Background/Purpose: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease characterized by autoantibody production and periods of elevated and suppressed disease activity. Various genetic and environmental factors likely contribute to disease pathogenesis. Epstein Barr Virus (EBV) is one such environmental factor that has been consistently associated with SLE. EBV maintains latency in infected B cells and shows frequent reactivation, which can be measured indirectly in terms of antibodies to EBV Early Antigen (EA). Our data show that elevated concentrations of EA IgG increase the probability of transitioning to SLE in unaffected SLE family members, suggesting that viral reactivation may contribute to development or worsening of SLE autoimmune responses. EBV encodes homologs of cellular cytokines to escape host anti-viral response and establish latency. One such protein is a late lytic phase protein encoded by BCRF-1 gene and is an IL10 homolog. Monocytes are one of the first cells to respond following infection and dysregulation of monocytes plays a dynamic role in the initiation and continuation of the systemic autoimmune response in SLE. However, the effects of vIL-10 on monocyte function have not been studied. In this study we examine whether vIL10 has similar inhibitory effects on monocytes as hIL10.

Methods: Plasma from 8 SLE patients with varying disease activity and 6 healthy unrelated controls were concentrated and vIL10 was detected by western blotting. The band intensities were normalized to known concentration of recombinant vIL10. Monocytes were enriched from peripheral blood mononuclear cells from healthy donors and stimulated with human or viral IL10. STAT phosphorylation, expression of cell surface markers, and uptake of apoptotic Jurkat cells were determined by flow cytometry. Gene expression was performed using microfluidics quantitative PCRs (Fluidigm).

Results: SLE patients showed significantly higher levels of plasma vIL10 (25423±5968 vs 12968±8432, p<0.05). No correlation was observed between vIL10 and hIL10. To determine whether this increased vIL10 has functional consequences, we performed in vitro stimulation of healthy monocytes with human or viral IL10. vIL-10 induced significantly lower STAT-3 phosphorylation compared to hIL-10, and failed to downregulate IL10R1 gene expression, suggesting differences in signaling cascades activated by vIL10. Although less efficient in downregulating pro-inflammatory gene expression, vIL-10 significantly reduced the expression of scavenger receptor CD163 compared to hIL-10, suggesting inhibition of M2 polarization. In line with inhibition of M2 polarization, vIL10 stimulated monocytes were less efficient in clearance of apoptotic cells.

Conclusion: Our data show that lupus patients have increased levels of vIL-10 which may be a result of increased EBV reactivation. We show that vIL-10 increases pro-inflammatory cytokine secretion by monocytes while reducing the phagocytic capability. The reduced clearance may lead to accumulation of cell debris and fuel the autoimmune response through death associated molecular patterns prior to initial disease flare.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/epstein-barr-virus-interluekin-10-vil10-in-systemic-lupus-erythematosus/