Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by periods of elevated and suppressed disease activity. SLE is characterized with systemic immune dysregulation mediated by abnormal activation of adaptive immune responses potentially through interactions with innate immune cells, such as monocytes. Although the complete etiology is unknown, several environmental factors also likely contribute to lupus disease progression. Epstein Barr virus (EBV) infection is an environmental factor that is strongly associated with SLE. Retrospective analysis of SLE family members shows that increased serological reactivation of EBV as measured by increased anti-EA IgG responses, prior to SLE classification, associates with increased probability of transitioning to SLE. However, the role of EBV infection or reactivation in SLE flares is not known. SLE patients have increased levels of a EBV lytic phase protein, which is a homologue of human interleukin 10 (IL10). Viral IL10 (vIL10), in contrast to human IL10 (hIL10), induces monocytes to become more inflammatory and fails to upregulate negative regulators of inflammation. Monocytes treated with vIL10 show reduced ability to uptake apoptotic cells. Our data also show that vIL10 can inhibit hIL10-mediated induction of suppressors of inflammatory response. This proposal will test the hypothesis that increased levels of vIL10 due to increased EBV reactivation inhibit efficient clearance of infected dying cells during EBV reactivation. This reduced clearance, together with suppressive effect on anti-inflammatory function of hIL10 leads to SLE flares by fueling autoimmune response through death associated molecular patterns. In the first aim the molecular mechanisms by which vIL10 regulates the observed differential activation of monocytes will be assessed. In the second aim the functional effects of vIL10 on monocytes from SLE patients and healthy controls will be characterized and potential pathways that are dysregulated by vIL10 in monocytes will be identified. The ability of vIL10 to influence monocyte differentiation into phagocytic macrophages or cells with enhanced antigen presentation will be determined. Finally, the association of vIL10 levels with SLE disease activity and inflammatory cytokines using longitudinal samples collected from SLE patients before, at, and after a clinical flare will be evaluated. Infections are considered as a possible trigger for SLE flare. Access to well characterized longitudinal samples will enable deciphering the possible role of a common viral infection in causing flares using human samples. This study will improve the current understanding of EBV infection in SLE, and will provide a potential mechanism for SLE flares.
Lupus flares are periods when the disease symptoms are worse and lead to increased damage, medication toxicity and poor patient outcomes. Unfortunately, little is known about what causes flares. In this study we will study the role of reactivation of a common viral infection as a potential trigger for lupus flares and uncover new mechanisms for a common viral protein.