Background/Purpose: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease characterized by periods of elevated and suppressed disease activity. Epstein Barr Virus (EBV) has been associated with SLE. EBV maintains latency in infected B cells and shows intermittent reactivation.  Response to EBV can lead to loss of tolerance to lupus autoantigen Ro/SS-A by molecular mimicry and epitope spreading.  Elevated levels of EBV Viral capsid antigen (VCA) and Early Antigen (EA) IgG, which are indirect measures of viral reactivation, increase the probability of transitioning to SLE in unaffected family members, which underscores the importance of EBV reactivation in SLE autoimmune responses. Viral IL10 (vIL10), an EBV lytic protein, is a homolog of interleukin 10, and we showed increased plasma vIL-10 in SLE patients compared to controls. In this study we aimed to understand the importance of vIL-10 in SLE clinical disease progression.

Methods: Plasma from 28 SLE patients with varying disease activity and 19 matched healthy unrelated controls were concentrated and vIL10 detected by western blotting and normalized to pooled control sera. Plasma cytokines were measured by xMAP assays. EBV EA IgG were measured by ELISA. Transcriptional co-expression signature module scores were calculated from Illumina Beadchip Microarray gene expression data for 29 immune pathway related modules.

Results: The levels of vIL-10 correlated with EA IgG (r=0.4468, p=0.0044). vIL-10 and EA IgG correlated with IFN gene expression module score (r=0.604, p=0.006, r=0.588, p=0.003, respectively). vIL10 levels additionally correlated with IFNβ, IFNg, and B cell modules. vIL-10 levels were independent of steroid, hydroxychloroquine, or immunosuppressant use or SLE disease activity. vIL-10 levels were significantly higher in patients that were Ro positive compared to Ro negative patients (p=0.0365).  We did not observe any differences in vIL-10 levels between patients based on dsDNA or RNP antibody positivity, nor based upon clinical ACR classification criteria. There was significant positive correlation between vIL10 levels and plasma cytokines, including: MIP1 α (r=0.5264, p=0.0020), MIP1β (r=0.5620, p=0.0008), TRAIL (r=0.4501, p=0.0097), and  IL-17A (r=0.4543, p= 0.009), IL-21 (r=0.4659, p=0.0072), IFNg (r=0.3834, p=0.0303), IL-1 α (r=0.4710, p=0.0065), MCP3 (r=0.3994, p=0.0235), and IL-13 (r=0.3604, p=0.0427),  which are cytokines that are elevated in SLE patient plasma prior to a flare (Figure 1). The levels of vIL-10 did not correlate with IL-6, IL-8, or IP-10 that are associated with disease activity.

Conclusion: The correlation of vIL-10 levels with B cell and anti-viral and gene expression modules supports increased EBV reactivation. The correlation of vIL-10 with cytokines elevated pre-flare suggests that increased reactivation followed by increased vIL-10 preceding a flare may initiate an inflammatory cascade that culminates in a flare. An increased vIL-10 level in Ro+ patients suggests that distinct pathways may regulate autoimmune response in patients based on autoantibody specificities.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/epstein-barr-virus-interleukin-10-in-sle-pathogenesis/