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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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Increased intraepithelial iNKT cells in celiac disease patients and correlation with Vα24-Jα18 mRNA expression. Percentage of iNKT cells (CD45+CD3+Vα24-Jα18+) among the total number of Intraepithelial Lymphocytes (IELs) 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) (A). Percentage of Intraepithelial CD4+ iNKT cells among the total number of iNKT cells in aCD, GFD-CD, I-controls and C-controls (B). Percentage of iNKT cells among the total number of Lamina Propria Lymphocytes (LPLs) in aCD, GFD-CD, I-controls and C controls (C). Horizontal bars are median values. Statistically significant differences are shown (two tailed Mann Whitney U test; p < 0.05). Correlation between Vα24-Jα18 mRNA expression, in arbitrary units (AU) and the percentage of iNKT cells among the total number of IELs in aCD, GFD-CD, I-controls and C controls (C-controls: Spearman r = 0.8603, p value<0.001; I-controls: Spearman r = −0.9455, p value < 0.0001; GFD-CD: Spearman r = −0.9297, p value < 0.0001; uCD: Spearman r = 0.8287, p value = 0.001) (D).
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nutrients-07-05444-f006: Increased intraepithelial iNKT cells in celiac disease patients and correlation with Vα24-Jα18 mRNA expression. Percentage of iNKT cells (CD45+CD3+Vα24-Jα18+) among the total number of Intraepithelial Lymphocytes (IELs) 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) (A). Percentage of Intraepithelial CD4+ iNKT cells among the total number of iNKT cells in aCD, GFD-CD, I-controls and C-controls (B). Percentage of iNKT cells among the total number of Lamina Propria Lymphocytes (LPLs) in aCD, GFD-CD, I-controls and C controls (C). Horizontal bars are median values. Statistically significant differences are shown (two tailed Mann Whitney U test; p < 0.05). Correlation between Vα24-Jα18 mRNA expression, in arbitrary units (AU) and the percentage of iNKT cells among the total number of IELs in aCD, GFD-CD, I-controls and C controls (C-controls: Spearman r = 0.8603, p value<0.001; I-controls: Spearman r = −0.9455, p value < 0.0001; GFD-CD: Spearman r = −0.9297, p value < 0.0001; uCD: Spearman r = 0.8287, p value = 0.001) (D).

Mentions: As suggested by molecular studies (Figure 2A,B), iNKT cells (as characterized in Figure 1B) were increased within the IEL compartment from CD patients (in both, uCD: 7.4%/3.9 and GFD-CD: 6.1%/5.7) compared with non-CD groups (C-controls: 1.9%/0.8 and I-controls: 2.9%/1.5) (Figure 6A).


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)

Increased intraepithelial iNKT cells in celiac disease patients and correlation with Vα24-Jα18 mRNA expression. Percentage of iNKT cells (CD45+CD3+Vα24-Jα18+) among the total number of Intraepithelial Lymphocytes (IELs) 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) (A). Percentage of Intraepithelial CD4+ iNKT cells among the total number of iNKT cells in aCD, GFD-CD, I-controls and C-controls (B). Percentage of iNKT cells among the total number of Lamina Propria Lymphocytes (LPLs) in aCD, GFD-CD, I-controls and C controls (C). Horizontal bars are median values. Statistically significant differences are shown (two tailed Mann Whitney U test; p < 0.05). Correlation between Vα24-Jα18 mRNA expression, in arbitrary units (AU) and the percentage of iNKT cells among the total number of IELs in aCD, GFD-CD, I-controls and C controls (C-controls: Spearman r = 0.8603, p value<0.001; I-controls: Spearman r = −0.9455, p value < 0.0001; GFD-CD: Spearman r = −0.9297, p value < 0.0001; uCD: Spearman r = 0.8287, p value = 0.001) (D).
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nutrients-07-05444-f006: Increased intraepithelial iNKT cells in celiac disease patients and correlation with Vα24-Jα18 mRNA expression. Percentage of iNKT cells (CD45+CD3+Vα24-Jα18+) among the total number of Intraepithelial Lymphocytes (IELs) 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) (A). Percentage of Intraepithelial CD4+ iNKT cells among the total number of iNKT cells in aCD, GFD-CD, I-controls and C-controls (B). Percentage of iNKT cells among the total number of Lamina Propria Lymphocytes (LPLs) in aCD, GFD-CD, I-controls and C controls (C). Horizontal bars are median values. Statistically significant differences are shown (two tailed Mann Whitney U test; p < 0.05). Correlation between Vα24-Jα18 mRNA expression, in arbitrary units (AU) and the percentage of iNKT cells among the total number of IELs in aCD, GFD-CD, I-controls and C controls (C-controls: Spearman r = 0.8603, p value<0.001; I-controls: Spearman r = −0.9455, p value < 0.0001; GFD-CD: Spearman r = −0.9297, p value < 0.0001; uCD: Spearman r = 0.8287, p value = 0.001) (D).
Mentions: As suggested by molecular studies (Figure 2A,B), iNKT cells (as characterized in Figure 1B) were increased within the IEL compartment from CD patients (in both, uCD: 7.4%/3.9 and GFD-CD: 6.1%/5.7) compared with non-CD groups (C-controls: 1.9%/0.8 and I-controls: 2.9%/1.5) (Figure 6A).

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