The Humoral Immune Response against Human Endogenous Retroviruses in Celiac Disease: A Case-Control Study

Abstract

Background: Celiac disease (CD) is an immune-mediated disease characterized by disruptions of the small intestine. Factors such as viral and bacterial infections can trigger CD. Recently, the reactivation of Human Endogenous Retroviruses (HERVs) has also been implicated, but little is known about their specific role in patients with celiac disease.

Methods: The purpose of this study is to explore the humoral immune response mounted against epitopes derived from the envelope portion of three families of HERVs (HERV-K, HERV-H, and HERV-W) in CD patients. Reactivity against the HERV-K, HERV-H, and HERV-W env-su peptides was tested by indirect ELISAs in plasma of 40 patients with celiac disease and 41 age-matched healthy subjects (HCs).

Results: HERV-K, HERV-H, and HERV-W env-su peptides triggered different antibody responses in CD patients compared to HCs, with a stronger reactivity (p = 0.0001).

Conclusions: Present results show, for the first time, that epitopes of HERV-K, HERV-H, and HERV-W are more recognized in patients with CD. Taking into consideration their proinflammatory and autoimmune features, this might suggest that HERVs may contribute to the development of CD or its exacerbation in genetically predisposed subjects. Finally, to elucidate the interplay between gut inflammation and HERVs during the inflammatory process, further studies are required. Those investigations should focus on the expression levels of HERVs and their relationship with the immune response, specifically examining anti-transglutaminase 2 (TG2) antibody levels under both gluten-free and gluten-containing dietary conditions.

Keywords: HERV-H; HERV-K; HERV-W; antigenic peptides; celiac disease; humoral immune response.

Figure 1

An ELISA-based analysis of Ab reactivity against viral derived peptides in the patients with celiac disease (CD) and in the healthy controls (HCs). (A) The sera were tested against the plate-coated HERV-K env-su_19-37, (B) the HERV-H env-su_229-241, (C) the HERV-W env-su_129-14, and (D) INF-α peptides. The bars represent the median ± interquartile range. (A–D) The thresholds for Abs are indicated with dashed lines. The p-values and the AUC are indicated above the distributions. (E) The prevalence of the Abs tested against the HERV epitopes and INF-α in the patients with CD and in the HCs. Total percentage of Abs positivity to at least one peptide is represented by the first bar in each group. The other bars correspond to a single-peptide positivity relative to each epitope. (F) The prevalence of multiple Abs in patients with CD and in HCs. Seroreactivity against the INF-α antigen is compared to the humoral responses to the HERV-K, HERV-H, and HERV-W peptides. The horizontal bars indicate Abs against at least two antigens identified in the samples.

Figure 2

A scatter plot showing the correlations between Ab titers identifying (A) HERV-H env-su_229-241 and HERV-K env-su_19-37, (B) HERV-W env-su_129-143 and HERV-K env-su_19-37, (C) HERV-W env-su_129-143 and HERV-H env-su_229-241, (D) HERV-K env-su_19-37 and α-transglutaminase, (E) HERV-H env-su_229-241 and α-transglutaminase, and (F) HERV-W env-su_129-143 and α-transglutaminase in 40 patients with CD. Person’s correlation was calculated through GraphPad Prism version. 8.0 software.

Figure 3

Scatter plot showing correlations between Abs titers recognizing: (A) HERV-K env-su19-37 and INF-α, (B) HERV-H env-su229-241 and INF-α, (C) HERV-W env-su129-143 and INF-α, (D) anti-transglutaminase 2 Abs and INF-α in CD patients. Scatter plot showing correlations between Abs titers recognizing: (E) HERV-K env-su19-37 and INF-α, (F) HERV-H env-su229-241 and INF-α, (G) HERV-W env-su129-143 and INF-α in 41 HCs. Person’s correlation was calculated through GraphPad Prism v. 8.0 software.