API

This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 1701

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

Activation/Proliferation, T-cells leads to Increase, Allergic Respiratory Hypersensitivity Response

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Activation/Proliferation, T-cells
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Increase, Allergic Respiratory Hypersensitivity Response

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 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
mouse Mus musculus High NCBI

Sex Applicability

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

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

In brief, once antigen has been processed and presented by DCs and Th2 cells activated (KEs 398 and 272), the differentiation and clonal expansion of Th2 cells lead to production of Th2 cytokines that induce immunoglobulin (Ig) class switching to production of antigen-specific allergic antibody (IgE) by B cells and clonal expansion of naive and memory B cell populations. (Dearman et al., 2003) These antibodies are then found throughout the body, in circulation and/or bound to Fce receptors on cells such as mast cells and basophils in tissues, including the respiratory tract. On subsequent re-exposure, antigen can crosslink IgE bound to the surface of the aforementioned cells and induce degranulation, releasing various mediators that lead to the clinical symptoms of asthma and rhinitis.

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

There is still remaining uncertainty regarding the role of IgE in chemical respiratory allergy, because specific IgE has not been demonstrated in all subjects sensitized to chemicals. (Kimber et al., 2014b, Kimber et al., 2014a, Quirce, 2014)

IgE production can occur both in the germinal centers of lymph nodes and locally in the airway mucosa, with the latter reported to be linked to nasal polyps associated with chronic rhinosinusitis and in response to inhaled protein allergens. (Baba et al., 2014, Hoddeson et al., 2010) The extent of germinal center involvement or local IgE production in respiratory sensitizers is currently unknown.

While there is considerable evidence that DCs are likely the most efficient APC for stimulating naive T cells, there is evidence that IgE at the surface of allergen-specific IgE-positive B cells and other APCs, such as alveolar macrophages, may also facilitate antigen presentation. (Zhong et al., 1997) A role for airway and alveolar epithelial cells in antigen presentation and induction and maintenance of adaptive responses is also becoming increasingly recognized. (Hasenberg et al., 2013)

Recent characterizations of the role of IL-21 in mouse models of protein allergy show that IL-21 promotes IgG1 in B cells when IL-4 is in low supply. This was supported by the finding that human ex-vivo naïve B cells from tonsils increased IgG1 but not IgE, suggesting that IgG1 may be associated with skin sensitization. (Gong et al., 2019) IL-21 was found to suppress the IgE response through IL-21R - STAT3 signaling in murine B cells. (Yang et al., 2020) However, these studies focused on murine models of allergy including dust mite and peanut, as well as a 4-hydroxy-3-nigrophenylacetyl-modified globulin, so the relevance of these mechanisms to low molecular weight chemical allergy is not clear.

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
Modulating Factor (MF) MF Specification Effect(s) on the KER Reference(s)
miR-155   Type 2 innate lymphoid cells have been shown to be dependent on miR-155 to induce airway hyperresponse and IgE elevation in mice. Using a murine miR-155 KO model, mice who did not express miR-155 did not display these effects following dermal senstization to toluene diisocyanate, in contrast to control mice.  Blomme et al., 2020)

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