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Event: 2253

Key Event Title

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

Gluten-reactive T cell receptors, generation

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
Generation of gluten-reactive T cell receptors
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Biological Context

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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
T 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
thymus

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
gene conversion alpha-beta T cell receptor 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

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
During development and at adulthood

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

For T cell recognition of the HLA-DQ2/8-gluten complexes, T cell receptors specifically tuned to recognize these complexes must be generated (Molberg et al., 1997; Arentz-Hansen et al., 2000; Vader et al., 2002; Broughton et al., 2012; Qiao et al., 2014). This occurs through gene rearrangement during T cell development (Sollid et al., 1989; Molberg et al., 1997; Molberg et al., 1998; Vader et al., 2002). Notably, T cell receptors specific for the immunodominant gluten epitopes exhibit distinct characteristics, which are consistently shared among patients with celiac disease (Lundin et al., 1993; Dieterich et al., 1997; Molberg et al., 1997; Molberg et al., 1998; Vader et al., 2002; Vader et al., 2002b; Meresse et al., 2004; Tollefsen et al., 2006; Fallang et al., 2009; Qiao et al., 2011; Broughton et al., 2012; Petersen et al., 2014).

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

  • TCR sequencing: To identify the specific gene sequences of gluten-reactive T cell receptors (Sollid et al., 1989; Vader et al., 2002; Qiao et al., 2011; Qiao et al., 2014).

  • T cell proliferation assays: To measure the activation and proliferation of gluten-reactive T cells in response to gluten peptides (Lundin et al., 1993; Molberg et al., 1998; Meresse et al., 2006; Fallang et al., 2009).

  • Flow cytometry: To detect TCR expression and cell surface markers on gluten-reactive T cells (Meresse et al., 2004; Broughton et al., 2012).

  • Tetramer staining: To identify gluten-reactive T cells by binding HLA-peptide complexes to T cells (Molberg et al., 1997; Tollefsen et al., 2006).

  • Cytokine production assays: To measure cytokine release (e.g., IFN-γ) to assess T cell activation (Nilsen et al., 1998; Meresse et al., 2004).

  • Mass spectrometry: To analyze deamidated gluten peptides and their interactions with TCRs (van de Wal et al., 1998; Vader et al., 2003).

  • Chromium release assays: To measure the cytotoxicity of gluten-specific CD8+ T cells (Molberg et al., 1998; Tollefsen et al., 2006).

Domain of Applicability

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

Individuals with celiac disease, especially those expressing HLA-DQ2 (such as HLA-DQ2.5) or HLA-DQ8 (Sollid et al., 1989; Lundin et al., 1993; Molberg et al., 1997; Vader et al., 2002). The generation of these T cell receptors is specific to patients with a genetic predisposition to celiac disease (Sollid et al., 1989; Molberg et al., 1997; Qiao et al., 2011; Di Niro et al., 2012). Celiac disease patients with HLA-DQ2.2 are still susceptible to generating gluten-reactive T cell receptors, but their risk of developing the disease is generally lower than for those carrying HLA-DQ2.5 (Sollid et al., 1989; Vader et al., 2003; Tollefsen et al., 2006; Qiao et al., 2014).

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.