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Event: 2256

Key Event Title

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

Gluten-reactive B cells and transglutaminase 2-reactive B cells, activation

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
Activation of gluten- and TG2-reactive B cells
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Biological Context

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Level of Biological Organization
Cellular

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
B 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
B cell activation involved in immune response B cell occurrence

Key Event Overview

AOPs Including This Key Event

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AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Gluten-driven immune activation leading to celiac disease KeyEvent 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
All life stages

Sex Applicability

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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

B cells specific to tissue transglutaminase 2 (TG2) are activated in a CD4+ T-cell-dependent manner. Gluten-specific T cells, once activated, provide the necessary "help" to TG2-reactive B cells, facilitating their activation and differentiation into plasma cells that produce anti-TG2 antibodies in the lamina propria (Di Niro et al., 2012). TG2-specific B cells appear to undergo limited affinity maturation, even under chronic antigen exposure, suggesting that their activation relies on naive B cells and is sustained by ongoing gluten exposure (Di Niro et al., 2012; Steinsbo et al., 2014). The crosslinking of TG2 with B-cell receptors (BCRs) may lower the activation threshold for naive TG2-specific B cells, enhancing their activation and subsequent proliferation. This contributes to the high abundance of plasma cells secreting anti-TG2 antibodies, creating a feedback loop that further amplifies antigen presentation to T cells (Di Niro et al., 2012).

Mechanistic Insights

The selection of high-affinity B cells during affinity maturation depends on peptide presentation to T cells. Evidence from Di Niro et al. (2012) supports the necessity of T-cell help, as mutations reducing affinity were linked to a loss of function. B cells engineered to express anti-TG2 BCRs were shown to process and present TG2-gliadin complexes, activating gluten-specific T cells derived from celiac patients, confirming a T-cell-dependent model for antibody generation (Sollid et al., 1997; Sollid et al., 2002; Di Niro et al., 2012).

Further insights by Fleur du Pré et al. (2020) reveal that while most autoreactive B cells are typically removed or silenced through central and peripheral tolerance mechanisms, in celiac disease these controls fail. Anti-TG2 B cells survive and produce autoantibodies when T-cell help is available. These autoreactive B cells act as antigen-presenting cells (APCs), driving the anti-gluten T-cell response, creating an amplification loop central to disease pathogenesis.

Failure of Tolerance Mechanisms

In healthy individuals, autoreactive B cells are controlled through receptor editing, apoptosis, or anergy (Gay et al., 1993; Tiegs et al., 1993; Nemazee and Bürki, 1989; Goodnow et al., 1988). However, in celiac disease, TG2-reactive B cells escape these mechanisms. Some autoreactive B cells may remain "ignorant" in the absence of sufficient antigenic stimulation but become pathogenic when gluten-derived peptides and TG2 form complexes. This failure enables both TG2- and gluten-reactive B cells to survive and contribute to the disease state (Fleur du Pre et al 2020).

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

B cell activation can be evaluated by measuring the generation of monoclonal antibodies. Single plasma cells can be isolated from intestinal biopsies and cultured or sorted with gluten peptide tetramers. The resulting monoclonal antibodies can be analyzed for their reactivity to gluten and TG2 antigens, by ELISA or AlphaLISA​ (Di Niro et al., 2012). Alternatively, fluorescently labeled peptides (e.g., biotinylated gliadin peptides) can be used in flow cytometry to sort and analyze gluten-specific IgA+ plasma cells, allowing for the detection and characterization of B cell activation in celiac lesions​ (Di Niro et al., 2012).

Domain of Applicability

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

Activation of B cells specific to tissue transglutaminase 2 (TG2) are well documented in humans. Although Irish setter can develop partial lymphocyte infiltration in response to wheat diet, it is not a CD4 T cell mediated disease. Monkeys can produce anti gliadins IgA and IgG but the levels of these antibodies do not change with removal or reintroduction of dietary gluten. In mice there is a clear antibody response to TG, but not in a gluten dependent way (Marietta et al., 2011).

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.

  • 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.

  • du Pré MF, Blazevski J, Dewan AE, Stamnaes J, Kanduri C, Sandve GK, Johannesen MK, Lindstad CB, Hnida K, Fugger L, Melino G, Qiao SW, Sollid LM. (2020). B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2. J Exp Med. Feb 3;217(2):e20190860. doi: 10.1084/jem.20190860. 

  • 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.

  • Gay D, Saunders T, Camper S, and Weigert M. (1993). Receptor editing: an approach by autoreactive B cells to escape tolerance. J. Exp. Med. 177:999–1008. 10.1084/jem.177.4.999

  • Goodnow CC, Crosbie J, Adelstein S, Lavoie TB, Smith-Gill SJ, Brink RA, Pritchard-Briscoe H, Wotherspoon JS, Loblay RH, Raphael K. (1988). Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature. 334:676–682. 10.1038/334676a0

  • 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.

  • Marietta EV, David CS, Murray JA. (2011). Important lessons derived from animal models of celiac disease. Int Rev Immunol. Aug;30(4):197-206. doi: 10.3109/08830185.2011.598978.

  • Nemazee DA, and Bürki K. (1989). Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature. 337:562–566. 10.1038/337562a0

  • Sollid LM, Molberg O, McAdam S, Lundin KE. (1997). Autoantibodies in coeliac disease: tissue transglutaminase--guilt by association?. Gut  Dec;41(6):851-2. doi: 10.1136/gut.41.6.851.

  • Sollid LM. (2002). Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol. 2:647–655. 

  • 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.

  • Tiegs SL, Russell DM, and Nemazee D. (1993). Receptor editing in self-reactive bone marrow B cells. J. Exp. Med. 177:1009–1020. 10.1084/jem.177.4.1009

  • 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). 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.