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Relationship: 3342

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 gluten-reactive CD4+ T cells leads to Activation of gluten- and TG2-reactive B cells

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Activation of gluten-reactive CD4+ T cells
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Activation of gluten- and TG2-reactive B 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 Do not cite Under Review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
Homo sapiens Homo sapiens 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 High

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

The activation of gluten-reactive CD4+ T cells is a prerequisite for the activation of gluten- and TG2-reactive B cells. Gluten-reactive CD4+ T cells interact with B cells in the gastrointestinal lymphoid structures, providing the necessary signals for B cell activation and immunoglobulin class switching (Di Niro et al., 2012; Lindstad et al., 2021). This interaction produces plasma cells secreting IgA autoantibodies specific for transglutaminase 2 (TG2) and IgG antibodies specific for deamidated gliadin (Sollid et al., 1997). The production of these antibodies is a hallmark of celiac disease and is absent in healthy individuals (Dieterich et al., 1997).

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

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.

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

B cells require direct interaction with antigen-specific helper T cells for activation (Lanzavecchia, 1985). This interaction is facilitated by the antigen serving as a bridge, allowing the T cell receptor (TCR) on T cells to engage with the peptide-MHC complex on B cells. Such antigen-specific T-B cell cooperation is crucial for initiating and sustaining adaptive immune responses, including those observed in celiac disease.

In celiac disease, gluten-reactive CD4+ T cells recognize gluten peptides presented by HLA-DQ2/8 molecules on antigen-presenting cells (APCs) (Koning et al., 2015). These activated T cells then provide essential help to B cells that have internalized and processed gluten or TG2-gluten complexes. The T-B cell interaction leads to B cell activation, proliferation, and differentiation into plasma cells secreting IgA autoantibodies against TG2 and IgG antibodies against deamidated gliadin. 

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 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
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
  • Lindstad et al., (2021) showed strong T-cell proliferation when exposed to TG2-specific B cells at concentrations as low as 0.01 μg/mL.
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
  • In the study carried out by du Pre et al., (2019) it is demonstrated that antibody production occurs after exposure to gluten-specific T cell epitope, among other components, in contrast to not exposing the mice model to the T cell epitope. The time scale is unclear in the study, as the IgG measurement is done 6 days after administration, however, it indicates a sequential process. 
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

Deamidated gliadin—and TG2-specific B cells act as highly efficient antigen-presenting cells for the gluten-specific CD4 T cells, amplifying the gluten-specific T cell response, which, in turn, enhances B cell activation. (Di Niro et al., 2012).

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). 

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 (Janson-Knodell et al., 2019; Klein and Fanagan, 2016).

References

List of the literature that was cited for this KER description. More help
  • Di Niro R, Mesin L, Zheng NY, Stamnaes J, Morrissey M, Lee JH, Huang M, Iversen R, du Pré MF, Qiao SW, Lundin KE, Wilson PC, Sollid LM. High abundance of plasma cells secreting transglutaminase 2-specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions. Nat Med. 2012 Feb 26;18(3):441-5. doi: 10.1038/nm.2656. PMID: 22366952; PMCID: PMC4533878.
  • du Pré MF, Blazevski J, Dewan AE, Stamnaes J, Kanduri C, Sandve GK, Johannesen MK, Lindstad CB, Hnida K, Fugger L, Melino G, Qiao SW, Sollid LM. B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2. J Exp Med. 2020 Feb 3;217(2):e20190860. doi: 10.1084/jem.20190860. PMID: 31727780; PMCID: PMC7041703.
  • Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, Schuppan D. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med. 1997 Jul;3(7):797-801. doi: 10.1038/nm0797-797. PMID: 9212111.
  • Jansson-Knodell CL, Hujoel IA, West CP, Taneja V, Prokop LJ, Rubio-Tapia A, Murray JA. Sex Difference in Celiac Disease in Undiagnosed Populations: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2019 Sep;17(10):1954-1968.e13. doi: 10.1016/j.cgh.2018.11.013. Epub 2018 Nov 16. PMID: 30448593.
  • Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016 Oct;16(10):626-38. doi: 10.1038/nri.2016.90. Epub 2016 Aug 22. PMID: 27546235.
  • Koning F, Thomas R, Rossjohn J, Toes RE. Coeliac disease and rheumatoid arthritis: similar mechanisms, different antigens. Nat Rev Rheumatol. 2015 Aug;11(8):450-61. doi: 10.1038/nrrheum.2015.59. Epub 2015 May 19. PMID: 25986717.
  • Lanzavecchia A. Antigen-specific interaction between T and B cells. Nature. 1985 Apr 11-17;314(6011):537-9. doi: 10.1038/314537a0. PMID: 3157869.
  • Lindstad CB, Dewan AE, Stamnaes J, Sollid LM, du Pré MF. TG2-gluten complexes as antigens for gluten-specific and transglutaminase-2 specific B cells in celiac disease. PLoS One. 2021 Nov 3;16(11):e0259082. doi: 10.1371/journal.pone.0259082. PMID: 34731200; PMCID: PMC8565743. 
  • Marietta EV, David CS, Murray JA. Important lessons derived from animal models of celiac disease. Int Rev Immunol. 2011 Aug;30(4):197-206. doi: 10.3109/08830185.2011.598978. PMID: 21787225; PMCID: PMC3480308.  
  • Sollid LM, Molberg O, McAdam S, Lundin KE. Autoantibodies in coeliac disease: tissue transglutaminase--guilt by association? Gut. 1997 Dec;41(6):851-2. doi: 10.1136/gut.41.6.851. PMID: 9462222; PMCID: PMC1891617.