Natural History of Antibodies to Deamidated Gliadin Peptides and Transglutaminase in Early Childhood Celiac Disease

Liu, Edwin; Li, Marcella; Emery, Lisa M.; Taki, Iman; Barriga, Katherine; Tiberti, Claudio; Eisenbarth, George S.; Rewers, Marian; Hoffenberg, Edward J.

doi:10.1097/mpg.0b013e31806c7b34

Cited by 87 publications

(76 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…On the one hand, the presence of DGP-positive children in the biopsy-negative group may actually indicate that these children will develop CD later in life. There are reports documenting DGP Abs preceding tTG-IgA (22). Our study does not include follow-up.…”

Section: Discussionmentioning

confidence: 88%

Performance of Serology Assays for Diagnosing Celiac Disease in a Clinical Setting

Parizade

Bujanover

Weiss

et al. 2009

Clin Vaccine Immunol

View full text Add to dashboard Cite

Diagnosis of celiac disease frequently depends upon serology assays. We set out to prospectively assess the diagnostic value of five serology tests: an enzyme-linked immunosorbent assay (ELISA) for tissue transglutaminase (tTG)-immunoglobulin A (IgA) and tTG-IgG, a chemiluminescence assay for tTG-IgA, an ELISA for deamidated gliadin peptide (DGP) IgG and IgA screening, and detection of endomysial antibodies (Abs) by indirect immunofluorescence. One hundred sixteen children at high risk for developing celiac disease were evaluated clinically and underwent small bowel biopsies and blood serology tests. We examined differences between younger and older children in terms of clinical presentation, test performance, and the ability of high Ab levels to correctly predict diagnosis of celiac disease. Celiac disease was diagnosed for 85 (73%) children. No significant clinical differences were observed between the biopsy-positive and biopsy-negative groups. Children <3 years of age revealed higher concentrations of tTG-IgA and DGP Abs than children >3 years old (P ‫؍‬ 0.017 and 0.007, respectively). High Ab concentrations were predictive of villous atrophies, with sensitivities ranging from 92.8% to 97.9%, depending on the assay and the cutoff points applied. Sensitivities, specificities, positive predictive values, and negative predictive values varied among assays and improved after correction for best cutoff points. Assay specificities obtained in the clinical setting were lower than expected. The new tTG-IgA chemiluminescence assay demonstrated high throughput but low specificity (74.2%). The tTG-IgA ELISA exhibited the highest test efficiency, and the tTG-IgA chemiluminescence assay was suitable for large-scale screening, with reduced specificity. High concentrations of celiac disease-specific Abs bring into question the need for performance of biopsies on children at high risk.

show abstract

Section: Discussionmentioning

confidence: 88%

Performance of Serology Assays for Diagnosing Celiac Disease in a Clinical Setting

Parizade

Bujanover

Weiss

et al. 2009

Clin Vaccine Immunol

View full text Add to dashboard Cite

show abstract

“…The DGP concentrations declined and became negative more rapidly than the tTG concentrations. This difference in Ab kinetics has been described earlier (2,8).…”

mentioning

confidence: 83%

Positive Deamidated Gliadin Peptide Antibodies and Negative Tissue Transglutaminase IgA Antibodies in a Pediatric Population: To Biopsy or Not To Biopsy

Parizade

Shainberg

2010

Clin Vaccine Immunol

View full text Add to dashboard Cite

Reports from our clinical laboratory database show that 75% of children <2 years old tested for celiac serology who were found positive for deamidated gliadin peptide (DGP) antibodies had negative results for tissue transglutaminase IgA. DGP levels were shown to decline and disappear without a gluten-free diet. This observation questions DGP's specificity for diagnosis of celiac disease.Celiac serology tests are the necessary tool for correctly referring individuals for duodenal biopsies when diagnosing celiac disease (4). Testing for tissue transglutaminase IgA (tTG) antibodies (Abs) is currently the test of choice used for this purpose (5, 17). Since there are reports indicating lack of tTG sensitivity in infants (3, 7), we decided that all serum samples from infants Ͻ2 years old referred to our clinical laboratory for celiac disease testing should be additionally tested for deamidated gliadin peptide (DGP) (IgG and IgA) Abs (6, 13). Gliadin Abs exhibit weak performance (4), and endomysial IgA (EMA) testing adds limited diagnostic value to the tissue transglutaminase (tTG) assay (12,19); therefore, these assays were not included in our laboratory practice. Total IgA was measured to identify IgA deficiency (5). In many cases, inconsistency between serology results, namely, DGP positive/tTG negative, was observed. We have retrospectively analyzed this observation by contacting the referring physicians and learning the clinical outcome for these infants.Over a period of 17 months (July 2007 to December 2008), we tested serum samples from 5,036 infants (Ͻ2 years old) for celiac disease-specific Abs using two commercial enzymelinked immunosorbent assay (ELISA) kits, one for DGP Abs (Quanta Lite DGP IgGϩIgA screen [Inova Diagnostics, San Diego, CA]: intraassay coefficient of variation [CV], 0.5 to 4.7%; interassay CV, 2.4 to 5.8%; standard deviation, 0.1 to 3.8) and one for tTG Abs (Celikey tTG-IgA; Phadia, Freiburg, Germany). We compiled reports from the laboratory's database, listing all infants with contradicting positive and negative results.The DGP results were positive in 202 infants; of these, only 35 (17%) were positive for tTG (Fig. 1). Positive results for both Ab entities are highly suggestive of celiac disease and indicate the desirability of performing duodenal biopsies. Since these cases were not of interest in our study, no further follow-up was conducted. IgA deficiency (IgA at Ͻ6 mg/dl, determined with a BNII nephelometer; Siemens) was determined in 15 (7.4%) infants. These infants were referred for biopsies in order to make a final diagnosis. In the remaining 152 (75%) infants, tTG was negative (Ͻ3 U/ml) (Fig. 1). We contacted the referring physicians in order to discover the clinical outcome in 80 of these cases with contradictory serology results. Twelve infants were referred for duodenal biopsies, mainly due to their physician's approach, claiming that when clinical features are present, one positive serology measurement is an adequate indication for performing biopsies. Celiac disease was diagn...

show abstract

“…The primary antibody response in infants targets deamidated gliadin peptides (30) in which certain glutamines have been changed to glutamic acids. Some of these antibodies cross-reacted also with TG2 in an earlier study and TG2-specific mAbs recognized a complex of three-dimensionally shaped deamidated gliadin peptides indicating molecular mimicry (22).…”

Section: Discussionmentioning

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.

View full text Add to dashboard Cite

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

show abstract

Natural History of Antibodies to Deamidated Gliadin Peptides and Transglutaminase in Early Childhood Celiac Disease

Abstract: Measuring DGP antibodies may be more useful than TGAA in monitoring children on a gluten-free diet. DGP antibodies can precede the appearance of TGAA in some at-risk children.

Cited by 87 publications

References 27 publications

Performance of Serology Assays for Diagnosing Celiac Disease in a Clinical Setting

Performance of Serology Assays for Diagnosing Celiac Disease in a Clinical Setting

Positive Deamidated Gliadin Peptide Antibodies and Negative Tissue Transglutaminase IgA Antibodies in a Pediatric Population: To Biopsy or Not To Biopsy

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

Contact Info

Product

Resources

About