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

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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.