Identification of functional links between redox homeostasis and immunity

免疫系统对侵入性微生物的识别需要它们被专门的抗原呈递细胞（APC）摄取，所述APC将病原体衍生的免疫原性肽暴露于T辅助细胞。后者提供了消灭入侵者的“工具”，其反应的质量和效力受到APC的严格控制。越来越多的证据表明，APC的“氧化状态”在决定T辅助细胞被激活的类型以及免疫应答的类型方面起着重要作用。参与这些相互作用的机制目前尚不清楚，可能依赖于氧化剂对与T辅助细胞通信的APC的信使的影响。目前的研究计划旨在表征氧化剂对APC和T辅助细胞之间的通信信号的影响。鼠夏氏疟原虫adami疟疾模型已被选择用于本研究，因为该病原体的感染对APC产生强烈的氧化应激，这似乎依赖于被APC贪婪摄取的感染红细胞中存在的含铁化合物。此外，对P. c. adami寄生虫被很好地表征，并且包括由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。通过分子生物学、生物化学和免疫学的标准技术，将分析受感染的红细胞中存在的含铁化合物（如血红蛋白及其在APC上的降解产物）产生的氧化应激，并研究受这些化合物影响的关键信号分子。作为一个长期的观点，我们的研究将有助于描述其他氧化剂的作用，这些氧化剂的控制机制是自然选择的，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.