Adults with celiac disease exhibit overexpression of endogenous retroviruses, TRIM28, and SETDB1 despite gluten-free diet

Abstract

Celiac disease (CeD) is a disorder due to abnormal immune response to gluten protein in individuals with predisposing genotypes. Its origin is not fully understood. Human endogenous retroviruses (HERVs) derive from ancestral infections of germinal cells and represent 8 % of the human DNA. They are mostly inactive, but some can be activated. Their aberrant expressions are associated with inflammatory and immune-mediated diseases. HERV transcription is modulated by TRIM28 and SETDB1, which are also directly implicated in epigenetic processes and modulation of the immune response. We reported HERV overexpressions in CeD children at diagnosis. In the current prospective study, using a PCR real-time Taqman amplification assay, we explored the transcription levels of HERV-H-pol, -HERV-K-pol, and HERV-W-pol, of syncytin 1 (SYN1), SYN2, and HERV-W-env, as well as of TRIM28 and SETDB1 in the whole blood from 51 adults with CeD after years of good compliance with gluten-free diet (GFD) as compared to healthy controls (HC) of similar age. The transcriptional levels of every HERV and of TRIM28/SETDB1 were significantly higher in CeD patients than in HC (constantly with p < 0.0001). Positive correlations were found between the RNA levels of TRIM28 or SETDB1 and HERVs in CeD patients. The upregulation of HERVs, TRIM28, and SETDB1 and their positive correlations are suggestive clues of their contribution to the pathophysiology of CeD and might justify the persistent risk of developing, despite GFD, autoimmune diseases, neuropsychiatric disturbances, and cancers, all disorders characterized by enhanced HERV expressions and epigenetic alterations.

Keywords: Celiac disease; GFD; Human endogenous retroviruses; SETDB1; TRIM28; epigenetics.

Fig. 1

Transcription levels of the pol genes of HERV-H, HERV-K, and HERV-W in the whole blood from 51 patients with celiac disease (CeD) and 85 healthy controls (HC). RE = relative expression according to the 2−∆∆Ct method. Circles and squares show the median of three individual measurements; horizontal lines represent the median values. The p-values represent the result of the Mann–Whitney test.

Fig. 2

Transcription levels of Syncytin 1, Syncytin 2, and HERV-W-env in the whole blood from 51 patients with celiac disease (CeD) and 85 healthy controls (HC). RE = relative expression according to the 2−∆∆Ct method. Circles and squares show the median of three individual measurements; horizontal lines represent the median values. The p-values represent the result of the Mann–Whitney test.

Fig. 3

Transcription levels of TRIM28 and SETDB1 in the whole blood from 51 patients with celiac disease (CeD) and 85 healthy controls (HC). RE = relative expression according to the 2-ΔΔCt method. Circles and squares show the median of three individual measurements; horizontal lines represent the median values. The p-values represent the result of the Mann–Whitney test.

Fig. 4

Correlations between transcription levels of TRIM28 and HERVs in whole blood from 51 celiac disease patients (CeD). RE: Relative Expression. Circles show the mean of three individual measurements. Line: Linear regression line. Statistical analysis: Spearman correlation test.

Fig. 5

Correlations between transcription levels of TRIM28 and HERVs in healthy controls (HC). RE: Relative Expression. Circles show the mean of three individual measurements. Line: Linear regression line. Statistical analysis: Spearman correlation test.

Fig. 6

Correlations between transcription levels of SETDB1 and HERVs in whole blood from 51 CeD patients. RE: Relative Expression. Circles show the mean of three individual measurements. Line: Linear regression line. Statistical analysis: Spearman correlation test.

Fig. 7

Correlations between transcription levels of SETDB1 and HERVs in healthy controls. RE: Relative Expression. Circles show the mean of three individual measurements. Line: Linear regression line. Statistical analysis: Spearman correlation test.

Fig. 8

Expressions of HERVs, TRIM28 and SETDB1 in 36 CeD patients without hepatic damage (noHD) and 15 CeD patients with steatotic or fibrotic liver damage (13 steatosis and 2 fibrosis). RE = relative expression according to the 2-ΔΔCt method. Circles and squares show the median of three individual measurements; horizontal lines represent the median values. The p-values represent the result of the Mann–Whitney test.