Background Mechanisms explaining the well-known association of SLE with Epstein-Barr virus (EBV) infection are unknown. In other experiments, the Epstein-Barr nuclear antigen-2, -3C, & -LP (EBNA2, EBNA3C, EBNALP), all EBV-encoded transcription co-factors, have been shown to concentrate at SLE genetic risk loci, supporting the hypothesis that the host immune response to EBV initiates SLE autoimmune processes. Cross-reactions of the anti-EBNA1 heteroimmune response with the Sm B/B’, Sm D, Ro/SSA, and C1q autoantigens are convincing. Some of these cross reacting EBNA1 epitopes appear to be the initiating the autoantibodies in SLE patients and induce SLE-like disease in animals after immunization. EBNA1 aberrantly reduces T cell responses in normal individuals. Perhaps, the first SLE autoantibodies usually emerge from the anti-EBNA1 humoral response. If this hypothesis is the common sequence of events in SLE, then anti-EBNA1 responses would be predicted to be more frequent in EBV-infected SLE patients than in EBV-infected controls.
Methods We tested this prediction using the large dataset in East Asians published by Cui, et al (PLoS One 2018;13:e01931711) by matching controls to cases by age and sex and using conditional logistic regression.
Results All 232 SLE patients (100%) were EBV-infected, while 54 of 696 patient controls were not EBV infected (7.6%), resulting in a strong association (OR=28.6 (6.4-∞, p=5x10-8), further confirming the known close association of EBV infection with SLE with a 100% attributable fraction. Most importantly, virtually all the SLE cases tested for both anti-VCA IgG and anti-EBNA1 IgG also had anti-EBNA1 antibodies (124 of 125 (99.2%)), which were more frequent than in age- and sex-matched controls (232 of 250 (93.2%)) (OR=9.7, 95%CI 1.5-414, p=0.0078) for an 89.7% additional attributable fraction among those EBV-infected, thereby adding anti-EBNA1 antibodies as an SLE risk factor beyond EBV infection.
Conclusions These data (Cui, et al. PLoS One 2018;13:e01931711), also show strong association of EBV with SLE with anti-EBNA1 being more frequent in SLE cases than in concurrent patient controls, supporting the known association of EBV infection with SLE. Further, anti-EBNA1 is virtually always present in SLE and is present more frequently in EBA-infected SLE patients than in EBV-infected controls, consistent with the hypothesis that anti-EBNA1 is the usual immune response foundation from which pathogenic SLE autoimmunity emerges. These results support a model of the etiology of SLE that begins with EBV infection, leading to anti-EBNA1 antibodies. Then, a subset of these heteroimmune anti-EBNA1 antibodies cross react with SLE autoantigens (e.g., Sm as in figure 1, (EBV image, courtesy of NIAID/NIH; SLE malar rash image, courtesy of Mayo Foundation, all rights reserved)) that then mature into an SLE autoantibody response and result in in life-threatening clinical SLE. The specific role of the other EBV gene products, EBNA2, EBNA3C, and EBNALP, in this process (figure 1) await elucidation.
Acknowledgments Support is appreciated from US Department of Veterans Affairs Merit Award (I01 BX001834), and the National Institutes of Health (R01 AI24717 & U01 AI130830).
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