Identification of functional links between redox homeostasis and immunity

免疫系统对入侵微生物的识别需要它们被特异性抗原呈递细胞（APCs）摄取，这些细胞将病原体衍生的免疫原性肽暴露给T辅助细胞。后者提供了根除入侵者的“工具”，其响应的质量和有效性受到APC的强烈控制。越来越多的证据表明，APC的“氧化状态”在决定激活的T辅助细胞类型以及将要发生的免疫反应类型方面起着重要作用。这些相互作用的机制目前尚不清楚，可能依赖于氧化剂对apc与T辅助细胞通信的信使的影响。本研究旨在描述氧化剂对APC和T辅助细胞之间通信信号的影响。本研究选择了鼠chabaudi adami疟原虫疟疾模型，因为这种病原体的感染对apc产生强烈的氧化应激，这似乎依赖于存在于被感染红细胞中的含铁化合物，这些化合物被apc大量吸收。此外，对蟾蜍寄生虫的免疫具有很好的特征，包括由T辅助细胞控制的对比反应模式，这可能是由于氧化剂对T辅助细胞功能调节的影响。运用分子生物学、生物化学和免疫学的标准技术，分析感染红细胞中血红蛋白等含铁化合物及其在apc上的降解产物所产生的氧化应激，研究受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描述其他氧化剂的作用，如自然选择的控制机制，以保持体内平衡。

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.