Synthetic Neoepitopes of the Transglutaminase–Deamidated Gliadin Complex as Biomarkers for Diagnosing and Monitoring Celiac Disease

Choung, Rok Seon; Rostamkolaei, Shahryar K; Ju, Josephine M.; Marietta, Eric; Dyke, Carol T. Van; Rajasekaran, John J.; Jayaraman, Vasanth; Wang, Tianhao; Bei, Kang; Rajasekaran, Karenah E.; Krishna, Karthik; Krishnamurthy, Hari Krishnan; Murray, Joseph A.

doi:10.1053/j.gastro.2018.10.025

Cited by 33 publications

(23 citation statements)

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“…A combination of aDGP tests led to a sensitivity of 77.8% and a negative predictive value of 91.8%. One study found 87% sensitivity and 89% specificity of aDGP IgG for prediction of nonresponsive CD[ 6 ], while another study found only 48% sensitivity but 91% specificity of aDGP IgA for prediction of persistent VA[ 7 ]. The wide use of aDGP in future studies may contribute to a more precise role of it in detection of VA despite GFD.…”

Section: Discussionmentioning

confidence: 99%

“…However, there is not much data on anti-deamidated gliadin peptide antibodies (aDGP). There is one study evaluating aDGP as a reliable marker of persistent VA[ 6 ], while another study found only 48% sensitivity and 91% specificity of aDGP IgA for predicting persistent VA[ 7 ]. Currently, to the best of our knowledge, there are no studies indicating the absolute necessity of routine follow-up biopsy[ 8 , 9 ]; however, many centers recommend its implementation[ 9 , 10 ] and itis considered as an important tool in the follow-up of symptomatic patients with CD, based on the recommendations by the American Gastroenterology Association[ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Non-invasive prediction of persistent villous atrophy in celiac disease

Packová

Kovalčíková

Pavlovský

et al. 2020

WJG

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BACKGROUND Celiac disease (CD) is an immune-mediated enteropathy that is primarily treated with a gluten-free diet (GFD). Mucosal healing is the main target of the therapy. Currently, duodenal biopsy is the only way to evaluate mucosal healing, and non-invasive markers are challenging. Persistent elevation of anti-tissue transglutaminase antibodies (aTTG) is not an ideal predictor of persistent villous atrophy (VA). Data regarding prediction of atrophy using anti-deamidated gliadin peptide antibodies (aDGP) and abdominal ultrasonography are lacking. AIM To evaluate the ability of aTTG, aDGP, small bowel ultrasonography, and clinical and laboratory parameters in predicting persistent VA determined using histology. METHODS Patients with CD at least 1 year on a GFD and available follow-up duodenal biopsy, levels of aTTG and aDGP, and underwent small bowel ultrasonography were included in this retrospective cohort study. We evaluated the sensitivity, specificity, and positive and negative predictive values of aTTG, aDGP, small bowel ultrasonography, laboratory and clinical parameters to predict persistent VA. A receiver operating characteristic (ROC) curve analysis of antibody levels was used to calculate cut off values with the highest accuracy for atrophy prediction. RESULTS Complete data were available for 82 patients who were followed up over a period of four years (2014-2018). Among patients included in the analysis, women (67, 81.7%) were predominant and the mean age at diagnosis was 33.8 years. Follow-up biopsy revealed persistent VA in 19 patients (23.2%). The sensitivity and specificity of aTTG using the manufacturer’s diagnostic cutoff value to predict atrophy was 50% and 85.7%, respectively, while the sensitivity and specificity of aDGP (using the diagnostic cutoff value) was 77.8% and 75%, respectively. Calculation of an optimal cutoff value using ROC analysis (13.4 U/mL for aTTG IgA and 22.6 U/mL for aDGP IgA) increased the accuracy and reached 72.2% [95% confidence interval (CI): 46.5-90.3] sensitivity and 90% (95%CI: 79.5-96.2) specificity for aDGP IgA and 66.7% (95%CI: 41.0-86.7) sensitivity and 93.7% (95%CI: 84.5-98.2) specificity for aTTG IgA. The sensitivity and specificity of small bowel ultrasonography was 64.7% and 73.5%, respectively. A combination of serology with ultrasound imaging to predict persistent atrophy increased the positive predictive value and specificity to 88.9% and 98% for aTTG IgA and to 90.0% and 97.8% for aDGP IgA. Laboratory and clinical parameters had poor predictive values. CONCLUSION The sensitivity, specificity, and negative predictive value of aTTG and aDGP for predicting persistent VA improved by calculating the best cutoff values. The combination of serology and experienced bowel ultrasound examination may achieve better accuracy for the detection of atrophy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Non-invasive prediction of persistent villous atrophy in celiac disease

Packová

Kovalčíková

Pavlovský

et al. 2020

WJG

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“…Related research into tTG’s role in celiac disease has been quite active as well. Many studies have focused upon tTG antibodies, and crosslinked gliadin, as diagnostic tools [55,56] . Others have investigated systems in which activated tTG might be inhibited to model celiac disease, with one example being Caco-2 intestinal cancer cells, which express crosslinking-competent tTG on their surface [57,58] .…”

Section: Several Roles Of Ttg In Diseasementioning

confidence: 99%

Opening up about Tissue Transglutaminase: When Conformation Matters More than Enzymatic Activity

Katt

Antonyak

Cerione

2018

Med One

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Tissue transglutaminase (tTG), also referred to as type 2 transglutaminase or Gα h , can bind and hydrolyze GTP, as well as function as a protein crosslinking enzyme. tTG is widely expressed and can be detected both inside cells and in the extracellular space. In contrast to many enzymes, the active and inactive conformations of tTG are markedly different. The catalytically inactive form of tTG adopts a compact "closed-state" conformation, while the catalytically active form of the protein adopts an elongated "open-state" conformation. tTG has long been appreciated as an important player in numerous diseases, including celiac disease, neuronal degenerative diseases, and cancer, and its roles in these diseases often depend as much upon its conformation as its catalytic activity. While its ability to promote these diseases has been traditionally thought to be dependent on its protein crosslinking activity, more recent findings suggest that the conformational state tTG adopts is also important for mediating its effects. In particular, we and others have shown that the closed-state of tTG is important for promoting cell growth and survival, while maintaining tTG in the open-state is cytotoxic. In this review, we examine the two unique conformations of tTG and how they contribute to distinct biological processes. We will also describe how this information can be used to generate novel therapies to treat diseases, with a special focus on cancer.

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“…TGM2 deamidates Gln (Q) to Glu (E) in the gliadin which increases its affinity to the HLA‐DQ2 or HLA‐DQ8 molecules on antigen‐presenting cells 1 . Then antibodies against TGM2, gliadin, cross‐linked TGM2‐gliadin (called neoepitope) and actin develop through unclear mechanisms 1,9 . The epitopes of TGA and the biological effects of TGA have been intensively investigated, 8 while the TGG epitopes have never been investigated.…”

Section: Introductionmentioning

confidence: 99%

“…The epitopes of TGA and the biological effects of TGA have been intensively investigated, 8 while the TGG epitopes have never been investigated. Recently, anti‐neoepitope Abs are also being used to screen CD demonstrating that TGM2 not only deamidates gliadin but also crosslinks gliadin to TGM2 9 . Although TGM2‐Abs are present in most CD patients, they are also found in non‐CD individuals with inflammatory bowel disease, viral infections, or end‐stage heart failure 8 .…”

Section: Introductionmentioning

confidence: 99%

HLA‐DQ genotype and biochemical characterization of anti‐transglutaminase 2 antibodies in patients with type 1 diabetes mellitus in Taiwan

et al. 2020

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Human Leukocyte Antigen (HLA)‐DQ2 and HLA‐DQ8 are genetic risk factors for Type 1 Diabetes Mellitus (T1DM) and Celiac disease (CD) in Caucasians, but their association with Taiwanese Han population is unknown. We screened 532 Taiwanese T1DM patients for CD biomarkers including anti‐tissue transglutaminase (TGM2), anti‐gliadin and anti‐neoepitope antibodies (Abs), sequencing DQB1 genotypes, and characterized the TGM2 Abs. We report that 3.76% of Taiwanese patients had TGM2‐Abs and all had no CD's symptoms. In contrast to Caucasian's CD patients, DQ2/DQ8 only constituted ~4/5 of TGM2‐Abs positive patients, while the other ~1/5 patients belonged to different HLA genotypes. Either anti‐gliadin or anti‐neoepitope Abs coexisted with ~3/4 of TGM2‐Abs positive patients that were likely due to gluten‐ingestion, while the cause of TGM2‐Abs production for other ~1/4 of patients was unknown. Purified anti‐TGM2 IgA (TGA) and anti‐TGM2 IgG (TGG) could bind on endothelial cells surface, recognized native better than denatured forms of TGM2, and TGA inhibited TGM2’s transamidation activity by up to 80% but TGG had no effects. Epitope mapping of all TGM2‐Abs positive sera demonstrated that TGM2‐Abs had heterogeneity in specificities. This is the first study on the differences between Taiwanese Han group and Caucasian in HLA genotypes and properties of TGM2‐Abs.

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Synthetic Neoepitopes of the Transglutaminase–Deamidated Gliadin Complex as Biomarkers for Diagnosing and Monitoring Celiac Disease

Cited by 33 publications

References 50 publications

Non-invasive prediction of persistent villous atrophy in celiac disease

Non-invasive prediction of persistent villous atrophy in celiac disease

Opening up about Tissue Transglutaminase: When Conformation Matters More than Enzymatic Activity

HLA‐DQ genotype and biochemical characterization of anti‐transglutaminase 2 antibodies in patients with type 1 diabetes mellitus in Taiwan

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