Interleukin-15 (IL-15) is a key player in the pathogenesis of celiac disease (CD). We investigated the functional role of IL-15 in the process of epithelial cell phenotypic modification at different stages of CD.
Materials and Methods:
In this study, we looked for correlations between the IL-15 mRNA levels in duodenal tissue and serum protein levels in a cohort of Iranian patients affected by CD based on the degree of histopathology. Ninety-five formalin-fixed, paraffin-embedded duodenal tissue specimens were collected: 23 with a Marsh I value; 30 with a Marsh II value; 32 with a Marsh III value; and 10 normal controls. The expression levels of the IL-15 gene in these biopsy specimens were determined by real-time quantitative polymerase chain reaction (qPCR), and IL-15 serum protein concentrations were determined by enzyme-linked immunosorbent assay and compared to tissue expression.
Results:
The IL-15 mRNA levels were higher in patients with Marsh II compared with the control group, and the Marsh I, and Marsh III groups. The differences between the Marsh II and Marsh I patients were statistically significant (p = 0.03). Similarly, the serum concentration of IL-15 was higher in Marsh II patients compared to those with Marsh I and Marsh III lesions, although the differences were not statistically significant (p = 0.221).
Conclusions:
Our results demonstrate that IL-15 gene expression might be elevated only in the early stages of CD onset (and histological damage) and that IL-15 serum levels do not significantly correlate with its tissue expression whatever the degree of histopathology.
AbadieV, JabriB (2014) IL-15: a central regulator of celiac disease immunopathology. Immunol Rev, 260:221-234.
3.
AbedRM, YaaqoobLA, AlwanIA, et al. (2017) Evaluation of some serum cytokine and adipokines profile in Iraqi celiac patients before and after treatment. IOSR J Pharm Biol Sci, 12:36-41.
4.
CiacciC, CiclitiraP, HadjivassiliouM, et al. (2015) The gluten-free diet and its current application in coeliac disease and dermatitis herpetiformis. United European Gastroenterol J, 3:121-135.
5.
DewarDH, CiclitiraPJ (2005) Clinical features and diagnosis of celiac disease. Gastroenterology, 128:S19-S24.
6.
Di SabatinoA, CiccocioppoR, CupelliF, et al. (2006) Epithelium derived interleukin-15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease. Gut, 55:469-477.
7.
Di SabatinoA, VanoliA, GiuffridaP, et al. (2012) The function of tissue transglutaminase in celiac disease. Autoimmun Rev, 11:746-753.
8.
ElliL, BranchiF, TombaC, et al. (2015) Diagnosis of gluten related disorders: celiac disease, wheat allergy and non-celiac gluten sensitivity. World J Gastroenterol, 21:7110.
9.
FehnigerTA, CaligiuriMA (2001) Interleukin-15: biology and relevance to human disease. Blood, 97:14-32.
10.
FrancavillaR, CristoforiF, StellaM, et al. (2014) From gluten-free diet to novel therapies. Minerva Pediatr, 66:501-516.
11.
Gonzalez-AlvaroI, OrtizA, Garcia-VicuñaR, et al. (2003) Increased serum levels of interleukin-15 in rheumatoid arthritis with long-term disease. Clin Exp Rheumatol, 21:639-642.
12.
GrodeL, JensenTM, ParknerT, et al. (2019) Diagnostic accuracy of a point-of-care test for celiac disease antibody screening among infertile patients. Inflamm Intest Dis, 4:123-130.
13.
HeydariF, Rostami-NejadM, Moheb-AlianA, et al. (2018) Serum cytokines profile in treated celiac disease compared with non-celiac gluten sensitivity and control: a marker for differentiation. J Gastrointestin Liver Dis, 27:241-247.
14.
HisamatsuT, ErbenU, KühlAA (2016) The role of T-cell subsets in chronic inflammation in celiac disease and inflammatory bowel disease patients: more common mechanisms or more differences?. Inflamm Intest Dis, 1:52-62.
15.
HmidaNB, AhmedMB, MoussaA, et al. (2012) Impaired control of effector T cells by regulatory T cells: a clue to loss of oral tolerance and autoimmunity in celiac disease?. Am J Gastroenterol, 107:604.
16.
HüeS, MentionJ-J, MonteiroRC, et al. (2004) A direct role for NKG2D/MICAinteraction in villous atrophy during celiac disease. Immunity, 21:367-377.
17.
JabriB, De SerreNPM, CellierC, et al. (2000) Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease. Gastroenterology, 118:867-879.
18.
JabriB, SollidLM (2009) Tissue-mediated control of immunopathology in coeliac disease. Nat Rev Immunol, 9:858.
19.
JärvinenTT, KaukinenK, LaurilaK, et al. (2003) Intraepithelial lymphocytes in celiac disease. Am J Gastrenterol, 98:1332.
20.
KhoshbatenM, Rostami-NejadM, SharifiN, et al. (2012) Celiac disease in patients with chronic psychiatric disorders. Gastroenterol Hepatol Bed Bench, 5:90.
21.
KlöckC, DiRaimondoTR, KhoslaC (2012) Role of transglutaminase 2 in celiac disease pathogenesis. Semin Immunopathol, 34:513-522.
22.
KokkonenTS, AugustinMT, KokkonenJ, et al. (2012) Serum and tissue CD23, IL-15, and FasL in cow's-milk protein-sensitive enteropathy and in coeliac disease. J Pediatr Gastroent Nutr, 54:525-531.
23.
KuczyńskiS, WiniarskaH, AbramczykM, et al. (2005) IL-15 is elevated in serum patients with type 1 diabetes mellitus. Diabetes Res Clin Pract, 69:231-236.
24.
KutluT, BrousseN, RambaudC, et al. (1993) Numbers of T cell receptor (TCR) alpha beta+ but not of TcR gamma delta+ intraepithelial lymphocytes correlate with the grade of villous atrophy in coeliac patients on a long term normal diet. Gut, 34:208-214.
25.
MahadevaS, WyattJ, HowdleP (2002) Is a raised intraepithelial lymphocyte count with normal duodenal villous architecture clinically relevant?. J Clin Pathol, 55:424-428.
26.
MaiuriL, CiacciC, AuricchioS, et al. (2000) Interleukin-15 mediates epithelial changes in celiac disease. Gastroenterology, 119:996-1006.
27.
ManavalanJS, HernandezL, ShahJG, et al. (2010) Serum cytokine elevations in celiac disease: association with disease presentation. Hum Immunol, 71:50-57.
28.
MarshMN, JohnsonMW, RostamiK (2015) Mucosal histopathology in celiac disease: a rebuttal of Oberhuber's sub-division of Marsh III. Gastroenterol Hepatol Bed Bench, 8:99.
29.
MentionJ-J, AhmedMB, BègueB, et al. (2003) Interleukin-15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology, 125:730-745.
30.
NylundL, KaukinenK, LindforsK (2016) The microbiota as a component of the celiac disease and non-celiac gluten sensitivity. Clin Nutr Exp, 6:17-24.
31.
PelkowskiTD, VieraAJ (2014) Celiac disease: diagnosis and management. Am Fam Physician, 89:99-105.
32.
PereraPY, LichyJH, WaldmannTA, et al. (2012) The role of interleukin-15 in inflammation and immune responses to infection: implications for its therapeutic use. Microb Infect, 14:247-261.
33.
Pozo-RubioT, OlivaresM, NovaE, et al. (2012) Immune development and intestinal microbiota in celiac disease. Clin Dev Immunol, 2012:654143.
RostamiK, MarshMN, JohnsonMW, et al. (2017) ROC-king onwards: intraepithelial lymphocyte counts, distribution & role in coeliac disease mucosal interpretation. Gut, 66:2080-2086.
36.
Rostami-NejadM, RostamiK, CheraghipourK, et al. (2011) Celiac disease increases the risk of Toxoplasma gondii infection in a large cohort of pregnant women. Am J Gastroenterol, 106:548.
37.
SaadahO, Al AghaA, AlbokhariS, et al. (2004) P0408 Prevalence of celiac disease in Saudi children with type 1 diabetes mellitus. J Pediatr Gastroent Nutr, 39:S211.
38.
SánchezE, De PalmaG, CapillaA, et al. (2011) Influence of environmental and genetic factors linked to celiac disease risk on infant gut colonization by Bacteroides species. Appl Environ Microbiol, 77:5316-5323.
39.
SarraM, CupiM, MonteleoneI, et al. (2013) IL-15 positively regulates IL-21 production in celiac disease mucosa. Mucosal Immunol, 6:244.
40.
SchuppanD, JunkerY, BarisaniD (2009) Celiac disease: from pathogenesis to novel therapies. Gastroenterology, 137:1912-1933.
41.
SergiC, ShenF, BoumaG (2017) Intraepithelial lymphocytes, scores, mimickers and challenges in diagnosing gluten-sensitive enteropathy (celiac disease). World J Gastroenterol, 23:573.
42.
TersigniC, CastellaniR, De WaureC, et al. (2014) Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms. Hum Rep Update, 20:582-593.
43.
Van HeelD (2006) Interleukin-15: its role in intestinal inflammation. Gut, 55:444-445.
44.
WaldmannTA, DuboisS, TagayaY (2001) Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity, 14:105-110.
45.
WięchP, ChmielZ, BazalińskiD, et al. (2018) The relationship between body composition and a gluten free diet in children with celiac disease. Nutrients, 10:1817.
46.
ZhuY, CuiG, MiyauchiE, et al. (2020) Intestinal epithelial cell-derived IL-15 determines local maintenance and maturation of intraepithelial lymphocytes in the intestine. Int Immunol, 32:307-319.
