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Event: 2252

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Human leukocyte antigen DQ2/8-gluten complexes, formation

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Formation of HLA-DQ2/8-gluten complexes
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
dendritic cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
duodenum

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
antigen presentation trait Human leukocyte antigen complex occurrence

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Gluten-driven immune activation leading to celiac disease MolecularInitiatingEvent 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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
All life stages

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Celiac disease is an intestinal disorder triggered by gluten ingestion. It exclusively occurs in individuals who are positive for HLA-DQ2, HLA-DQ8, or both (Sollid, 1989; Dieterich, 1997). In patients with celiac disease, CD4+ T cells specifically recognize complexes formed between HLA-DQ2/8 molecules and modified gluten peptides (Molberg, 1997; Meresse, 2004; Sollid, 2012). The formation of these HLA-DQ2/8-gluten complexes is a prerequisite for T-cell activation (Molberg, 1998; Arentz-Hansen, 2000; Vader, 2002).

Upon gluten ingestion, proteolytic fragments are generated through enzymatic cleavage in the upper gastrointestinal tract. These fragments are subsequently modified by tissue transglutaminase (TG2), which converts specific glutamine residues into glutamic acid (Dieterich, 1997; Molberg, 1998). This modification introduces negatively charged residues, which are crucial for high-affinity binding of the modified peptides to HLA-DQ2 or HLA-DQ8, as these molecules preferentially bind peptides with such negatively charged residues (Vader, 2003; Sollid, 2012). This process underlies the immune response observed in celiac disease.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

  • Peptide binding assays: To measure the direct binding of gluten peptides to HLA-DQ molecules (Sollid, 1989; Arentz-Hansen, 2000; Sollid, 2012).

  • Mass spectrometry: To analyze deamidated gluten peptides and their interaction with HLA-DQ (Van de Wal, 1998b; Vader, 2002; Fallang, 2009).

  • HLA-binding assays: To assess the stability and affinity of peptide-HLA complexes (Molberg, 1998; Vader, 2002; Sollid, 2012).

  • T cell proliferation assays: To measure T cell response to gluten peptides (Lundin, 1993; Meresse, 2004; Tollefsen, 2006).

  • Tetramer staining: To detect gluten-specific T cells bound to HLA-DQ (Qiao, 2011; Broughton, 2012).

  • Flow cytometry: To analyze cell surface markers for gluten peptide presentation (Meresse, 2004; Di Niro, 2012; Steinsbo, 2014).

  • Immunohistochemistry & Immunofluorescence: To visualize tTG-gluten complexes (Dieterich, 1997; Di Niro, 2012).

  • ELISA: To detect IgA anti-tTG antibodies as a marker for gluten interaction (Dieterich, 1998; Di Niro, 2012).

  • Surface plasmon resonance (SPR): To measure TCR affinity for HLA-DQ-gluten complexes (Vader, 2002b; Broughton, 2012; Petersen, 2014).

  • HPLC: To purify gluten peptides for further analysis (Van de Wal, 1998b; Van de Wal, 1999; Vader, 2002).

  • Serological typing & ASO probes: To identify HLA-DQ alleles in patients (Sollid, 1989; Vader, 2003).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Human individuals with celiac disease, particularly those expressing HLA-DQ2 (including HLA-DQ2.5 and HLA-DQ2.2) or HLA-DQ8 (Sollid, 1989; Lundin, 1993; Dieterich, 1997; Molberg, 1997; Dieterich, 1998; Molberg, 1998; Nilsen, 1998; Van de Wal, 1998; Van de Wal, 1998b; Van de Wal, 1999; Arentz-Hansen, 2000; Vader, 2002; Vader, 2002b; Vader, 2003; Vader, 2003b; Meresse, 2004; Meresse, 2006; Tollefsen, 2006; Fallang, 2009; Qiao, 2011; Broughton, 2012; Di Niro, 2012; Sollid, 2012; Petersen, 2014; Qiao, 2014; Steinsbo, 2014). Patients with a genetic predisposition to celiac disease, especially those with specific haplotypes like DR3/DQw2, are most affected (Sollid, 1989; Nilsen, 1998; Van de Wal, 1998; Sollid, 2012).

References

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

  • Arentz-Hansen H, Körner R, Molberg Ø, Quarsten H, Vader W, Kooy YMC, Lundin KEA, Koning F, Roepstorff P, Sollid LM, McAdam S. (2000). The intestinal T cell response to α-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase. J Exp Med. 191:603-612.

  • Broughton SE, Petersen J, Theodossis A, Scally SW, Loh KL, Thompson A, van Bergen J, Kooy-Winkelaar Y, Henderson KN, Beddoe T, Tye-Din JA, Mannering SI, Purcell AW, McCluskey J, Anderson RP, Koning F, Reid HH, Rossjohn J. (2012). Biased T cell receptor usage directed against human leukocyte antigen DQ8-restricted gliadin peptides is associated with celiac disease. Immunity. 37:611-621.

  • 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. (2012). High abundance of plasma cells secreting transglutaminase 2-specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions. Nat Med. 18:441-445.

  • Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, Schuppan D. (1997). Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med. 3:797-801.

  • Dieterich W, Laag E, Schöpper H, Volta U, Ferguson A, Gillett H, Riecken EO, Schuppan D. (1998). Autoantibodies to tissue transglutaminase as predictors of celiac disease. Gastroenterology. 115:1317-1321.

  • Fallang LE, Bergseng E, Hotta K, Berg-Larsen A, Kim CY, Sollid LM. (2009). Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation. Nat Immunol. 10:1096-1101.

  • Lundin KE, Scott H, Hansen T, Paulsen G, Halstensen TS, Fausa O, Thorsby E, Sollid LM. (1993). Gliadin-specific, HLA-DQ(alpha 10501,beta 10201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients. J Exp Med. 178:187-196.

  • Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, Raulet DH, Lanier LL, Groh V, Spies T, Ebert EC, Green PH, Jabri B. (2004). Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity. 21:357-366.

  • Meresse B, Curran SA, Ciszewski C, Orbelyan G, Setty M, Bhagat G, Lee L, Tretiakova M, Semrad C, Kistner E, Winchester RJ, Braud V, Lanier LL, Geraghty DE, Green PH, Guandalini S, Jabri B. (2006). Reprogramming of CTLs into natural killer-like cells in celiac disease. J Exp Med. 203:1343-1355.

  • Molberg Ø, Kett K, Scott H, Thorsby E, Sollid LM, Lundin KE. (1997). Gliadin specific, HLA DQ2-restricted T cells are commonly found in small intestinal biopsies from coeliac disease patients, but not from controls. Scand J Immunol. 46:103-109.

  • Molberg Ø, McAdam SN, Körner R, Quarsten H, Kristiansen C, Madsen L, Fugger L, Scott H, Noren O, Roepstorff P, Lundin KE, Sjöström H, Sollid LM. (1998). Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med. 4:713-717.

  • Nilsen EM, Jahnsen FL, Lundin KE, Johansen FE, Fausa O, Sollid LM, Jahnsen J, Scott H, Brandtzaeg P. (1998). Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology. 115:551-563.

  • Petersen J, Montserrat V, Mujico JR, Loh KL, Beringer DX, van Liempt M, Thompson A, Mearin ML, Schweizer J, Kooy-Winkelaar Y, van Bergen J, Drijfhout JW, Kan WT, La Gruta NL, Anderson RP, Reid HH, Koning F, Rossjohn J. (2014). T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease. Nat Struct Mol Biol. 21:480-488.

  • Qiao SW, Christophersen A, Lundin KE, Sollid LM. (2014). Biased usage and preferred pairing of alpha- and beta-chains of TCRs specific for an immunodominant gluten epitope in coeliac disease. Int Immunol. 26:13-19.

  • Qiao SW, Raki M, Gunnarsen KS, Loset GA, Lundin KE, Sandlie I, Sollid LM. (2011). Posttranslational modification of gluten shapes TCR usage in celiac disease. J Immunol. 187:3064-3071.

  • Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F, Thorsby E. (1989). Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer. J Exp Med. 169:345-350.

  • Sollid LM, Qiao SW, Anderson RP, Gianfrani C, Koning F. (2012). Nomenclature and listing of celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ molecules. Immunogenetics. 64:455-460.

  • Steinsbø Ø, Henry Dunand CJ, Huang M, Mesin L, Salgado-Ferrer M, Lundin KE, Jahnsen J, Wilson PC, Sollid LM. (2014). Restricted VH/VL usage and limited mutations in gluten-specific IgA of coeliac disease lesion plasma cells. Nat Commun. 5:4041.

  • Tollefsen S, Arentz-Hansen H, Fleckenstein B, Molberg Ø, Raki M, Kwok WW, Jung G, Lundin KE, Sollid LM. (2006). HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease. J Clin Invest. 116:2226-2236.

  • Vader W, de Ru A, van der Wal Y, Kooy Y, Benckhuijsen W, Mearin L, Drijfhout JW, van Veelen P, Koning F. (2002). Specificity of tissue transglutaminase explains cereal toxicity in celiac disease. J Exp Med. 195:643-649.

  • Vader W, Stepniak D, Bunnik EM, Kooy Y, de Haan W, Drijfhout JW, van Veelen PA, Koning F. (2003). Characterization of cereal toxicity for celiac disease patients based on protein homology in grains. Gastroenterology. 125:1105-1113.

  • Vader W, Stepniak D, Kooy Y, Mearin ML, Thompson A, Spaenij L, Koning F. (2003). The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T-cell responses. Proc Natl Acad Sci U S A. 100:12390-12395.

  • Vader W, Kooy Y, van Veelen P, de Ru A, Harris D, Benckhuijsen W, Pena S, Mearin L, Drijfhout JW, Koning F. (2002). The gluten response in children with recent onset celiac disease. A highly diverse response towards multiple gliadin and glutenin-derived peptides. Gastroenterology. 122:1729-1737.

  • van de Wal Y, Kooy Y, van Veelen P, Pena S, Mearin L, Papadopoulos G, Koning F. (1998). Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol 161:1585-1588.

  • van de Wal Y, Kooy Y, van Veelen P, Pena S, Mearin L, Papadopoulos G, Koning F. (1998). Small intestinal T cells of celiac disease patients recognize a natural pepsin fragment of gliadin. Proc Natl Acad Sci U S A. 95:10050-10054.

  • van de Wal, Y., Kooy, Y.M.C., Veelen, van P., August, S.A., Drijfhout, J.W. and Koning, F. (1999). Glutenin is involved in the gluten-driven mucosal T cell response. Eur. J. Immunol. 29, 3133-3139.