TY - JOUR T1 - Anti-transglutaminase 6 Antibody Development in Children With Celiac Disease Correlates With Duration of Gluten Exposure. JF - J Pediatr Gastroenterol Nutr Y1 - 2018 A1 - De Leo, Luigina A1 - Aeschlimann, Daniel A1 - Hadjivassiliou, Marios A1 - Aeschlimann, Pascale A1 - Salce, Nicola A1 - Vatta, Serena A1 - Ziberna, Fabiana A1 - Cozzi, Giorgio A1 - Martelossi, Stefano A1 - Ventura, Alessandro A1 - Not, Tarcisio AB -

OBJECTIVES: Antibodies against transglutaminase 6 (anti-TG6) have been implicated in neurological manifestations in adult patients with genetic gluten intolerance, and it is unclear whether autoimmunity to TG6 develops following prolonged gluten exposure. We measured the anti-TG6 in children with celiac disease (CD) at the diagnosis time to establish a correlation between these autoantibodies and the duration of gluten exposure. We investigated a correlation between anti-TG6 and the presence of neurological disorders.

METHODS: Anti-TG6 (IgA/IgG) were measured by ELISA in sera of children with biopsy-proven CD and of children experiencing gastrointestinal disorders. CD patients positive for anti-TG6 were retested after 2 years of gluten-free diet (GFD).

RESULTS: We analyzed the sera of 274 CD children and of 121 controls. Anti-TG6 were detected in 68/274 (25%) CD patients and in 19/121 (16%) controls, with significant difference between the 2 groups (P = 0.04). None of the CD patients and of the controls testing positive for anti-TG6 were experiencing neurological disorders. Eleven of 18 (61%) CD patients with other autoimmune diseases were positive for anti-TG6. In CD patients, a significant correlation between the gluten exposure before the CD diagnosis and anti-TG6 concentration was found (P = 0.006 for IgA; P < 0.0001 for IgG). After GFD anti-TG6 concentrations were significantly reduced (P < 0.001). No significant correlation was observed between anti-TG6 and anti-TG2 serum concentrations.

CONCLUSIONS: Anti-TG6 are more prevalent in children with untreated CD in the absence of overt neurological disorders. The synthesis of the anti-TG6 is related to a longer exposure to gluten before the CD diagnosis, and the autoimmunity against TG6 is gluten dependent and disappeared during GFD.

VL - 66 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28542044?dopt=Abstract ER - TY - JOUR T1 - Immunohistologic analysis of the duodenal bulb: a new method for celiac disease diagnosis in children. JF - Gastrointest Endosc Y1 - 2018 A1 - De Leo, Luigina A1 - Villanacci, Vincenzo A1 - Ziberna, Fabiana A1 - Vatta, Serena A1 - Martelossi, Stefano A1 - Di Leo, Grazia A1 - Zanchi, Chiara A1 - Bramuzzo, Matteo A1 - Giudici, Fabiola A1 - Ventura, Alessandro A1 - Not, Tarcisio KW - Adolescent KW - Autoantibodies KW - Celiac Disease KW - Child KW - Child, Preschool KW - Duodenum KW - Female KW - Humans KW - Immunoglobulin A KW - Immunohistochemistry KW - Infant KW - Male KW - Prospective Studies KW - Transglutaminases AB -

BACKGROUND AND AIMS: Anti-tissue transglutaminase antibodies (anti-tTG) have simplified celiac disease (CD) diagnosis. However, in atypical forms of CD, intestinal biopsy sampling is still required. This prospective study investigates whether histologic analysis of the duodenal bulb combined with intestinal IgA anti-tTG deposit immunoassay makes CD diagnosis possible in at-risk children with low concentrations of serum anti-tTG.

METHODS: Histologic and intestinal IgA anti-tTG deposit immunoassays were used.

RESULTS: Two hundred forty-five symptomatic children positive for serum anti-tTG (>7 U/mL) were enrolled and divided into 3 groups: extensive duodenal atrophy (n = 209), with IgA anti-tTG deposits throughout the duodenum and high serum anti-tTG concentrations (157 ± 178 U/mL); bulb duodenal atrophy (n = 22), with widespread IgA anti-tTG deposits in 9 and in the bulb alone in 13 and low serum anti-tTG concentrations (13.9 ± 8.7 U/mL); and normal duodenum (n = 14), with widespread IgA anti-tTG deposits in 8 and in the bulb alone in 6 and low serum anti-tTG concentrations (10.6 ± 6.2 U/mL). All patients in the first 2 groups were diagnosed with CD and 8 from the third group. All improved after 1 year of gluten-free diet. Bulb duodenal analysis led to a 12% (30/245) increase in CD diagnosis. No CD-related lesions were observed in the 30 control subjects.

CONCLUSIONS: In children at risk for CD, bulb duodenum biopsy sampling is essential to identify villous atrophy and detect IgA anti-tTG deposits even in absence of intestinal lesions. These mucosal autoantibodies could well represent a new standard for diagnosing CD.

VL - 88 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29807020?dopt=Abstract ER - TY - JOUR T1 - Cross-sectional study of coeliac autoimmunity in a population of Vietnamese children. JF - BMJ Open Y1 - 2016 A1 - Zanella, Sara A1 - De Leo, Luigina A1 - Nguyen-Ngoc-Quynh, Le A1 - Nguyen-Duy, Bo A1 - Not, Tarcisio A1 - Tran-Thi-Chi, Mai A1 - Phung-Duc, Son A1 - Le-Thanh, Hai A1 - Malaventura, Cristina A1 - Vatta, Serena A1 - Ziberna, Fabiana A1 - Mazzocco, Martina A1 - Volpato, Stefano A1 - Phung-Tuyet, Lan A1 - Le-Thi-Minh, Huong A1 - Borgna-Pignatti, Caterina AB -

OBJECTIVE: The prevalence of coeliac disease (CD) in Vietnam is unknown. To fill this void, we assessed the prevalence of serological markers of CD autoimmunity in a population of children in Hanoi.

SETTING: The outpatient blood drawing laboratory of the largest paediatric hospital in North Vietnam was used for the study, which was part of an international project of collaboration between Italy and Vietnam.

PARTICIPANTS: Children having blood drawn for any reason were included. Exclusion criteria were age younger than 2 years, acquired or congenital immune deficiency and inadequate sample. A total of 1961 children (96%) were enrolled (838 females, 1123 males, median age 5.3 years).

OUTCOMES: Primary outcome was the prevalence of positive autoimmunity to both IgA antitransglutaminase antibodies (anti-tTG) assessed with an ELISA test and antiendomysial antibodies (EMA). Secondary outcome was the prevalence of CD predisposing human leucocyte antigens (HLA) (HLA DQ2/8) in the positive children and in a random group of samples negative for IgA anti-tTG.

RESULTS: The IgA anti-tTG test was positive in 21/1961 (1%; 95% CI 0.61% to 1.53%); however, EMA antibodies were negative in all. HLA DQ2/8 was present in 7/21 (33%; 95% CI 14.5% to 56.9%) of the anti-tTG-positive children and in 72/275 (26%; 95% CI 21% to 32%) of those who were negative.

CONCLUSIONS: Coeliac autoimmunity is rare in Vietnam, although prevalence of HLA DQ2/8 is similar to that of other countries. We hypothesise that the scarce exposure to gluten could be responsible for these findings.

VL - 6 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27329441?dopt=Abstract ER - TY - JOUR T1 - Lack of Evidence of Rotavirus-Dependent Molecular Mimicry as a Trigger of Celiac Disease. JF - Clin Exp Immunol Y1 - 2016 A1 - Ziberna, Fabiana A1 - De Lorenzo, Giuditta A1 - Schiavon, Valentina A1 - Arnoldi, Francesca A1 - Quaglia, Sara A1 - De Leo, Luigina A1 - Vatta, Serena A1 - Martelossi, Stefano A1 - Burrone, Oscar R A1 - Ventura, Alessandro A1 - Not, Tarcisio AB -

New data suggest the involvement of Rotavirus (RV) in triggering autoimmunity in celiac disease (CD) by molecular mimicry between the human-transglutaminase protein and the dodecapeptide (260-271 aa) of the RV protein VP7 (pVP7). To assess the role of RV in the onset of CD, we measured the anti-pVP7 antibodies in the sera of children with CD and of control groups. We analysed serum samples of 118 biopsy proven CD patients and 46 patients with potential-CD; 32 children with other gastrointestinal diseases; 107 no-CD children and 107 blood donors. By ELISA assay, we measured IgA-IgG antibodies against the synthetic peptides pVP7, the human transglutaminase-derived peptide (476-487 aa) which shows an homology with VP7 protein and a control peptide. The triple-layered RV particles (TLPs), containing the VP7 protein, and the double-layered RV-particles (DLPs), lacking the VP7 protein were also used as antigens in ELISA assay. Antibody reactivity to the RV-TLPs was positive in 22/118 (18%) CD patients and in both paediatric (17/107, 16%) and adult (29/107, 27%) control groups, without showing a statistically significant difference among them (p=0.6, p=0.1). Biopsy-proven CD patients as well as the adult control group demonstrated a high positive antibody reactivity against both pVP7 (34/118, 29% CD patients; 66/107, 62% adult controls) and control synthetic peptides (35/118, 30% CD patients; 56/107, 52% adult controls) suggesting a non-specific response against RV pVP7. We show that children with CD do not have higher immune reactivity to RV, thus questioning the molecular mimicry mechanism as a triggering factor of CD. This article is protected by copyright. All rights reserved.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27548641?dopt=Abstract ER - TY - JOUR T1 - Serum anti-tissue transglutaminase antibodies detected during febrile illness may not be produced by the intestinal mucosa. JF - J Pediatr Y1 - 2015 A1 - De Leo, Luigina A1 - Quaglia, Sara A1 - Ziberna, Fabiana A1 - Vatta, Serena A1 - Martelossi, Stefano A1 - Maschio, Massimo A1 - Not, Tarcisio KW - Autoantibodies KW - Celiac Disease KW - Child, Preschool KW - Diagnosis, Differential KW - Enzyme-Linked Immunosorbent Assay KW - Female KW - GTP-Binding Proteins KW - Humans KW - Intestinal Mucosa KW - Male KW - Transglutaminases AB -

Anti-transglutaminase antibodies are the diagnostic marker of celiac disease, and are considered to be synthesized only by intestinal B-lymphocytes. During an infectious disease, these antibodies are transiently detected in serum. We show that these infection-triggered antibodies may not originate in the intestinal mucosa and are not an indication of celiac disease.

VL - 166 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25722272?dopt=Abstract ER - TY - JOUR T1 - Intestinal-mucosa anti-transglutaminase antibody assays to test for genetic gluten intolerance. JF - Cell Mol Immunol Y1 - 2014 A1 - Quaglia, Sara A1 - De Leo, Luigina A1 - Ziberna, Fabiana A1 - Vatta, Serena A1 - Villanacci, Vincenzo A1 - Granzotto, Marilena A1 - Petix, Vincenzo A1 - Martelossi, Stefano A1 - Di Leo, Grazia A1 - Torelli, Lucio A1 - Not, Tarcisio KW - Celiac Disease KW - Cell Surface Display Techniques KW - Child KW - Diet, Gluten-Free KW - Disease Progression KW - Early Diagnosis KW - Female KW - Follow-Up Studies KW - HLA-DQ Antigens KW - Humans KW - Immunoassay KW - Immunoglobulin A KW - Intestinal Mucosa KW - Male KW - Prospective Studies KW - Transglutaminases VL - 11 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24769794?dopt=Abstract ER - TY - JOUR T1 - Cryptic genetic gluten intolerance revealed by intestinal antitransglutaminase antibodies and response to gluten-free diet. JF - Gut Y1 - 2011 A1 - Not, Tarcisio A1 - Ziberna, Fabiana A1 - Vatta, Serena A1 - Quaglia, Sara A1 - Martelossi, Stefano A1 - Villanacci, Vincenzo A1 - Marzari, Roberto A1 - Florian, Fiorella A1 - Vecchiet, Monica A1 - Sulic, Ana-Marija A1 - Ferrara, Fortunato A1 - Bradbury, Andrew A1 - Sblattero, Daniele A1 - Ventura, Alessandro KW - Adolescent KW - Adult KW - Antibodies, Anti-Idiotypic KW - Asymptomatic Diseases KW - Celiac Disease KW - Child KW - Child, Preschool KW - Diet, Gluten-Free KW - Fatty Acid-Binding Proteins KW - Female KW - Genetic Predisposition to Disease KW - GTP-Binding Proteins KW - Health Status KW - Humans KW - Intestinal Mucosa KW - Male KW - Middle Aged KW - Peptide Library KW - Transglutaminases KW - Young Adult AB -

BACKGROUND AND OBJECTIVE: Antitransglutaminase (anti-TG2) antibodies are synthesised in the intestine and their presence seems predictive of future coeliac disease (CD). This study investigates whether mucosal antibodies represent an early stage of gluten intolerance even in the absence of intestinal damage and serum anti-TG2 antibodies.

METHODS: This study investigated 22 relatives of patients with CD genetically predisposed to gluten intolerance but negative for both serum anti-TG2 antibodies and intestinal abnormalities. Fifteen subjects were symptomatic and seven were asymptomatic. The presence of immunoglobulin A anti-TG2 antibodies in the intestine was studied by creating phage-antibody libraries against TG-2. The presence of intestinal anti-TG2 antibodies was compared with the serum concentration of the intestinal fatty acid-binding protein (I-FABP), a marker for early intestinal mucosal damage. The effects of a 12-month gluten-free diet on anti-TG2 antibody production and the subjects' clinical condition was monitored. Twelve subjects entered the study as controls.

RESULTS: The intestinal mucosa appeared normal in 18/22; 4 had a slight increase in intraepithelial lymphocytes. Mucosal anti-TG2 antibodies were isolated in 15/22 subjects (68%); in particular symptomatic subjects were positive in 13/15 cases and asymptomatic subjects in 2/7 cases (p=0.01). No mucosal antibodies were selected from the controls' biopsies. There was significant correlation between the presence of intestinal anti-TG2 antibodies and positive concentrations of I-FABP (p=0.0008). After a gluten-free diet, 19/22 subjects underwent a second intestinal biopsy, which showed that anti-TG2 antibodies had disappeared in 12/15 (p=0.002), while I-FABP decreased significantly (p<0.0001). The diet resolved both extraintestinal and intestinal symptoms.

CONCLUSIONS: A new form of genetic-dependent gluten intolerance has been described in which none of the usual diagnostic markers is present. Symptoms and intestinal anti-TG2 antibodies respond to a gluten free-diet. The detection of intestinal anti-TG2 antibodies by the phage-antibody libraries has an important diagnostic and therapeutic impact for the subjects with gluten-dependent intestinal or extraintestinal symptoms. Clinical trial number NCT00677495.

VL - 60 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21471568?dopt=Abstract ER -