Keywords
tissue transglutaminase
autoimmune disease
enzymatic therapy
gliadin
How to Cite
Abstract
Gluten is a digestion-resistant glycoprotein due to its amino acid composition. Celiac disease is an immunological response to gluten in genetically predisposed individuals, affecting 1% of the Western population and causing a variety of gastrointestinal symptoms. The aim of this review is to supply a comprehensive view of celiac disease, addressing its etiology and treatments beyond a gluten-free diet. The immunological response is triggered when MHC-II presents gluten peptides, with CD4+ T cells playing a crucial role in producing proinflammatory cytokines. Genetics also play a significant role, with genetic markers like HLA-DQ2 and HLA-DQ8 increasing susceptibility to the disease. Furthermore, the enzyme tissue transglutaminase (tTG) plays a relevant role in gliadin deamidation and autoantibody production. Regarding available treatment alternatives, oral enzymatic therapy stands out, aiming to complement the effectiveness of gluten-free diets by enzymatic cleavage of gluten fragments for detoxification. Other treatment options include RNA interference or CRISPR-Cas9, which look to reduce gluten production in plants to make them more digestible, and the inhibition of tTG or vaccines aimed to induce immune tolerance to gluten.
References
1. Cobos OJ, Hernández GA, Remes JM. Trastornos relacionados con el gluten: panorama actual. Med Interna Mex 2017;33(4):487-502. ISSN 0186-4866
2. Biesiekierski JR. What is gluten? J gastroenterol hepatol 2017; 32(S1):78-81, https://doi.org/10.1111/jgh.13703
3. Torres S, Martínez Z. Base genética de la enfermedad celíaca en el diagnóstico. Rev Cubana Med 2012;51(2):170-182. ISSN 0034-7523
4. Pietzak M, Kerner JA. Celiac Disease, Wheat Allergy, and Gluten Sensitivity. JPEN. J Parenter Enteral Nutr 2012;36:68S-75S, https://doi.org/10.1177/0148607111426276
5. Jiménez AI, Martínez RM, Quiles MJ, Majid JA, González MJ. Enfermedad celiaca y nuevas patologías relacionadas con el gluten. Nutr Hosp 2016;33(suppl 4):44-48, https://doi.org/10.20960/nh.345
6. du Pré MF, Sollid LM. T-cell and B-cell immunity in celiac disease. Best Pract Res Clin Gastroenterol 2015;29(3):413-423, https://doi.org/10.1016/j.bpg.2015.04.001
7. Wosen JE, Mukhopadhyay D, Macaubas C, Mellins ED. Epithelial MHC Class II Expression and Its Role in Antigen Presentation in the Gastrointestinal and Respiratory Tracts. Front Immunol 2018;9:2144, https://doi.org/10.3389/fimmu.2018.02144
8. Gianfrani C, Auricchio S, Troncone R. Adaptive and innate immune responses in celiac disease. Immunol Lett 2005;99(2):141-145, https://doi.org/10.1016/j.imlet.2005.02.017
9. Meresse B, Malamut G, Cerf-Bensussan N. Celiac Disease: An Immunological Jigsaw. Immunity 2012;36(6):907-919, https://doi.org/10.1016/j.immuni.2012.06.006
10. Qiao S, Iversen R, Ráki M, Sollid LM. The adaptive immune response in celiac disease. Semin Immunopathol 2012;34(4):523-540, https://doi.org/10.1007/s00281-012-0314-z
11. Di Sabatino A, Vanoli A, Giuffrida P, Luinetti O, Solcia E, Corazza GR. The function of tissue transglutaminase in celiac disease. AutoinmunRev 2012;11(10):746-753, https://doi.org/10.1016/j.autrev.2012.01.007
12. Calle Idl, Ros G, Peñalver R, Nieto G. Enfermedad celiaca: causas, patología y valoración nutricional de la dieta sin gluten. Revisión. Nutr Hosp 2020;37(5):1043-1051, https://doi.org/10.20960/nh.02913
13. Rashtak S, Murray JA. Review article: coeliac disease, new approaches to therapy. Aliment pharmacol ther 2012;35(7):768-781, https://doi.org/10.1111/j.1365-2036.2012.05013.x
14. Shetty R, Vestergaard M, Jessen F, Hägglund P, Knorr V, Koehler P, Prakash HS, Hobley T. Discovery, cloning and characterisation of proline specific prolyl endopeptidase, a gluten degrading thermo-stable enzyme from Sphaerobacter thermophiles. Enzyme microb technol 2017;107:57-63, https://doi.org/10.1016/j.enzmictec.2017.08.002
15. Stoven S, Murray JA, Marietta E. Celiac Disease: Advances in Treatment via Gluten Modification. Clin gastroenterol hepatol 2012;10(8):859-862, 10.1016/j.cgh.2012.06.005
16. Yoosuf S, Makharia GK. Chapter 11 - Treatment of gluten-related disorders. In: Rostami-Nejad M, editor. Gluten-Related Disorders: Academic Press; 2022. p. 149-182, https://doi.org/10.1016/B978-0-12-821846-4.00006-1
17. Balakireva AV, Zamyatnin AA. Properties of Gluten Intolerance: Gluten Structure, Evolution, Pathogenicity and Detoxification Capabilities. Nutrients; 2016;8(10): 644:1–28, https://doi.org/10.3390/nu8100644
18. Kumar J, Kumar M, Pandey R, Chauhan NS. Physiopathology and Management of Gluten‐Induced Celiac Disease. J Food Sci 2017;82(2):270-277, https://doi.org/10.1111/1750-3841.13612
19. Moreno Amador MdL, Arévalo-Rodríguez M, Durán EM, Martínez Reyes JC, Sousa Martín C. A new microbial gluten-degrading prolyl endopeptidase: Potential application in celiac disease to reduce gluten immunogenic peptides. PLoS ONE 2019;14(6):e0218346, https://doi.org/10.1371/journal.pone.0218346
20. Sestak K, Thwin H, Dufour J, Liu DX, Alvarez X, Laine D, et al. Supplementation of Reduced Gluten Barley Diet with Oral Prolyl Endopeptidase Effectively Abrogates Enteropathy-Associated Changes in Gluten-Sensitive Macaques. Nutrients 2016;8(7):401:1-13, https://doi.org/10.3390/nu8070401
21. Szaflarska-Popławska A. Non-dietary methods in the treatment of celiac disease. Prz Gastroenterol 2015;10(1):12-17, https://doi.org/10.5114/pg.2014.47503
22. Kocadag Kocazorbaz E, Zihnioglu F. Purification, characterization, and the use of recombinant prolyl oligopeptidase from Myxococcus xanthus for gluten hydrolysis. Protein Expr Purif 2017;129:101-107, https://doi.org/10.1016/j.pep.2016.09.016
23. S. Yoosuf and G. K. Makharia. Evolving Therapy for Celiac Disease. Frontier Paeditric 2019. 14:7:143, https://doi.org/10.3389/fped.2019.00193
24. Lähdeaho M, Kaukinen K, Laurila K, Vuotikka P, Koivurova O, Kärjä-Lahdensuu T, et al. Glutenase ALV003 Attenuates Gluten-Induced Mucosal Injury in Patients With Celiac Disease. Gastroenterology 2014;146(7):1649-1658, https://doi.org/10.1053/j.gastro.2014.02.031
25. König J, Holster S, Bruins MJ, Brummer RJ. Randomized clinical trial: Effective gluten degradation by Aspergillus niger-derived enzyme in a complex meal setting. Sci Rep 2017;7(1):13100-7, https://doi.org/10.1038/s41598-017-13587-7
26. Wolf C, Siegel JB, Tinberg C, Camarca A, Gianfrani C, Paski S, et al. Engineering of Kuma030: A Gliadin Peptidase That Rapidly Degrades Immunogenic Gliadin Peptides in Gastric Conditions. J Am Che Soc 2015;137(40):13106-13113, https://doi.org/10.1021/jacs.5b08325
27. Cavaletti L, Taravella A, Carrano L, Carenzi G, Sigurtà A, Solinas N, et al. E40, a novel microbial protease efficiently detoxifying gluten proteins, for the dietary management of gluten intolerance. Sci Rep 2019;9(1):13147, https://doi.org/10.1038/s41598-019-48299-7
28. Janssen G, Christis C, Kooy-Winkelaar Y, Edens L, Smith D, van Veelen P, et al. Ineffective Degradation of Immunogenic Gluten Epitopes by Currently Available Digestive Enzyme Supplements. PLoS ONE 2015;10(6):e0128065, https://doi.org/10.1371/journal.pone.0128065
29. Segura V, Carnicer AR, Martín CS, Amador MLM. Nuevos horizontes para la enfermedad celiaca: terapias no dietéticas. RESCIFAR Revista Española de Ciencias Farmacéuticas 2020;1(2):196-209. ISSN 2660-6356
30. Sánchez-León S, Gil-Humanes J, Ozuna CV, Giménez MJ, Sousa C, Voytas DF, et al. Low-gluten, nontransgenic wheat engineered with CRISPR/Cas9. Plant Biotechnol J 2018;16(4):902-910, https://doi.org/10.1111/pbi.12837
31. Picozzi C, Mariotti M, Cappa C, Tedesco B, Vigentini I, Foschino R, et al. Development of a Type I gluten-free sourdough. Lett App Microbiol 2016;62(2):119-125, https://doi.org/10.1111/lam.12525
32. Moscoso F, Quera R. Enfermedad celíaca. revisión. Rev Med Chile 2016;144(2):211-221, http://dx.doi.org/10.4067/S0034-98872016000200010
33. Alhassan E, Yadav A, Kelly C, Mukherjee R. Novel Nondietary Therapies for Celiac Disease. Cell Mol Gastroenterol Hepatol 2019; 8(3):335-345, https://doi.org/10.1016/j.jcmgh.2019.04.017
34. Lähdeaho ML, Scheinin M, Vuotikka P, Taavela J, Popp A, Laukkarinen J, et al. Safety and efficacy of AMG 714 in adults with coeliac disease exposed to gluten challenge: a phase 2a, randomised, double-blind, placebo-controlled study. Lancet Gastroenterol Hepatol 2019;12:948-959, https://doi.org/10.1016/s2468-1253(19)30264-x
35. Tye-Din JA, Stewart JA, Dromey JA, Beissbarth T, van Heel DA, Tatham A, et al. Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease. Sci Transl Med 2010;2(41):41ra51, https://doi.org/10.1126/scitranslmed.3001012
36. Daveson AJM, Ee HC, Andrews JM, King T, Goldstein KE, Dzuris JL, et al. Epitope-Specific Immunotherapy Targeting CD4-Positive T Cells in Celiac Disease: Safety, Pharmacokinetics, and Effects on Intestinal Histology and Plasma Cytokines with Escalating Dose Regimens of Nexvax2 in a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study. EBioMedicine 2017;26:78-90, https://doi.org/10.1016/j.ebiom.2017.11.018