DNA methylation modulates HRES1/p28 expression in B cells from patients with Lupus

Abstract

Systemic lupus erythematosus (SLE) disease is an autoimmune disease of unknown aetiology that affects predominantly women of child bearing age. Since previous studies, including ours, have demonstrated that CD4+ T cells and B cells from SLE patients are defective in their ability to methylate their DNA upon antigen stimulation, the aim of this study was to investigate whether DNA demethylation affects the transcription of HRES-1 in B cells. HRES-1 is the prototype of Human Endogenous Retrovirus (HERV) overexpressed in SLE. We have observed that SLE B cells were characterized by their incapacity to methylate the HRES-1 promoter, both in unstimulated and in anti-IgM stimulated B cells. In turn, HRES-1/p28 expression was increased in SLE B cells after B cell receptor engagement, but not in controls. In SLE B cells the Erk/DNMT1 pathway was defective. In addition, blocking the autocrine-loop of IL-6 in SLE B cells with an anti-IL-6 receptor monoclonal antibody restores DNA methylation and control of HRES-1/p28 expression became effective. As a consequence, a better understanding of HERV dysregulation in SLE reinforces our comprehension of the disease and opens new therapeutic perspectives.

Editorial: LINEing Up to Boost Interferon Production: Activation of Endogenous Retroviral DNA in Autoimmunity

“…Interestingly, LINE‐1 transcription via hypomethylation is readily induced by oxidative stress, and it responds to treatment with the antioxidant N ‐acetylcysteine (NAC) . Similar to LINE‐1, expression of ERVs is also controlled by epigenetic mechanisms , primarily via methylation , which appears to also underlie the increased expression of HRES‐1/p28 in B cells from patients with SLE . Of note, oxidative stress is a cause of global DNA hypomethylation in SLE .…”

Antibody against envelope protein from human endogenous retrovirus activates neutrophils in systemic lupus erythematosus

“…ERVs have been increasingly associated with diseases ranging from cancer and neurodegenerative diseases to HIV (Rooney et al, 2015;Schmitt et al, 2013a;Michaud et al, 2014;Li et al, 2015). In SLE, studies have reported association between ERVs and disease, but they have been limited to a small number of ERV loci (Ogasawara et al, 2000;Fali et al, 2014;Perl et al, 1995). While ERVs have been implicated in lupus pathogenesis (Perl et al, 2009;Nelson et al, 2014;Yu, 2016;Mellors and Mellors, 1976), the mechanisms by which ERVs potentially contribute to systemic inflammation in SLE are still unknown.…”

Epigenetics in autoimmune diseases: Pathogenesis and prospects for therapy

“…Moreover, in a recent study, HRES-1, the prototype of Human Endogenous Retroviruses (HERV), is demonstrated hypomethylated in SLE B cells. This hypomethylation might provide explanations for increasing detection of HERV in patients with autoimmune diseases including SLE, pSS and MS. On the other hand, in these two studies, high level of interleukin-6 (IL-6) is also showed in SLE B cells, which could reduce the expression of DNMT1 by arresting the cell cycle at late G1 phase and thereby affect the methylation of CD5 and HRES-1, contributing to disease activity [30,31].…”