Abstract
INTRODUCTION: Human endogenous retroviruses (HERVs) are ancient retroviruses that infected the germline cells of our ancestors millions of years ago. Due to the typical replication process, they have endogenized and are fixed in the host genome, and at present, HERVs comprise approximately 8% of the human genome. HERVs play several roles in human physiology, but they are also involved in certain diseases, particularly in autoimmune diseases. However, there is limited information regarding the interplay of HERVs on vitiligo. Therefore, the aim of this study was to determine the frequency and the expression levels of HERV-W, HERV-K, and HERV-H, as well as the circulating levels of the pro- and anti-inflammatory cytokines, in patients with vitiligo. METHODS: Peripheral blood mononuclear cells and serum samples were collected from 30 vitiligo patients and 30 healthy subjects. The expression levels of HERV-W, HERV-K, and HERV-H were qualitatively and quantitatively assessed with real-time PCR using primers complementary to the HERV-W env, HERV-K gag, and HERV-H pol genes and with the 2(-ΔΔCt) method. Circulating levels of anti-HERV-W antibodies were assessed using an "in-house" ELISA. Moreover, the systemic pro-inflammatory cytokines IL-6, TNF-α, IFN-γ, and IFN-λ1 and the anti-inflammatory cytokine IL-10 were quantified using commercial ELISA kits. RESULTS: HERV-W env was upregulated in patients with vitiligo and expressed approximately 2.5-fold change when compared with healthy individuals (p = 0.005), whereas HERV-H pol and HERV-K gag were downregulated in these patients as the healthy controls expressed 3.5-fold change (p = 0.001) and twofold change (p = 0.005), respectively. Patients with vitiligo presented higher circulating levels of IFN-λ1 and IL-1b and ratios of IFN-λ1/IL-10 and IL-6/IL-10 (p < 0.05, p < 0.05, p < 0.001, and p < 0.01, respectively). HERV-W env expression was positively correlated with IFN-λ1 and IFN-γ. Brown people showed higher expression of HERV-W env than other ethnic groups (p < 0.05). Women with vitiligo not only presented higher expression levels of HERV-W env (p = 0.05) than men (p < 0.01), but these levels were also higher than those of HERV-H pol (p = 0.05). No differences were observed between the anti-HERV env antibody concentrations in vitiligo patients and healthy individuals (p = 0.07). Strikingly, patients with vitiligo whose lesions have worsened presented higher expression levels of HERV-W env higher than those with stable lesions p<0.001. CONCLUSIONS: Our findings suggest that HERV-W env may play a pivotal role in the immunopathogenesis of vitiligo and that it may be linked to the systemic pro-inflammatory status of the disease. Our findings also suggest that HERV-W env might be used as a biomarker of the disease and may be linked to the worsening of vitiligo lesions. Altogether, our results support the involvement of HERV elements in vitiligo and warrant further investigation into their mechanistic contribution.