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2. Efficacy and safety of gluten peptide-based antigen-specific immunotherapy (Nexvax2) in adults with coeliac disease after bolus exposure to gluten (RESET CeD): an interim analysis of a terminated randomised, double-blind, placebo-controlled phase 2 study

Author

Adams, Atoya, Andrews, Jane M, Behrend, Clint E, Brown, Gregor J E, Chen Yi Mei, Swee Lin, Coates, Allan G, DiMarino, Anthony J, Ee, Hooi, Elliott, David E, Epstein, Roger M, Feyen, Bryan John, Fogel, Ronald P, Friedenberg, Keith Alan, Gearry, Richard B, Gerdis, Michael S, Goldstein, Michael J, Gupta, Vipin K, Holmes, Robert John, Holtmann, Gerald J, Idarraga, Samuel H, James, George W, King, Tim, Klein, Terry D, Kupfer, Sonia S, Lebwohl, Benjamin, Lowe, Matthew John, Murray, Joseph A, Newton, Eric B, Quinn, Dean, Radin, David M, Ritter, Timothy E, Stacey, Helen Lee, Strout, Cynthia B, Stubbs, Richard S, Thackwray, Susan Lynn, Trivedi, Vivek M, Weber, John R, Wilson, Scott A, Tye-Din, Jason A, Daveson, A James M, Goel, Gautam, Goldstein, Kaela E, Hand, Holly L, Neff, Kristin M, Popp, Alina, Taavela, Juha, Maki, Markku, Isola, Jorma, Williams, Leslie J, Truitt, Kenneth E, and Anderson, Robert P

Published
2023
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4. A B-Cell Gene Signature Correlates With the Extent of Gluten-Induced Intestinal Injury in Celiac Disease.

Author

Garber, Mitchell, Saldanha, Alok, Parker, Joel, Jones, Wendell, Kaukinen, Katri, Laurila, Kaija, Lähdeaho, Marja-Leena, Khatri, Purvesh, Khosla, Chaitan, Adelman, Daniel, and Mäki, Markku

Subjects
Autoimmunity, Cd, crypt depth, CeD, celiac disease, Mucosal Immunity, Oral Tolerance, Regulatory B Cell, TG2, transglutaminase 2, TR, T-cell receptor, Vh, villus height, Vh:Cd, ratio of villus height to crypt depth, cRNA, complementary RNA
Abstract

BACKGROUND & AIMS: Celiac disease (CeD) provides an opportunity to study autoimmunity and the transition in immune cells as dietary gluten induces small intestinal lesions. METHODS: Seventy-three celiac disease patients on a long-term, gluten-free diet ingested a known amount of gluten daily for 6 weeks. A peripheral blood sample and intestinal biopsy specimens were taken before and 6 weeks after initiating the gluten challenge. Biopsy results were reported on a continuous numeric scale that measured the villus-height-to-crypt-depth ratio to quantify gluten-induced intestinal injury. Pooled B and T cells were isolated from whole blood, and RNA was analyzed by DNA microarray looking for changes in peripheral B- and T-cell gene expression that correlated with changes in villus height to crypt depth, as patients maintained a relatively healthy intestinal mucosa or deteriorated in the face of a gluten challenge. RESULTS: Gluten-dependent intestinal damage from baseline to 6 weeks varied widely across all patients, ranging from no change to extensive damage. Genes differentially expressed in B cells correlated strongly with the extent of intestinal damage. A relative increase in B-cell gene expression correlated with a lack of sensitivity to gluten whereas their relative decrease correlated with gluten-induced mucosal injury. A core B-cell gene module, representing a subset of B-cell genes analyzed, accounted for the correlation with intestinal injury. CONCLUSIONS: Genes comprising the core B-cell module showed a net increase in expression from baseline to 6 weeks in patients with little to no intestinal damage, suggesting that these individuals may have mounted a B-cell immune response to maintain mucosal homeostasis and circumvent inflammation. DNA microarray data were deposited at the GEO repository (accession number: GSE87629; available: https://www.ncbi.nlm.nih.gov/geo/).

Published
2017

8. Multiple common variants for celiac disease influencing immune gene expression

Author

Dubois, Patrick CA, Trynka, Gosia, Franke, Lude, Hunt, Karen A, Romanos, Jihane, Curtotti, Alessandra, Zhernakova, Alexandra, Heap, Graham AR, Ádány, Róza, Aromaa, Arpo, Bardella, Maria Teresa, van den Berg, Leonard H, Bockett, Nicholas A, de la Concha, Emilio G, Dema, Bárbara, Fehrmann, Rudolf SN, Fernández-Arquero, Miguel, Fiatal, Szilvia, Grandone, Elvira, Green, Peter M, Groen, Harry JM, Gwilliam, Rhian, Houwen, Roderick HJ, Hunt, Sarah E, Kaukinen, Katri, Kelleher, Dermot, Korponay-Szabo, Ilma, Kurppa, Kalle, MacMathuna, Padraic, Mäki, Markku, Mazzilli, Maria Cristina, McCann, Owen T, Mearin, M Luisa, Mein, Charles A, Mirza, Muddassar M, Mistry, Vanisha, Mora, Barbara, Morley, Katherine I, Mulder, Chris J, Murray, Joseph A, Núñez, Concepción, Oosterom, Elvira, Ophoff, Roel A, Polanco, Isabel, Peltonen, Leena, Platteel, Mathieu, Rybak, Anna, Salomaa, Veikko, Schweizer, Joachim J, Sperandeo, Maria Pia, Tack, Greetje J, Turner, Graham, Veldink, Jan H, Verbeek, Wieke HM, Weersma, Rinse K, Wolters, Victorien M, Urcelay, Elena, Cukrowska, Bozena, Greco, Luigi, Neuhausen, Susan L, McManus, Ross, Barisani, Donatella, Deloukas, Panos, Barrett, Jeffrey C, Saavalainen, Paivi, Wijmenga, Cisca, and van Heel, David A

Subjects
Biotechnology, Human Genome, Genetics, Digestive Diseases, 2.1 Biological and endogenous factors, Aetiology, Case-Control Studies, Celiac Disease, Gene Expression, Gene Expression Profiling, Genes, MHC Class I, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Risk, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.

Published
2010

9. Trends in the prevalence rates and predictive factors of coeliac disease: A long‐term nationwide follow‐up study.

Author

Taavela, Juha, Kurppa, Kalle, Jääskeläinen, Tuija, Kaartinen, Niina E., Rissanen, Harri, Huhtala, Heini, Mäki, Markku, and Kaukinen, Katri

Subjects
CELIAC disease, DISEASE prevalence, AUTOIMMUNE diseases, COMORBIDITY, HEALTH surveys
Abstract

Summary: Background: The prevalence of coeliac disease doubled in Finland from 1980 to 2000. Aims: To investigate whether this increase is continuing and if there are specific patient‐related factors predicting the development of coeliac disease at a population level. Methods: We elicited comprehensive health data in the nationwide Health 2000 and Health 2011 surveys. Serum samples were taken for the measurement of tissue transglutaminase antibodies (TGA); subjects who were seropositive were tested for endomysial antibodies (EmA). Coeliac disease was defined either as a reported diagnosis or as positive TGA and EmA. The surveys comprised, respectively, 6379 and 4056 individuals, forming representative samples for 2,946,057 and 2,079,438 Finnish adults. Altogether 3254 individuals participating in both surveys comprised a prospective follow‐up cohort. Results: Prevalence of coeliac disease was 2.12% in 2000 and 2.40% in 2011 (p = 0.156). In the prospective cohort, 16 out of the 3254 (0.49%) subjects developed coeliac disease during follow‐up from 2000 to 2011, with an annual incidence rate of 45 per 100,000 persons. Positive TGA without EmA (OR: 133, 95% CI: 30.3–584), TGA values in the upper normal range (51.1, 16.0–163), and after adjusting for TGA, previous autoimmune co‐morbidity (8.39, 4.98–35.9) in 2000 increased the likelihood of subsequent coeliac disease. Conclusions: The nationwide prevalence of coeliac disease kept on rising from 2.12% in 2000 to 2.40% in 2011 in Finland. Positive TGA without EmA, TGA titres in the upper normal range and a pre‐existing autoimmune disease predisposed to coeliac disease during the 10‐year follow‐up. [ABSTRACT FROM AUTHOR]

Published
2024
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13. The Oral Transglutaminase 2 Inhibitor ZED1227 Accumulates in the Villous Enterocytes in Celiac Disease Patients during Gluten Challenge and Drug Treatment

Author

Isola, Jorma, primary, Mäki, Markku, additional, Hils, Martin, additional, Pasternack, Ralf, additional, Viiri, Keijo, additional, Dotsenko, Valeriia, additional, Montonen, Toni, additional, Zimmermann, Timo, additional, Mohrbacher, Ralf, additional, Greinwald, Roland, additional, and Schuppan, Detlef, additional

Published
2023
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17. Transglutaminase 2-specific coeliac disease autoantibodies induce morphological changes and signs of inflammation in the small-bowel mucosa of mice

Author

Kalliokoski, Suvi, Piqueras, Victoria Ortín, Frías, Rafael, Sulic, Ana-Marija, Määttä, Juha A. E., Kähkönen, Niklas, Viiri, Keijo, Huhtala, Heini, Pasternack, Arja, Laurila, Kaija, Sblattero, Daniele, Korponay-Szabó, Ilma R., Mäki, Markku, Caja, Sergio, Kaukinen, Katri, and Lindfors, Katri

Published
2017
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18. Latiglutenase Protects the Mucosa and Attenuates Symptom Severity in Patients With Celiac Disease Exposed to a Gluten Challenge

Author

Murray, Joseph A., primary, Syage, Jack A., additional, Wu, Tsung-Teh, additional, Dickason, Matthew A., additional, Ramos, Ana G., additional, Van Dyke, Carol, additional, Horwath, Irina, additional, Lavin, Philip T., additional, Mäki, Markku, additional, Hujoel, Isabel, additional, Papadakis, Konstantinos A., additional, Bledsoe, Adam C., additional, Khosla, Chaitan, additional, Sealey-Voyksner, Jennifer A., additional, Hinson, Chad, additional, Loskutov, Vasiliy, additional, Norum, Anna, additional, Linberg, Steven, additional, Goldkind, Lawrence, additional, Isola, Jorma, additional, Voyksner, Robert, additional, Luong, Pauline, additional, Baldwin, Matthew, additional, and Nezzer, Jennifer, additional

Published
2022
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24. Healthy and pro-inflammatory gut ecology plays a crucial role in the digestion and tolerance of a novel Gluten Friendly™ bread in celiac subjects: a randomized, double blind, placebo controlin vivostudy

Author

Andriulli, Angelo, primary, Bevilacqua, Antonio, additional, Palmieri, Orazio, additional, Latiano, Anna, additional, Fontana, Rosanna, additional, Gioffreda, Domenica, additional, Castellana, Stefano, additional, Mazza, Tommaso, additional, Panza, Anna, additional, Menzaghi, Claudia, additional, Grandone, Elvira, additional, di Mauro, Lazzaro, additional, Decina, Ivana, additional, Tricarico, Michele, additional, Musaico, Daniela, additional, Mäki, Markku, additional, Isola, Jorma, additional, Popp, Alina, additional, Taavela, Juha, additional, Petruzzi, Leonardo, additional, Sinigaglia, Milena, additional, Rosaria Corbo, Maria, additional, and Lamacchia, Carmela, additional

Published
2022
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26. A randomized trial of a transglutaminase 2 inhibitor for celiac disease

Author

Schuppan, Detlef, Mäki, Markku, Lundin, Knut E.A., Isola, Jorma, Friesing-Sosnik, Tina, Taavela, Juha, Popp, Alina, Koskenpato, Jari, Langhorst, Jost, Hovde, Øistein, Lähdeaho, Marja-Leena, Fusco, Stefano, Schumann, Michael, Török, Helga P., Kupcinskas, Juozas, Zopf, Yurdagül, Lohse, Ansgar W., Scheinin, Mika, Kull, Karin, Biedermann, Luc, Byrnes, Valerie, Stallmach, Andreas, Jahnsen, Jørgen, Zeitz, Jonas, Mohrbacher, Ralf, Greinwald, Roland, The CEC-3 Trial Group, Tampere University, Clinical Medicine, Department of Paediatrics, and BioMediTech

Subjects
medicine.medical_specialty, Tissue transglutaminase, Medizin, Stimulation, Disease, 3121 Internal medicine, Gastroenterology, law.invention, Randomized controlled trial, law, 3123 Gynaecology and paediatrics, Internal medicine, Medicine, Research article, Deamidation, chemistry.chemical_classification, biology, business.industry, nutritional and metabolic diseases, General Medicine, Gluten, digestive system diseases, Glutamine, chemistry, biology.protein, business
Abstract

Background: In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease. Methods: In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life). Results: Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P = 0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P

Published
2021

31. Genome-Wide Transcriptomic Analysis of Intestinal Mucosa in Celiac Disease Patients on a Gluten-Free Diet and Postgluten Challenge

Author

Dotsenko, Valeriia, Oittinen, Mikko, Taavela, Juha, Popp, Alina, Peräaho, Markku, Staff, Synnöve, Sarin, Jani, Leon, Francisco, Isola, Jorma, Mäki, Markku, Viiri, Keijo, Tampere University, Clinical Medicine, and BioMediTech

Subjects
Adult, Male, Glutens, Duodenum, RNA-Seq, RNA-sequencing, Biopsy, Datasets as Topic, 3121 Internal medicine, Diet, Gluten-Free, Young Adult, Gluten Challenge, 3123 Gynaecology and paediatrics, GFD, gluten-free diet, IEL, intraepithelial lymphocyte, Humans, RNA-Seq, Gluten-Free Diet, Intestinal Mucosa, Original Research, PCA, principal component analysis, DC, disease control, HLA, human leukocyte antigen, Morphometry, GIP, gluten-specific immunogenic peptide, TG2, tissue transglutaminase 2, Middle Aged, log2FC|, absolute log2-fold change, VH:CrD, villus height-to-crypt depth ratio, NGS, next-generation sequencing, Celiac Disease, Female, PGC, post–gluten challenge, Transcriptome
Abstract

Background & Aims Gluten challenge studies are instrumental in understanding the pathophysiology of celiac disease. Our aims in this study were to reveal early gluten-induced transcriptomic changes in duodenal biopsies and to find tools for clinics. Methods Duodenal biopsies were collected from 15 celiac disease patients on a strict long-term gluten-free diet (GFD) prior to and post a gluten challenge (PGC) and from 6 healthy control individuals (DC). Biopsy RNA was subjected to genome-wide 3’ RNA-Seq. Sequencing data was used to determine the differences between the three groups and was compared to sequencing data from the public repositories. The biopsies underwent morphometric analyses. Results In DC vs. GFD group comparisons, 167 differentially expressed genes were identified with 117 genes downregulated and 50 genes upregulated. In PGC vs. GFD group comparisons, 417 differentially expressed genes were identified with 195 genes downregulated and 222 genes upregulated. Celiac disease patients on a GFD were not “healthy”. In particular, genes encoding proteins for transporting small molecules were expressed less. In addition to the activation of immune response genes, a gluten challenge induced hyperactive intestinal wnt-signaling and consequent immature crypt gene expression resulting in less differentiated epithelium. Biopsy gene expression in response to a gluten challenge correlated with the extent of the histological damage. Regression models using only four gene transcripts described 97.2% of the mucosal morphology and 98.0% of the inflammatory changes observed. Conclusions Our gluten challenge trial design provided an opportunity to study the transition from health to disease. The results show that even on a strict GFD, despite being deemed healthy, patients reveal patterns of ongoing disease. Here, a transcriptomic regression model estimating the extent of gluten-induced duodenal mucosal injury is presented., Graphical abstract

Published
2021

40. Cost-effective HLA typing with tagging SNPs predicts celiac disease risk haplotypes in the Finnish, Hungarian, and Italian populations

Author

Koskinen, Lotta, Romanos, Jihane, Kaukinen, Katri, Mustalahti, Kirsi, Korponay-Szabo, Ilma, Barisani, Donatella, Bardella, Maria Teresa, Ziberna, Fabiana, Vatta, Serena, Széles, György, Pocsai, Zsuzsa, Karell, Kati, Haimila, Katri, Ádány, Róza, Not, Tarcisio, Ventura, Alessandro, Mäki, Markku, Partanen, Jukka, Wijmenga, Cisca, and Saavalainen, Päivi

Published
2009
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45. Celiac disease

Author

Popp, Alina, primary, Balaban, Daniel Vasile, additional, and Mäki, Markku, additional

Published
2021
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47. Dissecting the contribution of single nucleotide polymorphisms in CCR9 and CCL25 genomic regions to the celiac disease phenotype

Author

Airaksinen, Laura, primary, Cerqueira, Juliana XM., additional, Huhtala, Heini, additional, Saavalainen, Päivi, additional, Yohannes, Dawit A., additional, Mäki, Markku, additional, Kurppa, Kalle, additional, Kilpeläinen, Elina, additional, Shcherban, Anastasia, additional, Palotie, Aarno, additional, Kaukinen, Katri, additional, and Lindfors, Katri, additional

Published
2021
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