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Relationship: 3341

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 of the innate immune response leads to Activation of gluten-reactive CD4+ T cells

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Activation of the innate immune response
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Activation of gluten-reactive CD4+ T 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
Gluten-driven immune activation leading to celiac disease in genetically predisposed individuals adjacent Moderate Antonio Fernandez Dumont (send email) Under development: Not open for comment. Do not cite Under Review

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
Male Moderate
Female High

Life Stage Applicability

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

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

Innate immune activation in the gastrointestinal tract will activate dendritic cells resulting in the processing and expression of specific antigens followed by migration to the draining lymphnodes. Alternatively, the antigens are captured by dendritic cells present in the Peyer's patches. Subsequently interaction between these activated, antigen-loaded dendritic cells with naive CD4 T cells expressing antigen specific T cell receptors will result in activation of these CD4 T cells, followed by proliferation and secretion of cytokines.

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 was collected through a combination of literature searches and expert consultations. Experts contributed by reviewing drafted material asynchronously and participating in online discussions to refine the evidence base. Additionally, they provided key articles relevant to the topic, which served as a foundation for further literature searches in Scopus, PubMed, and Google Scholar. Keywords were tailored to each key event (KE) and key event relationship (KER) to ensure comprehensive coverage of relevant studies. The collected literature was systematically categorized in an Excel spreadsheet based on its relevance to specific KEs and KERs within the AOP. This approach facilitated the organization of data supporting different aspects of the pathway. 

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Essential textbook knowledge

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Celiac disease is caused by an intolerance to gluten food proteins. There is an exceptionally strong association between the occurrence of celiac disease and the presence of HLA-DQ2 and/or HLA-DQ8 molecules. This association is explained by the observation that CD4 T cells specific for modified gluten peptides bound to either HLA-DQ2 or HLA-DQ8 are typically found in patients but not in healthy individuals. CD4 T cells belong to the adaptive immune system. The initiation of adaptive immune responses depends on activation of the innate immune system, dendritic cells in particular. Dendritic cells can be activated through pattern recognition receptors (PRRs) that bind pathogen associated molecular patterns (PAMPs) like bacterial cell wall components (LPS) and viral double-stranded ribonucleic acid (dsRNA). Upon activation of dendritic cells, they process antigen derived from such pathogens and present them to adaptive T cells, resulting in the initiation of long-lasting T cell responses to eradicate the pathogens. Thus, innate immune activation is required for the initiation of disease-causing gluten-specific CD4 T cells.

Importantly, activated gluten-specific CD4 T cells typically produce cytokines, including IFN gamma, a cytokine known to enhance the expression of HLA-molecules, like HLA-DQ2 and HLA-DQ8. This thus feeds back into MEI, formation of HLA-DQ-gluten complexes, and constitutes an amplification loop enhancing the adaptive CD4 T cell response to gluten.

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 are no known uncertainties or inconsistencies.

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

Gender is a strong modulator as females have an approximately 2 times higher chance of developing celiac disease. Other potential modulating factors are the composition of the intestinal microbiota. IgA deficiency is known to increase the risk of development of celiac disease.

Modulating Factor (MF) MF Specification Effect(s) on the KER Reference(s)
       
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Innate immune responses are immediate upon exposure to pathogens followed by        adaptive immune responses developing over a period of 1 to 2 weeks.

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Mucosal tolerance maintains homeostasis in the gastrointestinal tract by suppressing immune responses to harmless food derived antigens. In part this is achieved by the activity of T regulatory cells that can suppress the activity of effector T cells, like the gluten-specific CD4 T cells typically found in patients with celiac disease.

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

Celiac disease, as it is currently understood, is a human-specific autoimmune disorder. Some animal models have been developed to reproduce aspects of the disease, but celiac disease is exclusive to humans. (Marietta et al., 2011). It is particularly applicable during childhood and adulthood, as immune responses to gluten exposure are most pronounced in these life stages, with less prominent mechanisms observed in early infancy (Meresse et al., 2004; Qiao et al., 2011). While this KER applies to both sexes, it is important to note that females are more likely to be affected by celiac disease, and sex-based differences in immune response can influence clinical outcomes (Dieterich, 1997; Lundin et al., 1993).

References

List of the literature that was cited for this KER description. More help
    • Essential textbook knowledge

    • Meresse, B., Cerf-Bensussan, N., & Pender, S. L. (2004). The role of tissue transglutaminase in celiac disease. Current Opinion in Gastroenterology, 20(3), 269-274.

    • Qiao, S. W., et al. (2011). Gluten-specific immune responses and celiac disease. Immunology and Cell Biology, 89(2), 180-187. https://doi.org/10.1038/icb.2010.80

    • Dieterich, W. (1997). Celiac disease: immunopathogenesis and clinical features. Journal of Immunology, 158(7), 3244-3250.

    • Lundin, K. E., et al. (1993). The role of T cells in celiac disease. Gastroenterology, 105(4), 1021-1029. https://doi.org/10.1016/0016-5085(93)90133-V