Association of Epstein-Barr virus serological reactivation with transitioning to systemic lupus erythematosus in at risk individuals

OBJECTIVE. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with unknown etiology. Epstein-Barr virus (EBV) is an environmental factor associated with SLE. EBV maintains latency in B cells with frequent reactivation measured by antibodies against viral capsid antigen (VCA) and early antigen (EA). In this study, we determined whether EBV reactivation and single nucleotide polymorphisms (SNPs) in EBV-associated host genes are associated with SLE transition. METHODS. SLE patient relatives (n=436) who did not have SLE at baseline were re-contacted after 6.3 (±3.9) years and evaluated for interim transitioning to SLE (≥4 cumulative ACR criteria); 56 (13%) transitioned to SLE prior to the follow-up visit. At both visits, detailed demographic, environmental, clinical information, and blood samples were obtained. Antibodies against viral antigens were measured by ELISA. SNPs in IL10, CR2, TNFAIP3, and CD40 genes were typed by ImmunoChip™. Generalized estimating equations were used to test associations between viral antibody levels and transitioning to SLE. RESULTS. Mean baseline VCA IgG (4.879±1.797 vs 3.866±1.795, p=0.0003) and EA IgG (1.192±1.113 vs 0.7774±0.8484, p=0.0236) levels were higher in transitioned compared to autoantibody negative non-transition relatives. Increased VCA IgG and EA IgG were associated with transitioning to SLE (OR 1.28 95%CI 1.07–1.53 p=0.007, OR 1.43 95%CI 1.06–1.93 p=0.02, respectively). Significant interactions were observed between CD40 variant rs48100485 and VCA IgG levels, and IL10 variant rs3024493 and VCA IgA levels in transitioning to SLE. CONCLUSION. Heightened serologic reactivation of EBV increases the probability of transitioning to SLE in unaffected SLE relatives.