Antibody against envelope protein from human endogenous retrovirus activates neutrophils in systemic lupus erythematosus

Abstract

Neutrophil activation and the formation of neutrophil extracellular trap (NET) are hallmarks of innate immune activation in systemic lupus erythematosus (SLE) and contribute to the systemic interferon signature. Here we report that the expression of an endogenous retrovirus (ERV) locus ERV-K102, encoding an envelope protein, was significantly elevated in SLE patient blood and was correlated with higher interferon status. Induction of ERV-K102 expression most strongly correlated with reduced transcript levels of epigenetic silencing factors. SLE IgG promoted phagocytosis of ERV-K102 envelope protein by neutrophils through immune complex formation. ERV immune complex phagocytosis resulted in subsequent NET formation consisting of DNA, neutrophil elastase, and citrullinated histone H3. Finally, analysis of anti-ERV-K102 IgG in SLE patients showed that IgG2 likely mediates this effect. Together, we identified an immunostimulatory ERV-K envelope protein elevated in SLE that may be a target of SLE IgG and able to promote neutrophil activation.\n\neTOC summaryUsing ERVmap, the authors determined that the expression of ERV-K102 locus was elevated in SLE patient blood and correlated with the interferon signature. The envelope protein encoded by this locus activates human neutrophils through immune complex formation with SLE IgG.