API

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Relationship: 377

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Covalent Binding, Protein leads to Activation, Dendritic Cells

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Covalent Binding, Protein
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Activation, Dendritic Cells

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Covalent Protein binding leading to Skin Sensitisation adjacent High Agnes Aggy (send email) Open for citation & comment WPHA/WNT Endorsed
Covalent Binding, Protein, leading to Increase, Allergic Respiratory Hypersensitivity Response adjacent High Not Specified Arthur Author (send email) Under Development: Contributions and Comments Welcome Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Dendritic cells are activated directly by exposure to haptens in both skin and respiratory sensitization. This portion of the KER description is based only on the OECD document 2012 and needs updating:

As noted in the AOP during allergen contact with the skin, immature epidermal dendritic cells, known as Langerhans cells, and dermal dendritic cells serve as antigen-presenting cells[1];[2];[3]. In this role, they recognize and internalize the hapten-protein complex formed during covalent binding. Subsequently, the dendritic cell loses its ability to seize new hapten-protein complexes and gains the potential to display the allergen-MHC-complex to naive T-cells; this process is often referred to as dendritic cell maturation.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Map 2.0

ID Experimental Design Species Upstream Observation Downstream Observation Citation (first author, year) Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Title First Author
Biological Plausibility
Dose Concordance
Temporal Concordance
Incidence Concordance
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

The expression of other cytokines linked to skin sensitisers include IL-1 α, IL-1β, IL-18, and TNF-α form the basis for other dendritic cell assays. In general, an increase in cytokine/chemokine secretion or receptor expression is observed when sensitisers were tested but not when non-sensitisers were tested. However, there is currently only a limited number of chemicals evaluated in more than one assay and results are sometimes contradictory.

Much investigation has gone into assessing the specific mechanistic events involved in skin sensitizer-caused DC migration. Ex vivo studies with intact human skin, epidermal sheets, and MUTZ-3-derived Langerhans cells (LC) show that fibroblasts mediate migration of cytokine-matured LC via chemokines, including CXCL12, CXCR4, and dermis-derived CCL2 and CCL5. (Ouwehand et al., 2008, 2011, 2012) The relevance of these studies for respiratory sensitization is not known. Some evidence indicates that IL-10, upregulated by TMA, may block the migration of LC for a short period of time to allow a Th2 phenotype to develop.(Holden et al., 2008, Cumberbatch et al., 2005)

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help