Upstream eventActivation, Dendritic Cells
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Covalent Protein binding leading to Skin Sensitisation||adjacent||High|
|Sensitisation of the Respiratory Tract induced by Covalent Binding of Low Molecular Weight Organic Chemicals to Proteins||adjacent|
Life Stage Applicability
Key Event Relationship Description
Under the influence of fibroblast- blood endothelial- and lymph endothelial-chemokines (e.g. CCL19, CCL21) and epidermal cytokines (e.g. interleukin (IL), IL-1 α, IL-1β, IL-18, tumour necrosis factor alpha (TNF-α)) maturing dendritic cells migrate from the epidermis to the dermis of the skin and then to the proximal lymph nodes, where they can present the hapten-protein complex to T-cells via a major histocompatibility complex molecule (;). T-cells are typically affected by protein-hapten complexes presented by dendritic cells on MHC molecules. Molecular understanding of this process has improved in recent years (). Briefly, MHC molecules are membrane proteins which present the small peptide antigens placed in a “groove” of the MHC molecule during its intracellular synthesis and transport to the cell surface. In the context of the MHC molecular on the cell surface, the small peptide antigen is recognized via the T-cell receptors as self or non-self (e.g. foreign). If this peptide is a foreign peptide, such as part of a protein-hapten complex, the T-cell will be activated to form a memory T-cell, which subsequently proliferates (). These observations are consistent with the immunological mechanism presented with this AOP, where it is assumed that for an adverse outcome to commence, a certain number of dendritic cells is required to be activated and to migrate to the nearest lymph node in order to instigate the further cascade of biological events (see).
This KER description is based only on the OECD document 2012 and needs updating.
Evidence Supporting this KER
It is well accepted and experimentally proved that in the local lymph node, mature dendritic cells present the hapten-protein complex to T-cells via a major histocompatibility complex molecule (MHC);. T-cells are typically affected by protein-hapten complexes presented by dendritic cells on MHC molecules. The T-cell will be then activated to form a memory T-cell, which subsequently proliferates.
A recent study showed in mice model that dendritic cells coordinate the interactions that are necessary to initiate polyclonal regulatory T cells proliferation.
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- Antonopoulos C, Cumberbatch M, Mee JB, Dearman RJ, Wei XQ, Liew FY, Kimber I, Groves RW. 2008. IL-18 is a key proximal mediator of contact hypersensitivity and allergen induced Langerhans cell migration in murine epidermis. J. Leukoc. Biol. 83: 361-367.
- Ouwehand K, Santegoets SJAM, Bruynzeel DP, Scheper RJ, de Gruijl TD, Gibbs S. 2008. CXCL12 is essential for migration of activated Langerhans cells for epidermis to dermis. Eur. J. Immunol. 38: 3050-3059.
- Martin SF, Esser PR, Schmucker S, Dietz L, Naisbitt DJ, Park BK, Vocanson M, Nicolas JF, Keller M, Pichler WJ, Peiser M, Luch A, Wanner R, Maggi E, Cavani A, Rustemeyer T, Richter A, Thierse HJ, Sallusto F. 2010. T-cell recognition of chemical, protein allergens and drugs; toward the development of in vitro assays. Cell. Mol. Life Sci. 67: 4171-4184.
- Vocanson M, Hennino A, Rozieres A, Poyet G, Nicolas JF 2009. Effector and regulatory mechanisms in allergic contact dermatitis. Allergy 64: 1699-1714.
- Api AM, Basketter DA, Cadby PA, Cano MF, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA and Safford B. 2008. Dermal sensitisation quantitative risk assessment (QRA) for fragrance ingredients. Reg. Toxicol. Pharmcol. 52: 3-23.
- Zou T, Caton AJ, Koretzky GA, Kambayashi T. 2010. Dendritic cells induce regulatory T cell proliferation through antigen-dependent and –independent interactions. J. Immunol. 185:2790-2799.