胞(APC)摄取，APC将病原体来源的免疫原肽暴露于T辅助细胞。后者提供了根除入侵者的“工具”，其反应的质量和效果受到APC的严格控制。越来越多的证据表明，APC的“氧化状态”在决定要激活的T辅助细胞的类型以及要发展的免疫反应的类型中起着重要的作用。这些相互作用的机制目前尚不清楚，可能取决于氧化剂对传递APC和T辅助细胞的信使的影响。本研究旨在研究氧化剂对APC和辅助性T细胞之间通讯信号的影响。之所以选择小鼠查鲍迪阿达米疟疾模型进行研究，是因为感染这种病原体对APC施加了强烈的氧化应激，这种氧化应激似乎依赖于受感染的红细胞中存在的含铁化合物，这些化合物被APC贪婪地摄取。此外，对P.C.Adami寄生虫的免疫具有很好的特性，包括一种由T辅助细胞控制的不同反应模式，这可能是由于氧化剂对T辅助细胞功能的调节所致。将利用分子生物学、生物化学和免疫学的标准技术，分析感染红细胞中存在的含铁化合物(如血红蛋白及其降解产物)在APC上产生的氧化应激，并研究这些化合物影响的关键信号分子。从长远的角度来看，我们的研究将有助于表征其他氧化剂的效果，如自然选择的维持体内平衡的控制机制。

The recognition of invasive microorganisms by the immune system requires their uptake by specialized antigen presenting cells (APCs) which expose pathogen-derived immunogenic peptides to T helper cells. The latter provide the "tools" to eradicate the intruder, and the quality and efficacy of their responses is strongly controlled by the APC. There is cumulating evidence that the "oxidative state" of the APC plays an important role in determining the type of T helper cell to become activated as well as the type of immune response to be developed. The mechanisms involved in these interactions are presently unknown and may rely on the effect that oxidants have on messengers communicating APCs with T helper cells. The present research program aims to characterize the effects induced by oxidants on the communication signals between APC and T helper cells. The murine Plasmodium chabaudi adami malaria model has been chosen for this study since infections with this pathogen exert a strong oxidative stress on APCs, which seems dependent on iron-containing compounds present in infected red blood cells that are avidly taken up by APCs. In addition, the immunity against P. c. adami parasites is well characterized, and comprises a pattern of contrasting responses governed by T helper cells which may result from the effect of oxidants on the regulation of T helper cell function. By means of standard techniques in molecular biology, biochemistry and immunology, the oxidative stress generated by iron-containing compounds present in infected red blood cells such as hemoglobin and its degradation products on APCs will be analyzed, and key signaling molecules affected by these compounds will be studied. As a long-term perspective, our studies will help to characterize the effect of other oxidants such control mechanisms that have been naturally selected to preserve homeostasis.