@article {10416, title = {Anti-transglutaminase 6 Antibody Development in Children With Celiac Disease Correlates With Duration of Gluten Exposure.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {66}, year = {2018}, month = {2018 Jan}, pages = {64-68}, abstract = {

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.

}, issn = {1536-4801}, doi = {10.1097/MPG.0000000000001642}, author = {De Leo, Luigina and Aeschlimann, Daniel and Hadjivassiliou, Marios and Aeschlimann, Pascale and Salce, Nicola and Vatta, Serena and Ziberna, Fabiana and Cozzi, Giorgio and Martelossi, Stefano and Ventura, Alessandro and Not, Tarcisio} } @article {1602, title = {The active Zot domain (aa 288-293) increases ZO-1 and myosin 1C serine/threonine phosphorylation, alters interaction between ZO-1 and its binding partners, and induces tight junction disassembly through proteinase activated receptor 2 activation.}, journal = {FASEB J}, volume = {25}, year = {2011}, month = {2011 Jan}, pages = {144-58}, abstract = {

Vibrio cholerae-derived zonula occludins toxin (Zot) is a multifunctional protein that reversibly disassembles intestinal tight junctions (tjs). Zot structure-function analysis has mapped this activity to aa 288-293, named AT1002. AT1002 reduced transepithelial electrical resistance across rat small intestine, ex vivo, as did Zot and its processed mature form, ΔG. AT1002 increased in vivo permeability to sugar tracers, whereas scrambled control peptides did not. Binding and barrier assays in proteinase activated receptor (PAR)(2)-expressing and PAR(2)-null cells established AT1002 activity to be PAR(2) dependent. Coincident with the increased intestinal permeability, confocal microscopy of AT1002-exposed rat intestinal IEC6 cells revealed displacement of ZO-1 and occludin from intercellular boundaries. In coimmunoprecipitation assays, AT1002 decreased ZO-1-occludin and ZO-1-claudin 1 interactions coincident with PKCα-dependent ZO-1 serine/threonine phosphorylation. Further, AT1002 increased serine phosphorylation of myosin 1C and, at the same time, transiently diminished its association with ZO-1. The COOH-terminal domain of ZO-1 was required for its association with myosin 1C. These data indicate that the NH(2)-terminal portion of active Zot contains a PAR(2)-activating motif, FCIGRL, that increases PKCα-dependent ZO-1 and myosin 1C serine/threonine phosphorylation. These modifications provoke selective disengagement of ZO-1 from its binding partners, occludin, claudin 1, and myosin 1C, coincident with opening of tjs.

}, keywords = {Amino Acid Sequence, Animals, Caco-2 Cells, Cell Line, Cells, Cultured, Cholera Toxin, Epithelial Cells, Humans, Immunoblotting, Male, Membrane Proteins, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Myosins, Oligopeptides, Phosphoproteins, Phosphorylation, Protein Binding, Protein Kinase C-alpha, Rats, Rats, Wistar, Receptor, PAR-2, RNA Interference, Serine, Threonine, Tight Junctions, Zonula Occludens-1 Protein}, issn = {1530-6860}, doi = {10.1096/fj.10-158972}, author = {Goldblum, Simeon E and Rai, Usha and Tripathi, Amit and Thakar, Manjusha and De Leo, Luigina and Di Toro, Nicola and Not, Tarcisio and Ramachandran, Rithwik and Puche, Adam C and Hollenberg, Morley D and Fasano, Alessio} } @article {1794, title = {Ages of celiac disease: from changing environment to improved diagnostics.}, journal = {World J Gastroenterol}, volume = {17}, year = {2011}, month = {2011 Aug 28}, pages = {3665-71}, abstract = {

From the time of Gee{\textquoteright}s landmark writings, the recent history of celiac disease (CD) can be divided into many ages, each driven by a diagnostic advance and a deeper knowledge of disease pathogenesis. At the same time, these advances were paralleled by the identification of new clinical patterns associated with CD and by a continuous redefinition of the prevalence of the disease in population. In the beginning, CD was considered a chronic indigestion, even if the causative food was not known; later, the disease was proven to depend on an intolerance to wheat gliadin, leading to typical mucosal changes in the gut and to a malabsorption syndrome. This knowledge led to curing the disease with a gluten-free diet. After the identification of antibodies to gluten (AGA) in the serum of patients and the identification of gluten-specific lymphocytes in the mucosa, CD was described as an immune disorder, resembling a chronic "gluten infection". The use of serological testing for AGA allowed identification of the higher prevalence of this disorder, revealing atypical patterns of presentation. More recently, the characterization of autoantibodies to endomysium and to transglutaminase shifted the attention to a complex autoimmune pathogenesis and to the increased risk of developing autoimmune disorders in untreated CD. New diagnostic assays, based on molecular technologies, will introduce new changes, with the promise of better defining the spectrum of gluten reactivity and the real burden of gluten related-disorders in the population. Herein, we describe the different periods of CD experience, and further developments for the next celiac age will be proposed.

}, keywords = {Autoantibodies, Celiac Disease, Diet, Gluten-Free, Gliadin, Glutens, History, 19th Century, History, 20th Century, History, 21st Century, History, Ancient, History, Medieval, Humans, Transglutaminases}, issn = {2219-2840}, doi = {10.3748/wjg.v17.i32.3665}, author = {Tommasini, Alberto and Not, Tarcisio and Ventura, Alessandro} } @article {1626, title = {Anti transglutaminase antibodies cause ataxia in mice.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010}, pages = {e9698}, abstract = {

BACKGROUND: Celiac disease (CD) is an autoimmune gastrointestinal disorder characterized by the presence of anti-transglutaminase 2 (TG2) and anti-gliadin antibodies. Amongst the neurological dysfunctions associated with CD, ataxia represents the most common one.

METHODS: We analyzed by immunohistochemistry, the anti-neural reactivity of the serum from 20 CD patients. To determine the role of anti-TG2 antibodies in ataxia, two anti-TG2 single chain variable fragments (scFv), isolated from a phage-display IgA antibody library, were characterized by immunohistochemistry and ELISA, and injected in mice to study their effects on motor coordination. We found that 75\% of the CD patient population without evidence of neurological involvement, has circulating anti-neural IgA and/or IgG antibodies. Two anti-TG2 scFvs, cloned from one CD patient, stained blood vessels but only one reacted with neurons. This anti-TG2 antibody showed cross reactivity with the transglutaminase isozymes TG3 and TG6. Intraventricular injection of the anti-TG2 or the anti-TG2/3/6 cross-reactive scFv provoked transient, equally intensive ataxia in mice.

CONCLUSION: The serum from CD patients contains anti-TG2, TG3 and TG6 antibodies that may potentially cause ataxia.

}, keywords = {Adult, Animals, Antibodies, Ataxia, Autoimmune Diseases, Brain, Celiac Disease, Female, Gliadin, Humans, Isoenzymes, Male, Mice, Mice, Inbred C57BL, Middle Aged, Motor Skills, Rats, Rats, Sprague-Dawley, Transglutaminases}, issn = {1932-6203}, doi = {10.1371/journal.pone.0009698}, author = {Boscolo, Sabrina and Lorenzon, Andrea and Sblattero, Daniele and Florian, Fiorella and Stebel, Marco and Marzari, Roberto and Not, Tarcisio and Aeschlimann, Daniel and Ventura, Alessandro and Hadjivassiliou, Marios and Tongiorgi, Enrico} }