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Increased Intraepithelial Vα24 Invariant NKT Cells in the Celiac Duodenum.

Montalvillo E, Bernardo D, Martínez-Abad B, Allegretti Y, Fernández-Salazar L, Calvo C, Chirdo FG, Garrote JA, Arranz E - Nutrients (2015)

Bottom Line: The expression of Vα24-Jα18 correlated with Marsh score for the severity of mucosal lesion and also with increased mRNA IFNγ levels. uCD and GFD-CD patients had decreased mRNA expression of FoxP3 but increased expression of Vα24-Jα18, which revealed a CD-like molecular profile.In conclusion, we have found an increased number of iNKT cells in the duodenum from both uCD and GFD-CD patients, irrespective of the mucosal status.A CD-like molecular profile, defined by an increased mRNA expression of Vα24-Jα18 together with a decreased expression of FoxP3, may represent a pro-inflammatory signature of the CD duodenum.

View Article: PubMed Central - PubMed

Affiliation: Mucosal Immunology Lab, IBGM, University of Valladolid-CSIC, Sanz y Forés 3, 47003 Valladolid, Spain. emontalvillo@gmail.com.

ABSTRACT
Celiac Disease (CD) is an interferon (IFN)γ-mediated duodenal hypersensitivity to wheat gluten occurring in genetically predisposed individuals. Gluten-free diet (GFD) leads to a complete remission of the disease. Vα24-restricted invariant NKT (iNKT) cells are important to maintain immune homeostasis in the gut mucosa because of their unique capacity to rapidly produce large quantities of both T-helper (Th)1 and Th2 cytokines upon stimulation. We studied the presence of these cells in the CD duodenum. Duodenal biopsies were obtained from 45 untreated-CD patients (uCD), 15 Gluten Free Diet-CD patients (GFD-CD), 44 non-inflamed non-CD controls (C-controls) and 15 inflamed non-CD controls (I-controls). Two populations from Spain and Argentina were recruited. Messenger RNA (mRNA) expression of Vα24-Jα18 (invariant TCRα chain of human iNKT cells), IFNγ and intracellular transcription factor Forkhead Box P3 (Foxp3), and flow cytometry intraepithelial lymphocyte (IEL) profile were determined. Both uCD and GFD-CD patients had higher Vα24-Jα18 mRNA levels than non-CD controls (I and C-controls). The expression of Vα24-Jα18 correlated with Marsh score for the severity of mucosal lesion and also with increased mRNA IFNγ levels. uCD and GFD-CD patients had decreased mRNA expression of FoxP3 but increased expression of Vα24-Jα18, which revealed a CD-like molecular profile. Increased numbers of iNKT cells were confirmed by flow cytometry within the intraepithelial lymphocyte compartment of uCD and GFD-CD patients and correlated with Vα24-Jα18 mRNA expression. In conclusion, we have found an increased number of iNKT cells in the duodenum from both uCD and GFD-CD patients, irrespective of the mucosal status. A CD-like molecular profile, defined by an increased mRNA expression of Vα24-Jα18 together with a decreased expression of FoxP3, may represent a pro-inflammatory signature of the CD duodenum.

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Correlation between duodenal mRNA expression of Vα24-Jα18 and IFNγ. Expression levels of IFNγ mRNA in duodenal biopsies indicated as the ratio IFNγ/βactin, in arbitrary units (AU), in untreated Celiac Disease (uCD), Gluten Free Diet-CD patients (GFD-CD), inflamed non-CD controls (I-controls) and non-inflamed non-CD controls (C-controls) in the Spanish population (A) and in uCD and C-controls in the Argentinian population (B). Statistically significant differences are shown (two tailed Mann-Whitney U test; Krustall-Wallis test). Horizontal bars are median values. Correlation between the expression of IFNγ and Vα24-Jα18 mRNA, in arbitrary units (AU) in the Spanish population (C) (C-controls: Spearman r = 0.3115, p value = n.s; I-controls: Spearman r = 0.4265, p value = n.s; GFD-CD: Spearman r = 0.5393, p value < 0.05; uCD: Spearman r = 0.4323, p value < 0.05) and in the Argentinian population (D) (C-controls: Spearman r = 0.5895, p value < 0.05; uCD: Spearman r = 0.6917, p value < 0.001).
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nutrients-07-05444-f003: Correlation between duodenal mRNA expression of Vα24-Jα18 and IFNγ. Expression levels of IFNγ mRNA in duodenal biopsies indicated as the ratio IFNγ/βactin, in arbitrary units (AU), in untreated Celiac Disease (uCD), Gluten Free Diet-CD patients (GFD-CD), inflamed non-CD controls (I-controls) and non-inflamed non-CD controls (C-controls) in the Spanish population (A) and in uCD and C-controls in the Argentinian population (B). Statistically significant differences are shown (two tailed Mann-Whitney U test; Krustall-Wallis test). Horizontal bars are median values. Correlation between the expression of IFNγ and Vα24-Jα18 mRNA, in arbitrary units (AU) in the Spanish population (C) (C-controls: Spearman r = 0.3115, p value = n.s; I-controls: Spearman r = 0.4265, p value = n.s; GFD-CD: Spearman r = 0.5393, p value < 0.05; uCD: Spearman r = 0.4323, p value < 0.05) and in the Argentinian population (D) (C-controls: Spearman r = 0.5895, p value < 0.05; uCD: Spearman r = 0.6917, p value < 0.001).

Mentions: Duodenal samples from CD patients (either treated and untreated) had increased IFNγ mRNA expression compared with non-inflamed non-CD controls both in the Spanish (GFD-CD, p < 0.05; uCD, p < 0.001) (Figure 3A) and the Argentinian populations (uCD, p < 0.05) (Figure 3B) as previously described [30,31]. Since both mRNA levels of IFNγ [2,30] and Vα24-Jα18 (Figure 2C) correlated with the Marsh score for the severity of the mucosal lesion, we studied if the expression of IFNγ and Vα24-Jα18 was related. A correlation was found between the mRNA levels of IFNγ and Vα24-Jα18 in treated and untreated CD samples in both the Spanish (C-controls: Spearman’s r = 0.3115, p value = n.s; I-controls: Spearman’s r = 0.4265, p value = n.s; GFD-CD: Spearman’s r = 0.5393, p < 0.05; uCD: Spearman’s r = 0.4323, p < 0.05) and the Argentinian populations (C-controls: Spearman’s r = 0.5895, p < 0.05; uCD: Spearman’s r = 0.6917, p < 0.001) (Figure 3C,D).


Increased Intraepithelial Vα24 Invariant NKT Cells in the Celiac Duodenum.

Montalvillo E, Bernardo D, Martínez-Abad B, Allegretti Y, Fernández-Salazar L, Calvo C, Chirdo FG, Garrote JA, Arranz E - Nutrients (2015)

Correlation between duodenal mRNA expression of Vα24-Jα18 and IFNγ. Expression levels of IFNγ mRNA in duodenal biopsies indicated as the ratio IFNγ/βactin, in arbitrary units (AU), in untreated Celiac Disease (uCD), Gluten Free Diet-CD patients (GFD-CD), inflamed non-CD controls (I-controls) and non-inflamed non-CD controls (C-controls) in the Spanish population (A) and in uCD and C-controls in the Argentinian population (B). Statistically significant differences are shown (two tailed Mann-Whitney U test; Krustall-Wallis test). Horizontal bars are median values. Correlation between the expression of IFNγ and Vα24-Jα18 mRNA, in arbitrary units (AU) in the Spanish population (C) (C-controls: Spearman r = 0.3115, p value = n.s; I-controls: Spearman r = 0.4265, p value = n.s; GFD-CD: Spearman r = 0.5393, p value < 0.05; uCD: Spearman r = 0.4323, p value < 0.05) and in the Argentinian population (D) (C-controls: Spearman r = 0.5895, p value < 0.05; uCD: Spearman r = 0.6917, p value < 0.001).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4663572&req=5

nutrients-07-05444-f003: Correlation between duodenal mRNA expression of Vα24-Jα18 and IFNγ. Expression levels of IFNγ mRNA in duodenal biopsies indicated as the ratio IFNγ/βactin, in arbitrary units (AU), in untreated Celiac Disease (uCD), Gluten Free Diet-CD patients (GFD-CD), inflamed non-CD controls (I-controls) and non-inflamed non-CD controls (C-controls) in the Spanish population (A) and in uCD and C-controls in the Argentinian population (B). Statistically significant differences are shown (two tailed Mann-Whitney U test; Krustall-Wallis test). Horizontal bars are median values. Correlation between the expression of IFNγ and Vα24-Jα18 mRNA, in arbitrary units (AU) in the Spanish population (C) (C-controls: Spearman r = 0.3115, p value = n.s; I-controls: Spearman r = 0.4265, p value = n.s; GFD-CD: Spearman r = 0.5393, p value < 0.05; uCD: Spearman r = 0.4323, p value < 0.05) and in the Argentinian population (D) (C-controls: Spearman r = 0.5895, p value < 0.05; uCD: Spearman r = 0.6917, p value < 0.001).
Mentions: Duodenal samples from CD patients (either treated and untreated) had increased IFNγ mRNA expression compared with non-inflamed non-CD controls both in the Spanish (GFD-CD, p < 0.05; uCD, p < 0.001) (Figure 3A) and the Argentinian populations (uCD, p < 0.05) (Figure 3B) as previously described [30,31]. Since both mRNA levels of IFNγ [2,30] and Vα24-Jα18 (Figure 2C) correlated with the Marsh score for the severity of the mucosal lesion, we studied if the expression of IFNγ and Vα24-Jα18 was related. A correlation was found between the mRNA levels of IFNγ and Vα24-Jα18 in treated and untreated CD samples in both the Spanish (C-controls: Spearman’s r = 0.3115, p value = n.s; I-controls: Spearman’s r = 0.4265, p value = n.s; GFD-CD: Spearman’s r = 0.5393, p < 0.05; uCD: Spearman’s r = 0.4323, p < 0.05) and the Argentinian populations (C-controls: Spearman’s r = 0.5895, p < 0.05; uCD: Spearman’s r = 0.6917, p < 0.001) (Figure 3C,D).

Bottom Line: The expression of Vα24-Jα18 correlated with Marsh score for the severity of mucosal lesion and also with increased mRNA IFNγ levels. uCD and GFD-CD patients had decreased mRNA expression of FoxP3 but increased expression of Vα24-Jα18, which revealed a CD-like molecular profile.In conclusion, we have found an increased number of iNKT cells in the duodenum from both uCD and GFD-CD patients, irrespective of the mucosal status.A CD-like molecular profile, defined by an increased mRNA expression of Vα24-Jα18 together with a decreased expression of FoxP3, may represent a pro-inflammatory signature of the CD duodenum.

View Article: PubMed Central - PubMed

Affiliation: Mucosal Immunology Lab, IBGM, University of Valladolid-CSIC, Sanz y Forés 3, 47003 Valladolid, Spain. emontalvillo@gmail.com.

ABSTRACT
Celiac Disease (CD) is an interferon (IFN)γ-mediated duodenal hypersensitivity to wheat gluten occurring in genetically predisposed individuals. Gluten-free diet (GFD) leads to a complete remission of the disease. Vα24-restricted invariant NKT (iNKT) cells are important to maintain immune homeostasis in the gut mucosa because of their unique capacity to rapidly produce large quantities of both T-helper (Th)1 and Th2 cytokines upon stimulation. We studied the presence of these cells in the CD duodenum. Duodenal biopsies were obtained from 45 untreated-CD patients (uCD), 15 Gluten Free Diet-CD patients (GFD-CD), 44 non-inflamed non-CD controls (C-controls) and 15 inflamed non-CD controls (I-controls). Two populations from Spain and Argentina were recruited. Messenger RNA (mRNA) expression of Vα24-Jα18 (invariant TCRα chain of human iNKT cells), IFNγ and intracellular transcription factor Forkhead Box P3 (Foxp3), and flow cytometry intraepithelial lymphocyte (IEL) profile were determined. Both uCD and GFD-CD patients had higher Vα24-Jα18 mRNA levels than non-CD controls (I and C-controls). The expression of Vα24-Jα18 correlated with Marsh score for the severity of mucosal lesion and also with increased mRNA IFNγ levels. uCD and GFD-CD patients had decreased mRNA expression of FoxP3 but increased expression of Vα24-Jα18, which revealed a CD-like molecular profile. Increased numbers of iNKT cells were confirmed by flow cytometry within the intraepithelial lymphocyte compartment of uCD and GFD-CD patients and correlated with Vα24-Jα18 mRNA expression. In conclusion, we have found an increased number of iNKT cells in the duodenum from both uCD and GFD-CD patients, irrespective of the mucosal status. A CD-like molecular profile, defined by an increased mRNA expression of Vα24-Jα18 together with a decreased expression of FoxP3, may represent a pro-inflammatory signature of the CD duodenum.

Show MeSH
Related in: MedlinePlus