Injection of prototypic celiac anti-transglutaminase 2 antibodies in mice does not cause enteropathy

Lindstad, Christian Borgen; Pré, M. Fleur du; Stamnæs, Jorunn; Sollid, Ludvig M.

doi:10.1371/journal.pone.0266543

Cited by 4 publications

(2 citation statements)

References 37 publications

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“…Comforting an important role of B cells in CD pathogenesis, in vivo elimination of B cells by anti-CD20 antibody attenuated villous atrophy in a CD mouse model of CD. 38 Since the autoantibodies do not seem to induce intestinal damage in vivo, 39 the most likely hypothesis to date is indeed that autoreactive B cells are instrumental for gluten presentation to T cells. Overall, these data explain why anti-TG2 antibodies are exclusively present in patients exposed to gluten and why these antibodies represent a highly reliable biomarker to monitor the antigluten response.…”

Section: The Driver Role Of the Gluten-specific Immune Responsementioning

confidence: 99%

Immunopathogenesis and environmental triggers in coeliac disease

Levescot

Malamut

Cerf‐Bensussan

2022

Gut

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Coeliac disease (CD) is a frequent immune enteropathy induced by gluten in genetically predisposed individuals. Its pathogenesis has been extensively studied and CD has emerged as a model disease to decipher how the interplay between environmental and genetic factors can predispose to autoimmunity and promote lymphomagenesis. The keystone event is the activation of a gluten-specific immune response that is driven by molecular interactions between gluten, the indispensable environmental factor, HLA-DQ2/8, the main predisposing genetic factor and transglutaminase 2, the CD-specific autoantigen. The antigluten response is however not sufficient to induce epithelial damage which requires the activation of cytotoxic CD8+ intraepithelial lymphocytes (IEL). In a plausible scenario, cooperation between cytokines released by gluten-specific CD4+ T cells and interleukin-15 produced in excess in the coeliac gut, licenses the autoimmune-like attack of the gut epithelium, likely via sustained activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway in IEL. Demonstration that lymphomas complicating CD arise from IEL that have acquired gain-of-function JAK1 or STAT3 mutations stresses the key role of this pathway and explains how gluten-driven chronic inflammation may promote this rare but most severe complication. If our understanding of CD pathogenesis has considerably progressed, several questions and challenges remain. One unsolved question concerns the considerable variability in disease penetrance, severity and presentation, pointing to the role of additional genetic and environmental factors that remain however uneasy to untangle and hierarchize. A current challenge is to transfer the considerable mechanistic insight gained into CD pathogenesis into benefits for the patients, notably to alleviate the gluten-free diet, a burden for many patients.

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Section: The Driver Role Of the Gluten-specific Immune Responsementioning

confidence: 99%

Immunopathogenesis and environmental triggers in coeliac disease

Levescot

Malamut

Cerf‐Bensussan

2022

Gut

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“…However, there is no clear evidence indicating a specific pathogenetic role for TG2 autoantibodies. A number of studies, sometimes with discordant results, have tried to clarify the biological effects of these antibodies, suggesting that their presence in the intestine and other areas could be a contributing factor in disease development [ 85 , 86 ]. Here, we briefly focus attention on the features of CD mucosal lesion that could be induced by anti-TG2 antibodies.…”

Section: Tg2 In CD Pathogenesismentioning

confidence: 99%

Type 2 Transglutaminase in Coeliac Disease: A Key Player in Pathogenesis, Diagnosis and Therapy

Paolella

Sposito

Romanelli

et al. 2022

IJMS

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Type 2 transglutaminase (TG2) is the main autoantigen in coeliac disease (CD), a widespread inflammatory enteropathy caused by the ingestion of gluten-containing cereals in genetically predisposed individuals. As a consequence, serum antibodies to TG2 represent a very useful marker in CD diagnosis. However, TG2 is also an important player in CD pathogenesis, for its ability to deamidate some Gln residues of gluten peptides, which become more immunogenic in CD intestinal mucosa. Given the importance of TG2 enzymatic activities in CD, several studies have sought to discover specific and potent inhibitors that could be employed in new therapeutical approaches for CD, as alternatives to a lifelong gluten-free diet. In this review, we summarise all the aspects regarding TG2 involvement in CD, including its enzymatic reactions in pathogenesis, the role of anti-TG2 antibodies in disease management, and the exploration of recent strategies to reduce deamidation or to use transamidation to detoxify gluten.

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Loss of tolerance to dietary proteins: From mouse models to human model diseases

Levescot,

Cerf‐Bensussan

2024

Immunological Reviews

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SummaryThe critical importance of the immunoregulatory mechanisms, which prevent adverse responses to dietary proteins is demonstrated by the consequences of their failure in two common but distinct human pathological conditions, food allergy and celiac disease. The mechanisms of tolerance to dietary proteins have been extensively studied in mouse models but the extent to which the results in mice can be extrapolated to humans remains unclear. Here, after summarizing the mechanisms known to control oral tolerance in mouse models, we discuss how the monogenic immune disorders associated with food allergy on the one hand, and celiac disease, on the other hand, represent model diseases to gain insight into the key immunoregulatory pathways that control immune responses to food antigens in humans. The spectrum of monogenic disorders, in which the dysfunction of a single gene, is strongly associated with TH2‐mediated food allergy suggests an important overlap between the mechanisms that regulate TH2 and IgE responses to food antigens in humans and mice. In contrast, celiac disease provides a unique example of the link between autoimmunity and loss of tolerance to a food antigen.

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Injection of prototypic celiac anti-transglutaminase 2 antibodies in mice does not cause enteropathy

Cited by 4 publications

References 37 publications

Immunopathogenesis and environmental triggers in coeliac disease

Immunopathogenesis and environmental triggers in coeliac disease

Type 2 Transglutaminase in Coeliac Disease: A Key Player in Pathogenesis, Diagnosis and Therapy

Loss of tolerance to dietary proteins: From mouse models to human model diseases

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