Serum IL-21 levels from celiac disease patients correlates with anti-tTG IgA autoantibodies and mucosal damage

References

• Tye-Din JA, Galipeau HJ, Agardh D. Celiac disease: a review of current concepts in pathogenesis, prevention, and novel therapies. Front Pediatr. 2018;6:350–369.
   PubMed Web of Science ®Google Scholar
• Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancet. 2018;391(10115):70–81.
   PubMed Web of Science ®Google Scholar
• Ludvigsson JF, Leffler DA, Bai JC, et al. The Oslo definitions for celiac disease and related terms. Gut. 2013;62(1):43–52.
   PubMed Web of Science ®Google Scholar
• Koskinen O, Collin P, Korponay-Szabo I, et al. Glutendependent small bowel mucosal transglutaminase 2-specific IgA deposits in overt and mild enteropathy celiac disease. J Pediatr Gastroenterol Nutr. 2008;47(5):436–442.
   PubMedGoogle Scholar
• Kurppa K, Ashorn M, Iltanen S, et al. Celiac disease without villous atrophy in children: A prospective study. J Pediatr. 2010;157(3):373–380, 380.e1.
   PubMed Web of Science ®Google Scholar
• Tosco A, Salvati VM, Auricchio R, et al. Most children with potential celiac disease are healthy but one/third of them develop villous atrophy at 3 years follow-up. Clin Gastroenterol Hepatol. 2011;9(4):320–325.
   PubMedGoogle Scholar
• Sperandeo MP, Tosco A, Izzo V, et al. Potential celiac patients: a model of celiac disease pathogenesis. PLoS One. 2011;6(7):e21281.
   PubMed Web of Science ®Google Scholar
• Auricchio R, Mandile R, Del Vecchio MR, et al. Progression of celiac disease in children with antibodies against tissue transglutaminase and normal duodenal architecture. Gastroenterology. 2019;157(2):413–420.
   PubMed Web of Science ®Google Scholar
• Auricchio R, Galatola M, Cielo D, et al. A phospholipid profile at 4 months predicts the onset of celiac disease in at-risk infants. Sci Rep. 2019;9(1):14303.
   PubMedGoogle Scholar
• Borrelli M, Gianfrani C, Lania G, et al. In the intestinal mucosa of children with potential celiac disease IL-21 and IL-17A are less expressed than in the active disease. Am J Gastroenterol. 2016;111(1):134–144.
   PubMed Web of Science ®Google Scholar
• Borrelli M, Salvati VM, Maglio M, et al. Immunoregulatory pathways are active in the small intestinal mucosa of patients with potential celiac disease. Am J Gastroenterol. 2013;108(11):1775–1784.
   PubMed Web of Science ®Google Scholar
• Jabri B, Sollid LM. T cells in celiac disease. J Immunol. 2017;198(8):3005–3014.
   PubMed Web of Science ®Google Scholar
• Jabri B, Chen X, Sollid LM. How T cells taste gluten in celiac disease. Nat Struct Mol Biol. 2014;21(5):429–431.
   PubMed Web of Science ®Google Scholar
• Gianfrani C, Levings MK, Sartirana C, et al. Gliadin-specific type 1 regulatory T cells from the intestinal mucosa of treated celiac patients inhibit pathogenic T cells. J Immunol. 2006;177(6):4178–4186.
   PubMed Web of Science ®Google Scholar
• O’Garra A, Vieira P. T(H)1 cells control themselves by producing interleukin-10. Nat Rev Immunol. 2007;7:425–428.
   PubMed Web of Science ®Google Scholar
• Nilsen EM, Jahnsen FL, Lundin KE, et al. Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology. 1998;115(3):551–563.
   PubMed Web of Science ®Google Scholar
• Salvati VM, MacDonald TT, Bajaj-Elliott M, et al. Interleukin 18 and associated markers of T helper cell type 1 activity in celiac disease. Gut. 2002;50(2):186–189.
   PubMed Web of Science ®Google Scholar
• Mazzarella G, MacDonald TT, Salvati VM, et al. Constitutive activation of the signal transducer and activator of transcription pathway in celiac disease lesions. Am J Pathol. 2003;162(6):1845–1855.
   PubMed Web of Science ®Google Scholar
• Fina D, Sarra M, Caruso R, et al. Interleukin 21 contributes to the mucosal T helper cell type 1 response in coeliac disease. Gut. 2008;57(7):887–892.
   PubMed Web of Science ®Google Scholar
• Einarsdottir E, Koskinen LLE, de Kauwe AL, et al. Genome-wide analysis of extended pedigrees confirms IL2–IL21 linkage and shows additional regions of interest potentially influencing coeliac disease risk. Tissue Antigens. 2011;78(6):428–437.
   PubMedGoogle Scholar
• Galatola M, Izzo V, Cielo D, et al. Gene expression profile of peripheral blood monocytes: a step towards the molecular diagnosis of celiac disease? PLoS One. 2013;8(9):e74747.
   PubMed Web of Science ®Google Scholar
• Cielo D, Galatola M, Fernandez-Jimenez N, et al. Combined analysis of methylation and gene expression profiles in separate compartments of small bowel mucosa identified celiac disease patients’ signatures. Sci Rep. 2019;9(1):10020.
   PubMedGoogle Scholar
• Pène J, Gauchat JF, Lécart S, et al. Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells. J Immunol. 2004;172(9):5154–5157.
   PubMed Web of Science ®Google Scholar
• Ozaki R, Spolski CG, Chen F, Qi F, et al. Critical role for IL-21 in regulating immunoglobulin production. Science. 2002;298(5598):1630–1634.
   PubMed Web of Science ®Google Scholar
• Strengell M, Matikainen S, Sirén J, et al. IL-21 in synergy with IL-15 or IL-18 enhances IFN-g production in human NK and T cells. J Immunol. 2003;170(11):5464–5469.
   PubMed Web of Science ®Google Scholar
• Brandt K, Bulfone-Paus S, Foster DC, et al. Interleukin-21 inhibits dendritic cell activation and maturation. Blood. 2003;102(12):4090–4098.
   PubMed Web of Science ®Google Scholar
• Korn T, Bettelli E, Gao W, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature. 2007;448(7152):484–487.
   PubMed Web of Science ®Google Scholar
• Pot C, Jin H, Awasthi A, et al. IL-27 induces the transcription factor c-Maf, cytokine IL-21 and costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol. 2009;183(2):797–801.
   PubMed Web of Science ®Google Scholar
• Peluso I, Fantini MC, Fina D, et al. IL-21 counteracts the regulatory T cell mediated suppression of human CD4+ T lymphocytes. J Immunol. 2007;178(2):732–739.
   PubMed Web of Science ®Google Scholar
• Konforte D, Simard N, Paige CJ. IL-21: an executor of B cell fate. J Immunol. 2009;182(4):1781–1787.
   PubMed Web of Science ®Google Scholar
• Zhang N, Tai J, Qu Z, et al. Increased CD4CXCR5T follicular helper cells in diabetic nephropathy. Autoimmunity. 2016;49(6):405–413.
   PubMed Web of Science ®Google Scholar
• Kunisato T, Watanabe M, Inoue N, et al. Polymorphisms in Th17-related genes and the pathogenesis of autoimmune thyroid disease. Autoimmunity. 2018;51(7):1–10.
   PubMed Web of Science ®Google Scholar
• Castellanos-Rubio A, Santin I, Irastorza I, et al. TH17 (and TH1) signatures of intestinal biopsies of CD patients in response to gliadin. Autoimmunity. 2009;42(1):69–73.
   PubMed Web of Science ®Google Scholar
• Klatka M, Grywalska E, Partyka M, et al. Th17 and Treg cells in adolescents with Graves’ disease. Impact of treatment with methimazole on these cell subsets. Autoimmunity. 2014;47(3):201–211.
   PubMed Web of Science ®Google Scholar
• Long D, Chen Y, Wu H, et al. Clinical significance and immunobiology of IL-21 in autoimmunity. J Autoimmun. 2019;99:1–14.
   PubMed Web of Science ®Google Scholar
• Sarra M, Cupi ML, Monteleone I, et al. IL-15 positively regulates IL-21 production in celiac disease mucosa. Mucosal Immunol. 2013;6(2):244–255.
   PubMed Web of Science ®Google Scholar
• Zanzi D, Stefanile R, Santagata S, et al. IL-15 interferes with suppressive activity of intestinal regulatory T cells expanded in celiac disease. Am J Gastroenterol. 2011;106(7):1308–1317.
   PubMed Web of Science ®Google Scholar
• Clough LE, Wang CJ, Schmidt EM, et al. Release from regulatory T cell mediated suppression during the onset of tissue-specific autoimmunity is associated with elevated IL-21. J Immunol. 2008;180(8):5393–5401.
   PubMed Web of Science ®Google Scholar
• Bodd M, Ràki M, Tollefsen S, et al. HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22. Mucosal Immunol. 2010;3(6):594–601.
   PubMed Web of Science ®Google Scholar
• Working Group of ESPGAHN. Revised criteria for diagnosis of celiac disease. Arch Dis Child. 1990;65:909–911.
   PubMed Web of Science ®Google Scholar
• Simone R, Brizzolara R, Chiappori A, et al. A functional soluble form of CTLA-4 is present in the serum of celiac patients and correlates with mucosal injury. Int Immunol. 2009;21(9):1037–1045.
   PubMed Web of Science ®Google Scholar
• Sarra M, Pallone F, Monteleone G. Interleukin-21 in chronic inflammatory diseases. Biofactors. 2013;39(4):368–373.
   PubMed Web of Science ®Google Scholar
• Sutherland AP, Van Belle T, Wurster AL, et al. Interleukin-21 is required for the development of type 1 diabetes in NOD mice. Diabetes. 2009;58(5):1144–1155.
   PubMed Web of Science ®Google Scholar
• Mazzarella G. Effector and suppressor T cells in celiac disease. World J Gasteroenterol. 2015;21(24):7349–7356.
   PubMed Web of Science ®Google Scholar
• Jin H, Carrio R, Yu A, et al. Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis. J Immunol. 2004;173(1):657–665.
   PubMed Web of Science ®Google Scholar