Antibodies against human endogenous retrovirus K102 envelope activate neutrophils in systemic lupus erythematosus Maria Tokuyama, Bronwyn M. Gunn, Arvind Venkataraman, Yong Kong, Insoo Kang, Tasfia Rakib, Michael J. Townsend, Karen H. Costenbader, Galit Alter and Akiko Iwasaki Journal of Experimental Medicine (2021) 218 (7): e20191766. https://doi.org/10.1084/jem.20191766 Neutrophil activation and the formation of neutrophil extracellular traps (NETs) are hallmarks of innate immune activation in systemic lupus erythematosus (SLE). 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 correlated with autoantibody levels and higher interferon status. Induction of ERV-K102 in SLE negatively correlated with the expression of epigenetic silencing factors. Anti-ERV-K102 IgG levels in SLE plasma correlated with higher interferon stimulated gene expression, and further promoted enhanced neutrophil phagocytosis of ERV-K102 envelope protein through immune complex formation. Finally, phagocytosis of ERV-K102 immune complexes resulted in the formation of NETs consisting of DNA, neutrophil elastase, and citrullinated histone H3. Together, we identified an immunostimulatory ERV-K envelope protein that in an immune complex with SLE IgG is capable of activating neutrophils. My personal comment: there is always a real trigger!