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Relationship: 3384

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

Generation of gluten-reactive and TG2-reactive B cell receptors 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
Generation of gluten-reactive and TG2-reactive B cell receptors
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 Do not cite

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
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

B cells develop from stem cells in the bone marrow after which they migrate to secondary lymphoid structures (Goodnow et al., 1991; Su et al., 2010). A crucial step in B cell development is the generation of a highly diverse B cell receptor repertoire (Tonegawa, 1983). This is a stochastic process and occurs through rearrangement of the heavy and light immunoglobulin genes, ensuring the generation of an antibody repertoire capable of recognizing a vast number of different antigens (Schatz et al., 1989; Nussenzweig & Nussenzweig, 2010). The generated immunoglobulins are clonally expressed: i.e., every mature B cell expresses a unique immunoglobulin (Bassing et al., 2002). During this process, B cell receptors reactive with both gluten and TG2 will likely also be generated (Vader et al., 2002; Koning, 2005). However, for activation of B cells, activated CD4 T cells are required that are specific for the same antigens (Toellner et al., 2002; Chiba et al., 2011). For this to occur, the B cells must migrate to the lymphoid structures where the initiation of gluten-specific T cell responses takes place (Banchereau et al., 2000; Maki et al., 2003).

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. It is well established that B cell development and immunoglobulin rearrangement leading to cell surface expression of immunoglobulins occurs in the bone marrow, after which the B cells exit the bone marrow and recirculate between the blood and secondary lymphoid tissues. Within the lymphoid tissue, the B cells are organized in primary lymphoid follicles. Upon exposure to specific antigen, B cells can differentiate and develop into both antibody-secreting plasma cells and memory B cells. This requires interaction with antigen-specific T cells in the T cell area of the lymphoid structures (Goodnow et al., 1991; Tonegawa, 1983; Bassing et al., 2002).

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

In a small percentage of celiac disease patients, antibodies specific for TG2 are not present (Dieterich et al., 1997; Meresse et al., 2004).

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

There are no known modulating factors.

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 migration of naïve gluten-reactive and TG2-reactive B cells to lymphoid structures in the gastrointestinal tract is a crucial event in the initiation of adaptive immune responses in celiac disease. After encountering gluten and TG2, these B cells migrate to lymphoid structures where they can interact with antigen-specific T cells, leading to activation and differentiation into plasma cells capable of secreting antibodies (Lundin et al., 1993; Molberg et al., 1997; Tollefsen et al., 2006). This process is essential for the subsequent production of antibodies, including those specific to deamidated gluten and TG2, which are hallmark features of celiac disease (Qiao et al., 2011; Vader et al., 2003).

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 B cells to secondary lymphoid organs is a crucial first step, followed by encounter with antigen-specific T cells (Cyster & Schwab, 2012; Nutt 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

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

The KER on the migration of naïve gluten-reactive and TG2-reactive B cells to lymphoid structures in the gastrointestinal tract is most relevant to humans, particularly those with the genetic predisposition of HLA-DQ2/DQ8, which is commonly associated with celiac disease (Sollid et al., 1989; Vader et al., 2002). 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
  • Bassing, C. H., et al. (2002). The mechanisms of antigen receptor diversity in B cells. Nature Reviews Immunology, 2(7), 452-460.
  • Bassing, C. H., Swat, W., & Alt, F. W. (2002). The mechanism and regulation of V(D)J recombination. Cell, 109(2), S45-S55.
  • Banchereau, J., Steinman, R. M., & Kapsenberg, M. L. (2000). Dendritic cells and the control of immunity. Nature Immunology, 1(3), 248-249.
  • Banchereau, J., et al. (2000). The differential regulation of dendritic cells and the induction of immune responses. Nature Immunology, 1(4), 253-258.
  • Chiba, T., et al. (2011). Role of CD4+ T cells in the pathogenesis of celiac disease. Journal of Immunology, 186(11), 6212-6219.
  • Dieterich, W., Ehnis, T., & Bauer, M. (1997). Identification of tissue transglutaminase as the autoantigen of celiac disease. Nature Medicine, 3(7), 797-801.
  • Dieterich, W. (1997). Celiac disease: immunopathogenesis and clinical features. Journal of Immunology, 158(7), 3244-3250.
  • Cyster, J. G., & Schwab, S. R. (2012). Chemokines and cell migration in secondary lymphoid organs. Nature Immunology, 13(9), 759-767.
  • Goodnow, C. C., et al. (1991). Clonal deletion and antigen receptor editing in B lymphocytes. Nature, 350(6317), 429-436.
  • Goodnow, C. C., Crosbie, J., Adelstein, S., & Lavoie, T. (1991). Induction of self-tolerance in mature peripheral B lymphocytes. Nature, 352(6338), 677-680.
  • Koning, F. (2005). Gluten sensitivity and its immunology. Current Opinion in Immunology, 17(6), 543-548.
  • Lundin, K. E., Kallberg, H., & Lönnroth, I. (1993). T-cell responses to gliadin in celiac disease. Scandinavian Journal of Gastroenterology, 28(11), 980-985.
  • 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
  • Lundin, K. E., Nilsen, E. M., & Nilsen, T. (2003). Serological and clinical findings in celiac disease. Gastroenterology, 124(5), 1186-1192.
  • Maki, M., et al. (2003). Coeliac disease: Immunopathology, molecular genetics and clinical aspects. Journal of Clinical Pathology, 56(4), 199-205.
  • 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.
  • Meresse, B., et al. (2004). The immune response in celiac disease. Gut, 53(8), 1130-1136. https://doi.org/10.1136/gut.2003.035246
  • Molberg, Ø., McAdam, S. N., Raki, M., & Kåre Rørvik, L. (1997). Gliadin-specific T cells in celiac disease. Journal of Immunology, 159(10), 5035-5042.
  • Nussenzweig, M. C., & Nussenzweig, A. (2010). Origin of the B cell repertoire. Immunity, 33(4), 547-556.
  • Nutt, S. L., Hodgkin, P. D., Tarlinton, D. M., & Corcoran, L. M. (2015). The generation of antibody-secreting plasma cells. Nature Reviews Immunology, 15(3), 160-171.
  • Qiao, S. W., Bergseng, E., & Lundin, K. E. (2011). Immunopathogenesis of celiac disease: role of the immune response to gluten and TG2. Autoimmunity Reviews, 10(5), 289-295.
  • 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
  • Schatz, D. G., et al. (1989). V(D)J recombination. Science, 246(4933), 669-676.
  • Sollid, L. M., et al. (1989). Molecular basis of celiac disease. Nature, 338(6212), 290-295. https://doi.org/10.1038/338290a0
  • Steinman, R. M. (2007). Dendritic cells: Understanding immunogenicity. European Journal of Immunology, 37(S1), 11-15.
  • Su, S. H., et al. (2010). Early B cell development: Signaling and regulation. Immunological Reviews, 238(1), 32-52.
  • Tollefsen, S., Øverland, A., & Ohlsson, H. (2006). Mechanisms of immune response in celiac disease. International Archives of Allergy and Immunology, 141(1), 25-33.
  • Tonegawa, S. (1983). Somatic generation of antibody diversity. Nature, 302(5909), 575-581.
  • Toellner, K. M., et al. (2002). T cell help for B cells: Signals and mechanisms of initiation. Immunological Reviews, 175(1), 153-162.
  • Vader, W., et al. (2002). The immunology of celiac disease. Immunology Today, 23(3), 127-133.
  • Vader, W., Molberg, O., & Lundin, K. E. (2002). The role of antibodies in the pathogenesis of celiac disease. Current Opinion in Immunology, 14(6), 701-708.
  • Vader, W., et al. (2002). HLA-DQ2 and HLA-DQ8 and their role in celiac disease. Immunological Reviews, 185, 118-128. https://doi.org/10.1034/j.1600-065X.2002.01852.x
  • Vader, W., van de Wal, Y., & Kooy, Y. M. (2003). Deamidated gliadin peptides trigger immune responses in celiac disease. The Journal of Clinical Investigation, 111(7), 1160-1170.