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

在抗原形成水平上区分化学呼吸道和皮肤过敏。

• 批准号: 2448838
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2448838
• 关键词: Distinguishing; chemical; respiratory; skin; sensitisation

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.

氧化和亲电应激是细胞对正常生理和病理过程的一系列复杂反应。细胞的适应性已经允许暴露于各种反应分子或中间体，通过进化防御机制来保护这些中间体并修复所造成的损害。目前人们对氧化和亲电应激的机制理解很感兴趣，特别是暴露于诱导各种应激反应的化学物质引起的。 例如，皮肤暴露于小的亲电体可导致通过自身蛋白的共价修饰诱导皮肤致敏（半抗原化，信号1，抗原特异性）2。目前尚不清楚是什么加剧了随后的不良免疫结果。“危险”信号（抗原非特异性促炎信号，信号2）也是成功获得致敏所必需的3。亲电体破坏氧化还原平衡并激活Nrf 2途径4，5。因此，重要的是要研究氧化应激在增强皮肤致敏诱导中的作用。有了可用于定量和定性确定氧化应激过程中关键参数的综合方法6，外源性亲电体引起的氧化应激/氧化还原平衡破坏的严重程度是否可以量化并用于帮助确定效价？ 在氧化应激期间，脂质过氧化产生小的亲电体（例如MDA、4-HNE），其化学行为与外部引入的亲电体完全相同，半抗原化蛋白质并扰乱氧化还原平衡。目前还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。虽然对致敏中的半抗原化化学知之甚多，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。目前还不清楚内源性亲电体对蛋白质的半抗原化是否在诱导免疫应答中起任何作用。如果局部应用，内源性产生的亲电体是否可以作为皮肤致敏剂？当这些化合物内源性产生时，缺乏适应性免疫应答是否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？ 利用在UoS开发的新技术，定性和定量地分析选定的皮肤敏感物7，8和氧化应激途径的理解和方法的发展，以测量这些途径中的关键参数6，这种学生将调查这两种现象之间的定性和定性关系。