Expression,Functions And Mechanisms Of HERV-E Clone 4-1 In Systemic Lupus Erythematosus

Systemic lupus erythematosus(SLE)is an autoimmune disease and CD4~+T cells play important roles in its development.Human endogenous retroviruses(HERVs)are the offspring of the invasion of exogenous retroviruses,accounting for 8%of the human genome.HERV-E clone 4-1 is a member of the HERV-E family.Studies have shown that in CD4~+T cells of SLE patients,the mRNA expression of HERV-E clone4-1 is increased,and its expression level is related to the disease activity of SLE.Moreover,the methylation level of HERV-E clone 4-1 5'LTR in CD4~+T cells of SLE patients is low,which may be closely related to its high expression.This study aims to study the expression and clinical significance of HERV-E clone 4-1 in CD4~+T cells of SLE patients,and to explain the mechanism of its high expression,as well as to further explore the role of HERV-E clone 4-1 in the disease process of SLE.In this study,we first collected the peripheral blood of SLE patients to extracte CD4~+T cells,and confirmed that the expression of HERV-E clone 4-1 mRNA was up-regulated in CD4~+T cells of SLE patients by q RT-PCR.We also found that HERV-E clone 4-1 mRNA expression was positively correlated with the disease activity of SLE.In addition,we found that the expression of HERV-E clone 4-1mRNA could be used as a biological marker to monitor the therapeutic effect and diagnose SLE.Subsequently,we verifieded that the activation of nuclear factor of activated T cells 1(NFAT1)was increased in CD4~+T cells of SLE patients,and it promoted the transcription of HERV-E clone 4-1 by binding to the 5'LTR of HERV-E clone 4-1.Estrogen receptor-?(ER-?)can also promote the transcription of HERV-E clone 4-1by binding to the 5'LTR of HERV-E clone 4-1.Estrogen can up regulate the expression of HERV-E clone 4-1 mRNA by activating ER-?signaling pathway.NFAT1 and ER-?induced up-regulation of HERV-E clone 4-1 mRNA in CD4~+T cells of SLE patients is dependent on DNA hypomethylation of HERV-E clone 4-1 5'LTR.Finally,we found that HERV-E clone 4-1 3'LTR promoted the expression of Methyl-Cp G binding domain protein 2(MBD2)through competitively binding to mi R-302d in CD4~+T cells of SLE patients,which resulted in the decrease of the global DNA methylation level and the increase of IL-17 expression,thus participating in the pathogenesis of SLE.HERV-E clone 4-1 3'LTR could also promote the expression of Interferon regulatory factor 9(IRF9)through competitively binding to mi R-302d,and thereby activated type I interferon pathway to participate in the disease process of SLE.In conclusion,our study shows that the expression of HERV-E clone 4-1 mRNA is up-regulated in CD4~+T cells of SLE patients.Its expression is positively related to the disease activity of SLE and can be used as a biological marker to evaluate the therapeutic effect of SLE and diagnose SLE.The up-regulation of HERV-E clone 4-1mRNA in CD4~+T cells of SLE patients is due to the activation of NFAT1 and E2/ER-?signaling and DNA hypomethylation of 5'LTR.HERV-E clone 4-1 3'LTR in CD4~+T cells of SLE patients can promote the expression of MBD2 and IRF9 by competitively binding to mi R-302d,resulting in the decrease of the global DNA methylation level,the increase of IL-17 expression and the activation of type I interferon pathway to participate in the process of SLE.