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Relationship: 3335

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

Disruption of the intestinal barrier leads to Celiac disease

Upstream event

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

Disruption of the intestinal barrier

Downstream event

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

Celiac disease

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 Do not cite	Under Review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
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

Inflammation in the upper gastrointestinal tract is a hallmark of celiac disease (CD). This inflammation is characterized by a massive infiltration of lymphocytes in both the lamina propria and the epithelial layer of the small intestine (Sollid & Jabri, 2013; Abadie & Jabri, 2014). The density of antigen-presenting cells (APCs), including dendritic cells and macrophages, is significantly increased in the intestinal mucosa of CD patients, facilitating the activation of gluten-specific T cells (Di Niro et al., 2012; Jabri & Sollid, 2009).

T cells specific for gluten peptides are readily detectable in the lamina propria. Upon activation, these T cells produce pro-inflammatory cytokines such as interferon-gamma (IFN-γ), which perpetuate the inflammatory response (Sollid & Jabri, 2013). In addition, B and plasma cells are abundant in the lamina propria and secrete autoantibodies targeting tissue transglutaminase 2 (TG2) and deamidated gluten peptides, which are hallmark features of CD pathogenesis (Di Niro et al., 2012; Schumann et al., 2012).

IL-15, a pro-inflammatory cytokine, is overexpressed in the intestinal epithelium of CD patients, contributing to the activation of intraepithelial lymphocytes (IELs). These IELs acquire cytolytic properties, leading to the destruction of enterocytes and disruption of the epithelial barrier (Abadie & Jabri, 2014; McNab et al., 2015). This process culminates in villous atrophy, characterized by flattening of the intestinal villi, loss of barrier function, and reduced intestinal absorptive surface area (Abadie & Jabri, 2014; Schumann et al., 2012). The resulting epithelial damage contributes to common symptoms such as diarrhea, abdominal pain, malabsorption, failure to thrive in children, and fatigue (Leonard et al., 2017).

The withdrawal of gluten from the diet typically results in the resolution of symptoms and normalization of intestinal morphology. Upon reintroduction of gluten, patients quickly experience a resurgence of symptoms and intestinal damage (Leonard et al., 2017; Sollid & Jabri, 2013). Currently, a lifelong gluten-free diet (GFD) remains the only effective treatment for CD (Leonard et al., 2017; Fasano et al., 2012).

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

The biological plausibility of this KER is well established. Dr. Willem-Karel Dicke first demonstrated in the 1940s that the consumption of gluten is the primary trigger for the symptoms of celiac disease (CD). Gluten ingestion induces inflammation in the small intestine, characterized by lymphocyte infiltration, villous atrophy, and loss of epithelial barrier integrity, all of which are hallmark features of the disease (Sollid & Jabri, 2013; Abadie & Jabri, 2014). The disruption of the intestinal barrier allows gluten peptides to interact with the immune system, triggering an autoimmune response involving T cells and the production of antibodies against tissue transglutaminase (TG2) and gluten peptides (Di Niro et al., 2012; Leonard et al., 2017).

Moreover, IL-15 overexpression in the intestinal epithelium contributes to the activation of cytotoxic intraepithelial lymphocytes (IELs), which directly destroy epithelial cells and exacerbate intestinal damage (Abadie & Jabri, 2014). This sequence of events explains how gluten ingestion disrupts the intestinal barrier, ultimately leading to the pathology of CD.

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

A large body of empirical evidence supports the link between gluten consumption and the onset of CD symptoms. The therapeutic effect of a gluten-free diet (GFD) is well-documented, with studies showing rapid improvement in clinical symptoms and normalization of intestinal morphology upon gluten withdrawal (Fasano et al., 2012; Leonard et al., 2017). Conversely, the reintroduction of gluten into the diet quickly leads to the recurrence of symptoms, providing strong evidence for the causal role of gluten in disease pathogenesis (Sollid & Jabri, 2013).

Studies have consistently demonstrated that gluten-specific T cells are present in the intestinal mucosa of CD patients, and these cells produce pro-inflammatory cytokines upon gluten exposure (Sollid & Jabri, 2013; Di Niro et al., 2012). Additionally, the observation that antibodies against TG2 and gluten peptides are present in nearly all CD patients further substantiates the role of gluten in driving intestinal barrier dysfunction and subsequent autoimmune responses (Leonard et al., 2017).

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

Symptoms associated with celiac disease are highly variable. Also, not all patients are equally sensitive to gluten exposure. It is at present unclear what causes these differences. There are:

Variability in Gluten Sensitivity Thresholds: The amount of gluten necessary to trigger symptoms and intestinal damage varies significantly among patients. While some individuals react to minute quantities of gluten, others tolerate small amounts without noticeable symptoms. This variability complicates efforts to establish uniform thresholds for gluten exposure in dietary guidelines (Fasano et al., 2012).

Silent and Potential CD: A subset of patients with CD remains asymptomatic or presents with "silent" disease, where characteristic intestinal damage is evident but symptoms are absent. Additionally, individuals with potential CD exhibit positive serology but lack intestinal damage, raising questions about the progression and triggers of disease activation (Tosco et al., 2011).

Overlap with Non-Celiac Gluten Sensitivity (NCGS): The differentiation between CD and NCGS remains challenging due to overlapping symptoms. NCGS patients report gluten-related symptoms without the autoimmune or histological markers of CD, suggesting additional, poorly understood mechanisms (Uhde et al., 2016). Role of Environmental and Genetic Factors: Although HLA-DQ2/DQ8 is a necessary genetic factor, not all carriers develop CD. Environmental factors, such as infections or gut microbiota alterations, are thought to modulate disease onset but remain incompletely characterized (Abadie & Jabri, 2014).

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

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)
Certain infections	e.g. rotavirus	may exacerbate celiac disease	Abadie & Jabri, 2014
Quantity and frequency of gluten intake		individuals consuming high amounts of gluten are at increased risk of symptomatic disease and more pronounced intestinal damage	Fasano et al., 2012
IL-15 in the intestinal epithelium	overexpression	exacerbates tissue destruction and modulates the severity of disease progression	Abadie & Jabri, 2014

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

Gliadin Dose and Immune Response:

Studies have shown a dose-dependent relationship between gluten exposure and immune activation. Even small amounts of gluten (as low as 10-50 mg/day) can induce detectable mucosal damage and T-cell activation in individuals with CD. Higher doses lead to more severe villous atrophy, increased intraepithelial lymphocyte infiltration, and elevated antibody levels (Fasano et al., 2012).

IL-15 Expression and Cytotoxicity:

Increased levels of IL-15 correlate with enhanced cytotoxic activity of intraepithelial lymphocytes (IELs), promoting epithelial cell death and barrier disruption. Animal models and human biopsy data have confirmed that IL-15 overexpression accelerates epithelial destruction in response to gluten exposure (Abadie & Jabri, 2014).

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

The exact time-scale of the development of celiac disease is unknown as patients are usually only identified when disease symptoms are manifest. Besides, the progression of CD following intestinal barrier disruption varies depending on individual factors:

Acute Response: In gluten challenge studies, symptoms can appear within hours to days of gluten reintroduction. This aligns with the rapid activation of gluten-specific T cells and the early release of pro-inflammatory cytokines.

Histological Changes: Structural changes, such as villous atrophy and crypt hyperplasia, typically develop within weeks of continuous gluten exposure, as observed in longitudinal biopsy studies of gluten reintroduction in CD patients (Tosco et al., 2011).

Recovery Timeline: Following the initiation of a gluten-free diet (GFD), most individuals show significant symptom improvement within weeks. However, full histological recovery of the intestinal mucosa may take months to years, especially in adults (Fasano et al., 2012).

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

Not known

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 is a human-specific condition linked to HLA-DQ2/DQ8, so most studies have been conducted in humans

References

List of the literature that was cited for this KER description. More help

Abadie V, Jabri B. IL-15: a central regulator of celiac disease immunopathology. Immunol Rev. 2014 Jul;260(1):221-34.
Di Niro R, Mesin L, Zheng NY, et al. High abundance of plasma cells secreting transglutaminase 2-specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions. Nat Med. 2012 Mar;18(3):441-5.
Fasano A, Catassi C. Clinical practice. Celiac disease. N Engl J Med. 2012 Dec 20;367(25):2419-26.
Jabri B, Sollid LM. Tissue-mediated control of immunopathology in coeliac disease. Nat Rev Immunol. 2009 Dec;9(12):858-70.
Leonard MM, Sapone A, Catassi C, Fasano A. Celiac Disease and Nonceliac Gluten Sensitivity: A Review. JAMA. 2017 Aug 15;318(7):647-656.
McNab F, Mayer-Barber K, Sher A, et al. Type I interferons in infectious disease. Nat Rev Immunol. 2015 Feb;15(2):87-103.
Schumann M, Kamel S, Pahlitzsch ML, et al. Defective tight junctions in refractory celiac disease. Ann N Y Acad Sci. 2012 Jul;1258:43-51.
Sollid LM, Jabri B. Triggers and drivers of autoimmunity: lessons from coeliac disease. Nat Rev Immunol. 2013 Apr;13(4):294-302.
Tosco A, Salvati VM, Auricchio R, et al. Natural history of potential celiac disease in children. Clin Gastroenterol Hepatol. 2011 Apr;9(4):320-5.
Uhde M, Ajamian M, Caio G, et al. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut. 2016 Dec;65(12):1930-1937.