Distinguishing chemical respiratory and skin sensitisation at a level of antigen formation.

氧化应激和亲电应激是细胞对正常生理和病理生理过程的一系列复杂反应。细胞适应允许暴露于各种活性分子或中间体通过防御机制的进化，清除这些中间体和修复造成的损伤。目前人们对氧化和亲电应激的机制理解很感兴趣，特别是由于暴露于化学物质而引起的各种应激反应。例如，皮肤暴露于小亲电试剂可通过自身蛋白的共价修饰（半抗原化、信号1、抗原特异性）诱导皮肤致敏2。什么可能导致随后的不良免疫结果尚不清楚。“危险”信号（抗原非特异性促炎信号，信号2）也是致敏性成功获得所必需的3。亲电试剂破坏氧化还原平衡并激活Nrf2通路4,5。因此，重要的是研究氧化应激在增强皮肤致敏诱导中的作用。有了全面的方法可以定量和定性地确定氧化应激过程中的关键参数6，外源性亲电试剂对氧化应激的严重程度/氧化还原平衡的破坏是否可以量化并用于帮助确定效价？在氧化应激过程中，脂质过氧化产生小的亲电试剂（如MDA， 4-HNE），其化学行为与外部引入的亲电试剂完全相同，使蛋白质发生半抗原并扰乱氧化还原平衡。目前尚不清楚这种额外的亲电应激（尽管是内源性的）对诱导致敏的整个过程有什么影响。虽然对致敏过程中的半抗原化化学有很多了解，但关于靶蛋白或呈递给t细胞的抗原性质的知识才刚刚出现7,8。目前尚不清楚内源性亲电试剂对蛋白质的半抗原化是否在诱导免疫反应中有任何作用。如果局部使用，内源性亲电试剂是否可以作为皮肤致敏剂？当这些化合物内源性产生时，缺乏适应性免疫反应可能是由于不同的靶蛋白（与局部应用时相反）和/或缺乏对T细胞的呈递？利用UoS开发的新技术，通过选定的皮肤致敏剂定性和定量地表征发生和免疫表现7,8，以及对氧化应激途径的理解和测量这些途径中关键参数的方法的发展，该学生将研究这两种现象之间的定性和定性关系。

Oxidative and electrophilic stress are series of complex cellular responses to normal physiological and pathophysiological processes1. Cellular adaptations have allowed for exposure to a variety of reactive molecules or intermediates by evolution of defence mechanisms which scavenge these intermediates and repair the damage caused. There is a current interest in the mechanistic understanding of oxidative and electrophilic stress, particularly resulting from exposure to chemicals which induce a variety of stress responses. For example, cutaneous exposure to small electrophiles can results in induction of skin sensitisation by covalent modification of self-proteins (haptenation, signal 1, antigen-specific)2. What potentiates a subsequent adverse immunological outcome is unclear. 'Danger' signal (antigen non-specific proinflammatory signal, signal 2) is also required for successful acquisition of sensitisation3. Electrophiles disrupt the redox balance and activate the Nrf2 pathway4,5. It is, therefore, important to investigate the role of oxidative stress in potentiating induction of skin sensitisation. With comprehensive methods available to quantitatively and qualitatively determine the key parameters during oxidative stress6, could the severity of oxidative stress/disruption of redox balance from an exogenous electrophile be quantified and used to help determine the potency? During oxidative stress, lipid peroxidation generates small electrophiles (e.g. MDA, 4-HNE) which behave chemically exactly like externally introduced electrophiles ,haptenating proteins and disturbing the redox balance. It is unclear what effect this additional electrophilic stress, albeit endogenous, has on the overall process of induction of sensitisation. Whilst much is known about the haptenation chemistry in sensitisation, knowledge about target proteins or the nature of antigens presented to T-cells is just emerging7,8. It is unclear whether haptenation of proteins by endogenous electrophiles has any role in induction of an immune response. Could endogenously produced electrophiles act as skin sensitisers if applied topically? Could the lack of the adaptive immune response when these compounds are endogenously generated be due to different target proteins (as opposed to when topically applied) and/or lack of presentation to the T cells? Capitalising upon novel techniques developed at the UoS to characterise qualitatively and quantitively haptenation and immune presentation by selected skin sensitisers7,8 and developments in understanding of oxidative stress pathways and ways to measure the key parameters in these pathways6, this studentship will investigate qualitative and qualitative relationship between these two phenomena.