A Non-Human Primate Model for Gluten Sensitivity

Bethune, Michael T.; Borda, Juan T.; Ribka, Erin P.; Liu, Michael-Xun; Phillippi-Falkenstein, Kathrine; Jandacek, Ronald J.; Doxiadis, Gaby G. M.; Gray, Gary M.; Khosla, Chaitan; Sestak, Karol

doi:10.1371/journal.pone.0001614

Cited by 74 publications

(114 citation statements)

References 33 publications

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“…44 for review). A gluten-sensitive rhesus macaque model exhibited histological signs and symptoms of gluten-induced enteropathy accompanied by anti-gliadin antibody production; however, no anti-TG2 antibodies were observed and an association with MHC class II haplotypes has not yet been confirmed (43). Coadministration of gluten and an orally active glutaminespecific endoprotease to hydrolyze glutamine-rich gluten peptides in vivo prevented gluten-induced clinical relapse, indicating a marked loss of T-cell reactivity towards the shorter endoprotease-digested gluten peptides (45).…”

Section: Gluten Sensitivity Diseasesmentioning

confidence: 99%

Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

Iismaa¹,

Mearns²,

Lóránd³

et al. 2009

Physiological Reviews

301

336

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The human transglutaminase (TG) family consists of a structural protein, protein 4.2, that lacks catalytic activity, and eight zymogens/enzymes, designated factor XIII-A (FXIII-A) and TG1-7, that catalyze three types of posttranslational modification reactions: transamidation, esterification, and hydrolysis. These reactions are essential for biological processes such as blood coagulation, skin barrier formation, and extracellular matrix assembly but can also contribute to the pathophysiology of various inflammatory, autoimmune, and degenerative conditions. Some members of the TG family, for example, TG2, can participate in biological processes through actions unrelated to transamidase catalytic activity. We present here a comprehensive review of recent insights into the physiology and pathophysiology of TG family members that have come from studies of genetically engineered mouse models and/or inherited disorders. The review focuses on FXIII-A, TG1, TG2, TG5, and protein 4.2, as mice deficient in TG3, TG4, TG6, or TG7 have not yet been reported, nor have mutations in these proteins been linked to human disease.

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Section: Gluten Sensitivity Diseasesmentioning

confidence: 99%

Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

Iismaa¹,

Mearns²,

Lóránd³

et al. 2009

Physiological Reviews

301

336

View full text Add to dashboard Cite

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“…The villus height/crypt depth (V:C) ratios were obtained from linear measurements of five villus heights in each sample, divided by the corresponding crypt depths as described. 17 Immunohistological Analysis of the Small Intestine Immunohistochemistry on paraffin sections was performed using an anti-mouse IL-5 (Santa Cruz Biotechnology, Santa Cruz, CA, USA) or an anti-CD71 (ZYMED Laboratories, Invitrogen, Carlsbad, CA, USA). 18 Horseradish peroxidaseconjugated goat anti-rabbit IgG (Sigma) was used as secondary antibody.…”

Section: Histopathologymentioning

confidence: 99%

Gluten induces coeliac-like disease in sensitised mice involving IgA, CD71 and transglutaminase 2 interactions that are prevented by probiotics

Papista

Gerakopoulos

Kourelis

et al. 2012

Laboratory Investigation

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Coeliac disease (CD) is a malabsorptive enteropathy resulting from intolerance to gluten. Environmental factors and the microbiota are suggested to have critical roles in the onset of CD. The CD71 IgA receptor on epithelial cells is responsible for abnormal retrotranscytosis of IgA-gluten peptide complexes from the intestinal lumen into the lamina propria, inducing intestinal inflammation. However, understanding the role of gluten in the CD physiopathology has been hindered by the absence of relevant animal models. Here, we generated a mouse model for CD to study the factors controlling its pathogenesis as well as to investigate the influence of oral delivery of probiotics on disease development. Gluten sensitivity was established by feeding three generations of BALB/c mice a gluten-free diet (GÀ) followed by gluten challenge (G þ ) for 30 days. The G þ mice developed villous atrophy, crypt hyperplasia and infiltration of T cells and macrophages in the small intestine. Inflammation was associated with an overexpression of CD71 on the apical side of enterocytes and an increase of plasma cells producing IgA, which colocalised with the CD71. Moreover, IgA colocalised with the transglutaminase 2 (TG2), the production of which was increased in the lamina propria of G þ mice. These mice displayed increased production of cyclooxygenase-2 (COX-2), pro-inflammatory cytokines and IL-15, as well as anti-gliadin and anti-TG2 autoantibodies. The commensal flora-isolated presumptive probiotic Saccharomyces boulardii KK1 strain hydrolysed the 28-kDa a-gliadin fraction, and its oral delivery in G þ mice improved enteropathy development in association with decrease of epithelial cell CD71 expression and local cytokine production. In conclusion, the G þ BALB/c mouse represents a new mouse model for human CD based on histopathological features and expression of common biomarkers. The selected probiotic treatment reversing disease development will allow the study of the role of probiotics as a new therapeutic approach of CD.

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“…Animal models remained incomplete (12) and IgA anti-TG2 antibodies similar to those in patients' serum (13) and bound in different tissues in a greatly specific pattern along vessels and TG2-rich endomysium (14) were not produced. A gluten-free diet normalizes the gut lesions and eliminates TG2 antibodies from both serum and tissues.…”

mentioning

confidence: 99%

A single conformational transglutaminase 2 epitope contributed by three domains is critical for celiac antibody binding and effects

Simon-Vecsei

Király

Bagossi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The multifunctional, protein cross-linking transglutaminase 2 (TG2) is the main autoantigen in celiac disease, an autoimmune disorder with defined etiology. Glutamine-rich gliadin peptides from ingested cereals, after their deamidation by TG2, induce T-lymphocyte activation accompanied by autoantibody production against TG2 in 1-2% of the population. The pathogenic role and exact binding properties of these antibodies to TG2 are still unclear. Here we show that antibodies from different celiac patients target the same conformational TG2 epitope formed by spatially close amino acids of adjacent domains. Glu153 and 154 on the first alpha-helix of the core domain and Arg19 on first alpha-helix of the N-terminal domain determine the celiac epitope that is accessible both in the closed and open conformation of TG2 and dependent on the relative position of these helices. Met659 on the C-terminal domain also can cooperate in antibody binding. This composite epitope is diseasespecific, recognized by antibodies derived from celiac tissues and associated with biological effects when passively transferred from celiac mothers into their newborns. These findings suggest that celiac antibodies are produced in a surface-specific way for which certain homology of the central glutamic acid residues of the TG2 epitope with deamidated gliadin peptides could be a structural basis. Monoclonal mouse antibodies with partially overlapping epitope specificity released celiac antibodies from patient tissues and antagonized their harmful effects in cell culture experiments. Such antibodies or similar specific competitors will be useful in further functional studies and in exploring whether interference with celiac antibody actions leads to therapeutic benefits.conformational epitope | endomysial antibodies | immunotherapy

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A Non-Human Primate Model for Gluten Sensitivity

Cited by 74 publications

References 33 publications

Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

Gluten induces coeliac-like disease in sensitised mice involving IgA, CD71 and transglutaminase 2 interactions that are prevented by probiotics

A single conformational transglutaminase 2 epitope contributed by three domains is critical for celiac antibody binding and effects

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