AB0145 Putative Role of A Gene Encoding An Endogenous Retroviral Envelope Protein in Systemic Lupus Erythematosus (SLE). (15th July 2016) - Laska, M.J.
Abstract : Background: Human Endogenous Retroviruses (HERVs) are remnants of past retroviral infections in the human genome. Most of HERV elements have accumulated mutations and deletions and thus have become inactivated with time. At the same time the presence of open reading frames (ORFs) in only a few HERV genes, suggest an evolutionary selective pressure to maintain the protein coding capacity of some HERV envelope ORFs (1). HERVs have been implicated both in diseases such as cancers and autoimmune disorders but interesting also shown to have been adapted to play a role in important aspects of human biology such as development of the placenta. Objectives: We aimed to identify HERVs which affect development of Systemic Lupus Erythematosus (SLE) and to describe what role such putative HERV elements might play in autoimmunity. Methods: The study subjects compromised 45 female patients with SLE and 50 geographically and age matched healthy female controls, recruited consecutively from Aarhus University Hospital, Denmark. Using real-time RT-PCR strategy we analyzed transcriptome of 11 genes with coding capacity for complete envelope protein in Peripheral Blood Mononuclear Cells (PBMCs) isolated from SLE patients or healthy controls. The Mann-Whitney U test analyzes showed that the expression of HERV-H Env59 gene in SLE patients was significantly higher than in healthy controls. Subsequently we cloned the Env59 envelope gene and using psuedotyped lentiviral particles, examined whether it retains its activity as a retroviral fusion protein. A sequence analysis of the protein identified an immune suppressive domain (ISD). A peptide corresponding to this ISD was synthesized and examined in vitro for immune suppressive activity on stimulated human PBMCs and the monocytic THP-1 cells line. Results: We found that a specific HERV-H derived Env gene (Env59) is overexpressed in SLE patients ( P <0.0001). Interestingly, we found that the expression of this gene is negatively correlated with etiological factors of autoimmune rheumatic diseases such as IL-6 ( P =0.0065) and TLR-7 ( P =0.02) in patients. This gene is capable of encoding a fully functional envelope glycoprotein and contains a domain which shows strong anti-inflammatory activity including the ability to lower IL-6 levels in vitro . Conclusions: We interpret these results to show that the Env59 gene has been adapted by the immune system as a control mechanism in autoimmunity. More precisely the activity of the immune suppressive domain of this retroviral envelope protein seems to be directly responsible for lower IL-6 levels in some SLE-patients. The ISD peptide derived from this retroviral gene shows anti-inflammatory activity in vitro and represents a potentially new strategy for treatment of autoimmune diseases. References: Kurth R, Bannert N. Beneficial and detrimental effects of human endogenous retroviruses. Int J Cancer. 2010;126(2):306–14. Epub 2009/10/02. Disclosure of Interest: None declared