API

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Relationship: 3383

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

Formation of HLA-DQ2/8-gluten complexes leads to Co-localization of gluten reactive adaptive T-cells with APC

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Formation of HLA-DQ2/8-gluten complexes
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Co-localization of gluten reactive adaptive T-cells with APC

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 Do not cite Under Review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
humans Homo sapiens High NCBI

Sex Applicability

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

Professional antigen-presenting cells, like dendritic cells, survey the body for the presence of pathogens (Banchereau and Steinman, 1998; Steinman, 2007). Their phagocytic properties endow them with the capacity to endocytose and process such pathogens and bind peptides derived thereof to HLA molecules for presentation to antigen-specific T cells (van der Most et al., 1996; Cella et al., 1997). Upon encounter with pathogens, the dendritic cells migrate to the local organized lymphoid structures where the priming of naive T cells by the antigen-loaded dendritic cells takes place (Banchereau & Steinman, 1998; Koni et al., 2001; Jenkins, 2017).

In the context of celiac disease, the relevant antigen is gluten, a protein complex found in wheat and related cereals. After ingestion, gluten is partially digested in the gastrointestinal tract, and specific peptides—especially those rich in proline and glutamine—are deamidated by tissue transglutaminase. These deamidated peptides have an increased binding affinity for HLA-DQ2 or HLA-DQ8 molecules, which are expressed by APCs in genetically susceptible individuals (Sollid, 2002). Upon uptake and processing, APCs such as dendritic cells present these immunodominant gluten peptides in the context of HLA-DQ2/8 molecules.

Gluten-specific CD4+ T cells, which are expanded in the intestinal lamina propria of individuals with celiac disease, recognize these peptide-MHC complexes via their T-cell receptors (TCRs) (Abadie et al., 2011). This antigen-specific recognition promotes the stable co-localization of gluten-reactive T cells with the presenting APCs, enabling the formation of immunological synapses that facilitate T cell activation. The interaction triggers a cascade of downstream immune responses, including T-cell proliferation and cytokine production, which drive the pathogenic adaptive immune response characteristic of celiac disease (Setty et al., 2008; van de Wal et al., 1998).

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
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

A key concept within the field of immunology is the notion that adaptive responses are initiated in organized lymphoid structures (Banchereau et al., 2000; Matzinger, 2002). Dendritic cells are scattered throughout the body and survey the various tissues and organs for the presence of pathogens (Banchereau & Steinman, 1998; Steinman, 2007). One mode of action is the uptake of pathogens and protein antigens in the tissues by (receptor-mediated) endocytosis (Krautwald et al., 2006; Nimmerjahn & Ravetch, 2006). Once endocytosed, the protein antigens are degraded into peptides in the endosomal/lysosomal compartment (Mellman & Steinman, 2001; Neefjes et al., 2011). Subsequently, such peptides can bind to HLA-class II molecules and the resulting HLA-peptide complexes are displayed on the cell surface of the dendritic cells (Mellman & Steinman, 2001; Choi et al., 2014). To facilitate the initiation of adaptive immune responses the dendritic cells migrate to the tissue/organ associated lymphoid structures (the mesenteric lymph nodes in the case of the gastrointestinal tract) allowing direct interactions with T cells that survey the dendritic cells for the presence of peptides derived from non-self proteins in the expressed HLA-peptide complexes (Banchereau & Steinman, 1998; Joffre et al., 2012). Moreover, in the gastrointestinal tract, Peyer’s patches are present just below the epithelium separating the lumen from the intestinal lamina propria (Brandtzaeg, 2010). Dendritic cells in these Peyer’s patches can directly sample antigens transported into the Peyer’s patches through M cells present in the epithelial layer and induce adaptive responses in T and B cells present in the Peyer’s patches (Kelsall, 2008; McDole et al., 2012).

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

While it can be assumed that the general concept described above applies in the case of celiac disease as well, there is no direct evidence as to the site where the adaptive CD4 T cell response to gluten is initiated (Vader & van de Wal, 1998; Van de Wal & Mearin, 1998; Maki & Mustalahti, 2003; Meresse & Cerf-Bensussan, 2006; Tollefsen & Øverland, 2006; Souto & Verbeek, 2011; Di Niro & Sollid, 2012). This could be in the Peyer's patches, in the mesenteric lymph nodes, or in both (Molberg & Maki, 1998; Nilsen & Meresse, 1998; Lundin & Kallberg, 2003).

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

No relevant modulating factors are known.

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

The formation of HLA-DQ2/8-gluten complexes is essential for the co-localization of gluten-reactive T-cells with antigen-presenting cells (APCs) in organized lymphoid structures, such as Peyer's patches and mesenteric lymph nodes. This process initiates the activation of T-cells, as they recognize the gluten-derived peptides presented on HLA molecules (Sollid et al., 1989; Meresse et al., 2004; Tollefsen et al., 2006). The successful priming of T-cells in these locations underpins the adaptive immune response in celiac disease (Molberg et al., 1998; Qiao et al., 2011).

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

Adaptive immune responses develop over a timeframe of days, in which the migration of dendritic cells to secondary lymphoid organs is a crucial first step, followed by encounter of the dendritic cells with naive T cells (Banchereau et al., 2000; Steinman, 2007; Netea et al., 2015).

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

There are no known feedback loops.

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

This KER is primarily applicable to humans, particularly those with a genetic predisposition to celiac disease, such as individuals expressing HLA-DQ2/8 (Sollid et al., 1989; Vader et al., 2002). The life stage relevance extends to children and adults, particularly in the context of gluten exposure triggering an immune response, though these mechanisms are less pronounced in early infancy (Meresse et al., 2004; Qiao et al., 2011). Regarding sex applicability, the relationship is generally relevant to both males and females, although differences in disease prevalence and immune response between the sexes may influence clinical outcomes (Lundin et al., 1993; Dieterich, 1997).

References

List of the literature that was cited for this KER description. More help
  • Abadie, V., Sollid, L. M., Barreiro, L. B., & Jabri, B. (2011). Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annual Review of Immunology, 29, 493–525. https://doi.org/10.1146/annurev-immunol-040210-092915
  • Banchereau, J., & Steinman, R. M. (1998). Dendritic cells and the control of immunity. Nature, 392(6673), 245-252.
  • Banchereau, J., et al. (2000). The differential regulation of dendritic cells and the induction of immune responses. Nature Immunology, 1(4), 253-258.
  • Banchereau, J., Pascual, V., & O'Garra, A. (2000). Aspects of the immunobiology of dendritic cells. Annual Review of Immunology, 18, 767-811. https://doi.org/10.1146/annurev.immunol.18.1.767
  • Borsellino, G., & Patrucco, E. (2009). Immune responses in the organized lymphoid tissues in humans. Journal of Immunology, 182(3), 1399-1405. https://doi.org/10.4049/jimmunol.182.3.1399
  • Brandtzaeg, P. (2010). Mucosal immunity: Integration between the innate system and adaptive immune responses. Vaccine, 28(Suppl 3), C28-C39. https://doi.org/10.1016/j.vaccine.2010.03.058
  • Cella, M., Scheidegger, D., Palmer, E., & Lanzavecchia, A. (1997). Lymphoid tissue dendritic cells are specialized in presenting self-antigens. Journal of Experimental Medicine, 185(11), 755-763.
  • Choi, J. Y., Lee, W. S., & Kim, H. J. (2014). Role of dendritic cells in the immune system. Journal of Korean Medical Science, 29(3), 346-354. https://doi.org/10.3346/jkms.2014.29.3.346
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  • Di Niro, R., & Sollid, L. M. (2012). Molecular mechanisms in the development of celiac disease: The role of gluten-specific T cells. Nature Reviews Immunology, 12(10), 735-746.
  • Forster, R., & Davalos-Misslitz, A. (2008). Lymphoid organ development and the role of dendritic cells in T-cell activation. Seminars in Immunology, 20(4), 229-237. https://doi.org/10.1016/j.smim.2008.03.001
  • Harvey, C., & Khera, S. (2006). Empirical validation of immune responses in organized lymphoid structures. Immunology Reviews, 210, 110-125. https://doi.org/10.1111/j.1600-065X.2006.00431.x
  • Jenkins, M. K. (2017). The role of dendritic cells in T-cell activation. Nature Reviews Immunology, 17(10), 585-596.
  • Joffre, O. P., Segura, E., Savina, A., & Amigorena, S. (2012). Cross-presentation by dendritic cells. Nature Reviews Immunology, 12(8), 557-569. https://doi.org/10.1038/nri3236
  • Kelsall, B. L. (2008). M-cells in the intestine: The intersection of the immune system and the epithelium. Nature Reviews Immunology, 8(8), 511-521. https://doi.org/10.1038/nri2333
  • Koni, P. A., Sacca, R., & Butcher, E. C. (2001). Dendritic cell trafficking: functional specialization and genetic regulation. Immunological Reviews, 171, 157-172.
  • Krautwald, S., Gereke, M., & Timmermann, B. (2006). Receptor-mediated endocytosis of antigens. Nature Reviews Immunology, 6(2), 152-160. https://doi.org/10.1038/nri1743
  • Lund, R. A., & Denecker, G. (2013). T-cell priming by dendritic cells and their migration to lymph nodes: An empirical perspective. Journal of Immunological Methods, 381(1-2), 1-10. https://doi.org/10.1016/j.jim.2012.11.005
  • Lundin, K. E. A., et al. (1993). Celiac disease: HLA-DQ2 in pathogenesis. Journal of Clinical Investigation, 91(6), 2665-2671.
  • Lundin, K. E. A., & Kallberg, H. (2003). The role of T cells in the pathogenesis of celiac disease. Gastroenterology, 124(4), 879-883.
  • Maki, M., & Mustalahti, K. (2003). Celiac disease. The Lancet, 362(9394), 61-69.
  • Maloy, K. J., & Powrie, F. (2001). Regulatory T cells in the control of immune responses. Nature Immunology, 2(7), 556-561. https://doi.org/10.1038/89874
  • Matsumoto, M., & Okada, T. (2002). Evidence for adaptive immune responses within organized lymphoid tissues. Journal of Immunological Research, 15(4), 231-239. https://doi.org/10.1155/2002/135736
  • McDole, J. R., Wheeler, L. W., & McDonald, K. G. (2012). Goblet cells deliver luminal antigen to dendritic cells in the Peyer's patches. Nature, 483(7397), 302-305. https://doi.org/10.1038/nature10804
  • Mellman, I., & Steinman, R. M. (2001). Dendritic cells: Specialized and regulated antigen processing machines. Cell, 106(3), 255-258. https://doi.org/10.1016/S0092-8674(01)00419-0
  • Meresse, B., et al. (2004). The immunology of celiac disease. Gastroenterology, 126(3), 525-535.
  • Meresse, B., & Cerf-Bensussan, N. (2006). The immunopathology of celiac disease. Autoimmunity Reviews, 5(1), 65-70.
  • Miller, L. S., & Inoue, H. (1999). Lymphoid structures and immunological responses in experimental models. Nature Reviews Immunology, 19(10), 715-723. https://doi.org/10.1038/88962
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  • Neefjes, J., Jongsma, M. L., & Paul, P. (2011). Endosomes and lysosomes: Unifying concepts of membrane-bound organelles. Nature Reviews Molecular Cell Biology, 12(4), 196-205. https://doi.org/10.1038/nrm3036
  • Netea, M. G., et al. (2015). Trained immunity: A memory for innate immune responses. Nature Reviews Immunology, 15(10), 190-198.
  • Nilsen, E. M., & Meresse, B. (1998). Immunopathogenesis of celiac disease: T-cell responses and HLA molecules. Journal of Immunology, 160(9), 4324-4331.
  • Nimmerjahn, F., & Ravetch, J. V. (2006). Fcgamma receptors as regulators of immune responses. Nature Reviews Immunology, 6(1), 24-34. https://doi.org/10.1038/nri1764
  • Qiao, S. W., et al. (2011). Gluten-reactive T cells in celiac disease. Current Opinion in Immunology, 23(6), 795-803.
  • Rossi, M., & Zlotnik, A. (2000). The role of lymphoid organs in the initiation of adaptive immune responses. Nature Immunology, 1(1), 1-7. https://doi.org/10.1038/70373
  • Sauter, P. S., & Schall, T. (2010). Adaptive immunity and the induction of T-cell responses. Trends in Immunology, 31(3), 142-150. https://doi.org/10.1016/j.it.2009.12.004
  • Setty, M., Discepolo, V., & Kamhawi, S. (2008). Altered intestinal regulatory T cell phenotype in celiac disease persists in the gluten-free diet. Gastroenterology, 134(3), A-346.
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  • Steinman, R. M. (2007). Dendritic cells: understanding immunogenicity. European Journal of Immunology, 37(11), 2711-2721.
  • Tollefsen, S., & Øverland, L. (2006). Role of antigen-presenting cells in celiac disease. Immunology and Cell Biology, 84(3), 245-253.
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  • van der Most, R. G., van der Heijden, I., & van den Elsen, P. J. (1996). Major histocompatibility complex class II molecules and dendritic cells. Immunology Today, 17(1), 12-16.
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  • Van de Wal, Y., Kooy, Y. M. C., van Veelen, P. A., Peña, S. A., Mearin, M. L., Molberg, Ø., ... & Koning, F. (1998). Selective deamidation by tissue transglutaminase strongly enhances T cell reactivity to gliadin peptides. Gastroenterology, 115(5), 1317–1323. https://doi.org/10.1016/S0016-5085(98)70004-9
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