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Relationship: 3386

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

Co-localization of gluten reactive adaptive T-cells with APC leads to Activation of the innate immune response

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Co-localization of gluten reactive adaptive T-cells with APC

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Activation of the innate immune 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
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 Do not cite	Under Review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

A key concept within the field of immunology is that upon an infection the innate immune arm will respond immediately to combat the invading pathogen. This is achieved through so-called pattern recognition receptors that sense the presence of the pathogen, leading to various humoral and cellular responses to contain the infection (Bouziat et al 2017). Simultaneously, innate dendritic cells are activated which is a crucial step towards the development of adaptive, pathogen-specific immune responses. This concept has been verified in animal models and there is extensive evidence that this concept is valid in humans as well. Innate immune activation is thus required for the development of adaptive immune responses, such as gluten-specific T cell responses in celiac disease.A key concept within the field of immunology is that upon an infection the innate immune arm will respond immediately to combat the invading pathogen. This is achieved through so-called pattern recognition receptors that sense the presence of the pathogen, leading to various humoral and cellular responses to contain the infection. Simultaneously, innate dendritic cells are activated which is a crucial step towards the development of adaptive, pathogen-specific immune responses. This concept has been verified in animal models and there is extensive evidence that this concept is valid in humans as well. Innate immune activation is thus required for the development of adaptive immune responses, such as gluten-specific T cell responses in celiac disease.

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

-Petersen J, Ciacchi L, Tran MT, Loh KL, Kooy-Winkelaar Y, Croft NP, Hardy MY, Chen Z, McCluskey J, Anderson RP, Purcell AW, Tye-Din JA, Koning F, Reid HH, Rossjohn J. T cell receptor cross-reactivity between gliadin and bacterial peptides in celiac disease. Nat Struct Mol Biol. 2020 Jan;27(1):49-61. doi: 10.1038/s41594-019-0353-4. Epub 2019 Dec 23. PMID: 31873306.

- Bouziat R, Hinterleitner R, Brown JJ, Stencel-Baerenwald JE, Ikizler M, Mayassi T, Meisel M, Kim SM, Discepolo V, Pruijssers AJ, Ernest JD, Iskarpatyoti JA, Costes LM, Lawrence I, Palanski BA, Varma M, Zurenski MA, Khomandiak S, McAllister N, Aravamudhan P, Boehme KW, Hu F, Samsom JN, Reinecker HC, Kupfer SS, Guandalini S, Semrad CE, Abadie V, Khosla C, Barreiro LB, Xavier RJ, Ng A, Dermody TS, Jabri B. Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science. 2017 Apr 7;356(6333):44-50. doi: 10.1126/science.aah5298. PMID: 28386004; PMCID: PMC5506690.

- Matera M, Guandalini S. How the Microbiota May Affect Celiac Disease and What We Can Do. Nutrients. 2024 Jun 14;16(12):1882. doi: 10.3390/nu16121882. PMID: 38931237; PMCID: PMC11206804.

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

In the case of celiac disease both bacterial and viral infections have been linked to disease development. Petersen et al (2020) have found that several bacterial species express proteins that encode peptides that resemble known immunogenic gluten epitopes. Moreover, they demonstrated that gluten-specific T cells isolated from celiac disease patients cross-react with such bacterial peptides. This is compatible with a model where a bacterial infection leads to innate immune activation, followed by the development of a pathogen-specific adaptive T cell response that cross-reacts with gluten, and consequently development of celiac disease. In addition, Bouziat et al (2017) observed in an animal model that reovirus infection can lead to adaptive T cell responses to dietary antigens by promoting Th1 immunity. In addition, they presented evidence supporting this concept in patients with celiac disease as well.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

This is a well known concept of immunology and also described in celiac disease (Petersen et al 2020; Bouziat et al 2017; Voisin and Abadie 2021; Matera et al 2024).

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

Despite the evidence linking bacterial and viral infections to celiac disease development, it is extremely difficult to establish a causal relationship between these events in humans. As an animal model is lacking to confirm such relationships there remains a certain level of uncertainty. In addition, various papers have suggested that gluten itself may have innate stimulatory properties. However, a molecular mechanism through which gluten would exert such an effect has not been established. Moreover, it is unclear why such effects would manifest in only a minority of individuals.

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Co-localization of gluten reactive adaptive T cells with APC in secondary lymphoid structures does not lead to the initiation of T cell responses unless the APC are activated and loaded with the appropriate antigen which requires innate immune activation.

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 activation is immediate upon encounter with pathogens.

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

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

- Matera M, Guandalini S. How the Microbiota May Affect Celiac Disease and What We Can Do. Nutrients. 2024 Jun 14;16(12):1882. doi: 10.3390/nu16121882. PMID: 38931237; PMCID: PMC11206804.

- Voisine J, Abadie V. Interplay Between Gluten, HLA, Innate and Adaptive Immunity Orchestrates the Development of Coeliac Disease. Front Immunol. 2021 Jun 2;12:674313. doi: 10.3389/fimmu.2021.674313. PMID: 34149709; PMCID: PMC8206552.

- 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