Epstein-Barr Virus and Autoimmune Diseases: Role of the Viral Nuclear Antigen 2, EBNA2

The Epstein-Barr virus (EBV) belongs to the γ-herpesvirus subfamily and it is also known as human γ-herpesvirus 4 (HHV-4). EBV infects only humans and almost the 90% of the population is infected. The transmission of EBV occurs through infected saliva or sexual intercourse, especially among adolescents. EBV infects B cells and epithelial cells. The adsorption to target cells requires an interaction between the EBV envelope's glycoproteins gp350/320 and the cellular CR2/CD21 receptor, then EBV entry occurs by endocytosis involving BMRF2, a viral membrane protein, and integrins of host cells. EBV lytic replication occurs into the nucleus of B cells and epithelial cells. During latent infection, the virus remains within infected cells and the EBV genome assumes an episomal form. EBV codes for nuclear antigenic proteins (EBNA1-6) and for latent membrane proteins (LMP1, LMP2A, LMP2B). There are three types of EBV latent infection and EBNA1 is expressed in each type of latency. Primary EBV infection is asymptomatic, but it can progress to infectious mononucleosis (IM) or kissing disease. IM is due to the active proliferation of EBV-infected B lymphocytes and it is characterized by fever, rush and fatigue. Moreover, EBV has the ability to immortalize B lymphocytes and to establish a latent infection. As a result, B cells are transformed in lymphoblastoid cell lines (LCLs) that proliferate indefinitely and this suggests the association of the virus with different human cancers, such as Burkitt Lymphoma and Hodgkin Lymphoma. However, recent studies suggest EBV to be involved in the development of autoimmune diseases. In fact, the ability of EBV to establish a latent infection and the possibility of its reactivation could contribute to the pathogenesis of systemic autoimmune diseases (SADs). Even if the etiology of SADs is not clear, they are influenced by genetic and environmental factors, such as bacterial and viral infections, including EBV infection. There are many different mechanisms by which the virus could be implicated in the loss of tolerance and consequently in the development of autoimmunity. A new study suggests that EBNA2 could have a key role in increasing the risk for the development of several autoimmune diseases, called 'EBNA2 disorders', such as systemic lupus erythematosus (SLE), multiple sclerosis, inflammatory bowel disease, type 1 diabetes. EBNA2 is involved in the transformation of B cells in LCLs and it is a transcriptional transactivator of both viral genes, such as LMP1, LMP2 and cellular genes, such as CD21 and CD23. EBNA2 does not bind directly DNA, however it interacts with cellular RBP-jk/CBF1 to bind DNA and activate transcription. Indeed, a strong association between EBNA2 and SLE risk loci has been recently observed. The genome-wide association studies (GWAS) have identified more than 50 SLE risk loci, such as IKZF1, BLK, ARID5B, TNIP1, and two computational methods (RELI and MARIO) show that EBNA2 occupies half of the disease risk loci, increasing the risk for the development of SLE. Moreover, 60 human TFs, such as EP300, TBP, ATF2, cluster with the disease loci. 20 of these 60 TFs, such as RELA, RBPJ, NFKB1, NFKB2, intersect SLE risk loci only in presence of EBV infection and participate in EBV super-enhancers, which allow the proliferation of EBV-infected B cells. Several TFs, affected by EBNA2, can be targeted with drugs and this suggests the possibility to develop targeted therapies to stop their activity.