Tokuyama Maria, Gunn Bronwyn M, Venkataraman Arvind, Kong Yong, Kang Insoo, Rakib Tasfia, Townsend Michael J, Costenbader Karen H, Alter Galit, Iwasaki Akiko
Department of Immunobiology, Yale University School of Medicine, New Haven, CT.
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA.
J Exp Med. 2021 Jul 5;218(7). doi: 10.1084/jem.20191766. Epub 2021 May 21.
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.
中性粒细胞活化和中性粒细胞胞外陷阱（NETs）的形成是系统性红斑狼疮（SLE）中固有免疫激活的标志。在此，我们报告编码包膜蛋白的内源性逆转录病毒（ERV）位点ERV-K102在SLE患者血液中的表达显著升高，且与自身抗体水平及更高的干扰素状态相关。SLE中ERV-K102的诱导与表观遗传沉默因子的表达呈负相关。SLE血浆中抗ERV-K102 IgG水平与更高的干扰素刺激基因表达相关，并通过免疫复合物形成进一步促进中性粒细胞对ERV-K102包膜蛋白的吞噬增强。最后，ERV-K102免疫复合物的吞噬导致由DNA、中性粒细胞弹性蛋白酶和瓜氨酸化组蛋白H3组成的NETs形成。我们共同鉴定出一种免疫刺激性ERV-K包膜蛋白，其与SLE IgG形成免疫复合物时能够激活中性粒细胞。
