Abstract
BackgroundSeveral genetic and environmental factors have been linked to Systemic Lupus Erythematosus (SLE). One environmental trigger that has a strong association with SLE is the Epstein Barr Virus (EBV). Our laboratory previously demonstrated that BALB/c mice expressing the complete EBNA-1 protein can develop antibodies to double stranded DNA (dsDNA). The present study was undertaken to understand why anti-dsDNA antibodies arise during the immune response to EBNA-1.Methodology/Principal FindingsIn this study, we demonstrated that mouse antibodies elicited in response to EBNA-1 cross-react with dsDNA. First, we showed that adsorption of sera reactive with EBNA-1 and dsDNA, on dsDNA cellulose columns, diminished reactivity with EBNA-1. Next, we generated mononclonal antibodies (MAbs) to EBNA-1 and showed, by several methods, that they also reacted with dsDNA. Examination of two cross-reactive MAbs—3D4, generated in this laboratory, and 0211, a commercial MAb—revealed that 3D4 recognizes the carboxyl region of EBNA-1, while 0211 recognizes both the amino and carboxyl regions. In addition, 0211 binds moderately well to the ribonucleoprotein, Sm, which has been reported by others to elicit a cross-reactive response with EBNA-1, while 3D4 binds only weakly to Sm. This suggests that the epitope in the carboxyl region may be more important for cross-reactivity with dsDNA while the epitope in the amino region may be more important for cross-reactivity with Sm.Conclusions/SignificanceIn conclusion, our results demonstrate that antibodies to the EBNA-1 protein cross-react with dsDNA. This study is significant because it demonstrates a direct link between the viral antigen and the development of anti-dsDNA antibodies, which are the hallmark of SLE. Furthermore, it illustrates the crucial need to identify the epitopes in EBNA-1 responsible for this cross-reactivity so that therapeutic strategies can be designed to mask these regions from the immune system following EBV exposure.
Highlights
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by the production of antibodies to double stranded DNA and ribonucleoproteins
McClain et al observed that antibodies to a major Epstein Barr Virus (EBV) nuclear antigen, EBNA1, which is continuously expressed in latently infected B cells, arose in all pediatric SLE patients examined compared to only 69% of healthy pediatric controls [4]
EBNA-1 protein used for injections was prepared in our laboratory from a baculovirus vector obtained from Lori Frappier (McMaster University, Ontario, Canada)
Summary
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by the production of antibodies to double stranded DNA (dsDNA) and ribonucleoproteins. EBV is a lymphotropic, dsDNA herpes virus that infects 90–95% of adults in the United States [1] Despite this high incidence of infection, only a small subset of infected individuals will develop SLE [2]. James et al, observed seroconversion (development of IgG antibodies to EBV viral capsid antigen) in 99% of adolescent SLE patients compared to 70% of healthy adolescents and 72% of adolescents with other rheumatic diseases [3]. They observed by PCR analysis, the presence of EBV DNA in lymphocytes of 100% of SLE patients tested, compared to 72% of controls. The present study was undertaken to understand why anti-dsDNA antibodies arise during the immune response to EBNA-1
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