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Large Gliadin Peptides Detected in the Pancreas of NOD and Healthy Mice Following Oral Administration

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Large Gliadin Peptides Detected in the Pancreas of NOD and Healthy Mice Following Oral Administration Hindawi Publishing Corporation Journal of Diabetes Research Volume 2016, Article ID 2424306, 11 pages http://dx.doi.org/10.1155/2016/2424306 Research Article Large Gliadin Peptides Detected in the Pancreas of NOD and Healthy Mice following Oral Administration Susanne W. Bruun,1 Knud Josefsen,1 Julia T. Tanassi,2 Aleš Marek,3,4 Martin H. F. Pedersen,3 Ulrik Sidenius,5 Martin Haupt-Jorgensen,1 Julie C. Antvorskov,1 Jesper Larsen,1 Niels H. Heegaard,2 and Karsten Buschard1 1 The Bartholin Institute, Rigshospitalet, Copenhagen N, Denmark 2Clinical Biochemistry, Immunology & Genetics, Statens Serum Institut, Copenhagen S, Denmark 3The Hevesy Laboratory, DTU Nutech, Technical University of Denmark, Roskilde, Denmark 4Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague 6, Czech Republic 5Enzyme Purification and Characterization, Novozymes A/S, Bagsværd, Denmark Correspondence should be addressed to Knud Josefsen; [email protected] Received 6 May 2016; Accepted 10 August 2016 Academic Editor: Marco Songini Copyright © 2016 Susanne W. Bruun et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD mice and in non-diabetes- prone mice, it induces inflammation in the pancreatic lymph nodes, suggesting that gluten can initiate inflammation locally. Further, gliadin fragments stimulate insulin secretion from beta cells directly. Wehypothesized that gluten fragments may cross the intestinal barrier to be distributed to organs other than the gut. If present in pancreas, gliadin could interact directly with the immune system and the beta cells to initiate diabetes development. We orally and intravenously administered 33-mer and 19-mer gliadin peptide to NOD, BALB/c, and C57BL/6 mice and found that the peptides readily crossed the intestinal barrier in all strains. Several degradation products were found in the pancreas by mass spectroscopy. Notably, the exocrine pancreas incorporated large amounts of radioactive label shortly after administration of the peptides. The study demonstrates that, even in normal animals, large gliadin fragments can reach the pancreas. If applicable to humans, the increased gut permeability in prediabetes and type 1 diabetes patients could expose beta cells directly to gliadin fragments. Here they could initiate inflammation and induce beta cell stress and thus contribute to the development of type 1 diabetes. 1. Introduction inflammation. In healthy mice, gluten intake promotes a proinflammatory profile of regulatory T-cells in both mesen- A gluten-free (GF) diet reduces the incidence of diabetes teric and pancreatic lymph nodes [7]. In BALB/c and NOD in nonobese diabetic (NOD) mice and DP-BB rats [1, 2]. mice, we recently described changes in NK- and dendritic cell In humans, early exposure to gluten-containing food has populations in pancreatic lymph nodes, when comparing GF- been associated with increased risk of islet autoimmunity [3], with a gluten-containing diet [8, 9]. However, whether the and a recent case study has described a prolonged remission effects of gluten take place in the intestinal immune system period in a type 1 diabetes (T1D) patient adhering to the GF or by direct priming in the local lymph nodes and pancreas is diet [4, 5]. Finally, up to 10% of T1D patients have coeliac unknown. disorders, compared to 1% of the background population, Much evidences suggest that gliadin peptides cross the indicating a common pathogenesis in coeliac disease and T1D intestinal barrier. After gluten intake, large gliadin fragments [6]. are found in the small intestine due to partial resistance of A gluten-containing diet affects immune cells in the gliadin to digestive enzymes [10, 11]. Intestinal permeability pancreatic lymph nodes and possibly contributes to local and serum zonulin levels are increased in T1D patients even 2 Journal of Diabetes Research before clinical onset of the disease [12, 13]. This may likely chromatographic system was a 10 cm, ID 75 m, 3 mC18- enhance the entry of gliadin fragments into lamina propria A2 column (Thermo Scientific) with a flow of 300 nL/min andlymphoidtissue.Finally,enterovirusinfection,which with 0.1% formic acid as mobile phase A and 0.1% formic is associated with T1D, increases the intestinal permeability acid in acetonitrile as B. The MS scan was performed using [14]. After crossing the intestinal epithelium, it is likely that a resolution of 30000 and a scan range of 300–2000 /. gliadin peptides enter the bloodstream. This is seen for other dietary proteins such as ovalbumin when administered orally 2.4. SDS-PAGE Analysis. Sixmicereceived230–1200Ci 3 3 3 to mice [15], and, in one study, gliadin has been demonstrated of H-33-mer or H-19-mer i.v. or p.o. or 200 Ci of H- in serum and breast milk by ELISA [16], although the finding tyrosine (Perkin Elmer). Heparin-plasma was prepared from ∘ was never confirmed. tail blood at 0 C and analysed by SDS-PAGE without further The current study investigates the murine uptake and processing, after depletion of albumin and IgG using a biodistribution of 33-mer and 19-mer gliadin peptides. We commercial kit (Protea Biosciences) or after digestion with used the proline-rich 33-mer (p56–88) and 19-mer (p31– trypsin (incubation with 125 mM dithiothreitol, 0.05% SDS ∘ 49) alpha-gliadin peptides, which are resistant to digestive at 53 C, pH 7.5 for 45 min, followed by digestion with trypsin ∘ proteases [10, 11, 17] and widely studied due to their impli- (Fluka) at 37 C).Thegelwasfixedin15%formalin/25% cation in coeliac disease (CD) [18, 19]. Their transepithelial ethanol and Coomassie-stained. For fluorography, the fixed passageinvitroislowinhealthyindividualscomparedto gels were soaked in 7% glycerol and Amplify Fluorographic CD patients, in whom the fragments are transported by Reagent (GE Healthcare), each for 30 min, dried, and exposed ∘ protected transcellular transport [17, 20, 21]. We show that on Amersham Hyperfilm MP at −80 C. Subsequently, the these large gliadin peptides are present in circulation after driedgelswererehydratedin7%aceticacidfor2–4hand oral administration and that large gliadin fragments access Coomassie-stained. pancreas even in nondiabetic BALB/c and C57BL/6 mice. For scintillation counting, gel slices were excised from the This may contribute to local inflammation and beta cell stress, nonfixed gel, covered with 600 L of 30% hydrogen peroxide, ∘ which could accelerate the development of type 1 diabetes. and heated at 50 C overnight before measurement. 2. Methods 2.5. Matrix-Assisted Laser Desorption Ionization Time-of- Flight Mass Spectrometry (MALDI-TOF MS). Plasma was 2.1. Gliadin Peptides. The peptides H-LQLQPFPQPELPYP- fractionated in Amicon Ultra 10 kDa centrifugal filter QPELPYPQPELPYPQPQPF-OHY (33-mer) and H-LGQ- units (Merck Millipore), Vivaspin 500, 5 kDa filter units QQPFPPQQPYPQPQPF-OHY (19-mer), 98% pure (Schafer- (Sartorius), PD10 columns, Amicon Ultra 0.5 mL 10 kDa 3 N, Denmark), were H-labeledintheunderlinedpositions centrifugal filters, or SEP-PAK C18 Plus short cartridges using diiodotyrosine (Y(3,5-I2)) iodinated peptides by stan- (Waters), or they were ethanol-precipitated or acid-ethanol extracted. Slices from nonfixed gels were extracted overnight dardtechnique[22,23].TheyweredissolvedinDMSO,mixed ∘ with 10% palladium on carbon catalyst, and subjected to 10 Ci at 37 Cin100Lof50mMNH4CO3 with or without tritium gas in a tritium manifold system (RC Tritec) for 2 h at 12.5 ng/L Endoproteinase Glu-C Sequencing Grade (Roche room temperature, then purified by HPLC, and conserved by Diagnostics). The gel slices were further extracted ona addition of 50 mM ascorbic acid. pH was 7.5 for intravenous shaker for 15 min in 20 L extraction buffer (1 : 2 (vol/vol) use (i.v.) and 6 for peroral (p.o.) use. Radiochemical stability 50 mM NH4HCO3/acetonitrile). The extracts were com- was 10 days, during which the animal experiments were bined. performed. Samples were dried in a vacuum concentrator (Eppendorf 5301) and reconstituted in 20 L 5% acetic acid before 2.2. Mice. BALB/cA BomTac (males), C57BL/6JBomTac desalting using POROS C18 matrix and elution onto a (males), and NOD/MrkTac mice were purchased from stainless steel 96-well MALDI target plate with 1 L - Taconic Europe A/S, Ejby, Denmark, kept in an SPF animal cyano-4-hydroxycinnamic acid (HCCA matrix) ready-made facility and fed standard Altromin 1324 diet. NOD mice were from Agilent (6 mg/mL in 30% acetonitrile, 30% methanol, bred in the same facility. Animal experiments were approved and 0.1% TFA) for dried droplet crystallization. Analysis by the Danish Animal Experiments Inspectorate and exper- wasdoneonBrukerUltraflexwithDaltonicsflexAnaly- iments performed according to international guidelines for sis software, externally calibrated using a standard pep- thecareanduseoflaboratoryanimals. tide mixture (Bruker, range: 1,000–3,200 Da). Spectra were recorded in positive linear mode and summed from 100 laser 2.3. Liquid Chromatography-Mass Spectrometry (LC-MS). shots. BALB/c mice, 4–16 weeks of age, were given 650–900 gof The MS mass of 84 fragments >800 Da was calculated. 33-mer, either i.v. or p.o., and heparin-plasma was prepared They were randomly generated from the 33-mer sequence, ∘ 15–60 min later at 0 C. Protein inhibitors were added to allowing for deamidation of up to two glutamine residues the tissues that were homogenized, mixed with internal (only one deamidation for Mr <1500 Da) and for sodium standard (GENESEQP:AZF58701), and precipitated with 50% andpotassiumionadductformation.Measuredmasseswere methanol, 1% TFA, and centrifugation. The samples were matchedtothepredictedmasses,usingadifferenceof analyzed using an Orbitrap XL (Thermo Scientific) equipped <0.5 Da as threshold. Masses from negative control samples with a Nano LC (Easy nLC II, Thermo Scientific). The were matched using a threshold of 1.0 and removed.
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