THE SKIN SENSITISATION ADVERSE OUTCOME PATHWAY (AOP)
The AOP for skin sensitisation describes the sequence of events from the molecular initiating event, through intermediate steps; leading to the adverse toxicological outcome of allergic sensitisation of the immune system via skin exposure. It is comprised of the four Key Events (KE) below.
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Together, these key events, either in sequence &/or combination, describe the molecular, cellular and tissue level processes that are involved in a susceptible individual to become sensitised to a chemical post exposure.
Key Event 1: The Molecular Initiating Event – Haptenation
The first key event (KE1) is based on the premise that a chemical can become a sensitiser via interaction with skin proteins for it to be recognised by cells of the immune system. This is considered the Molecular Initiating Event (MIE), where a chemical bound covalently with a protein forms a hapten, which is then recognised by elements of the immune system triggering a response.
The second key event (KE2) is an intermediate step of sensitising material inducing keratinocyte activation. This results in alterations in gene expression of pathways such as oxidative stress response, which then leads to a local inflammatory response and wider immune cell activation.
The third key event 3 (KE3) relates to dendritic cell activation and refers to the absolute requirement for a sensitising material to bind to and activate local dendritic cells. This in turn facilitates their interaction with and activation of allergen-reactive T cells within lymph nodes, leading to T cell proliferation which defines key event 4 (KE4).