"They initiate downstream inflammatory signalling pathways such as type I interferon (IFN), nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) by recognizing endogenous or exogenous nucleic acid11,12. In plasmacytoid dendritic cells (pDCs), activation of the TLR7 and TLR9 pathways leads to the release of large amounts of IFNs, promoting the presentation of autoantigens and the occurrence of inflammatory responses13."
"PLD4 is highly expressed in DCs, monocytes and B cells. It is a 5′ exonuclease that localizes in the endolysosomes and can cleave single-stranded RNA (ssRNA) and single-stranded DNA (ssDNA), thereby restricting the overactivation of TLR7 and TLR918,19,20,21,22,23. Pld4-knockout (KO) mice demonstrate a range of autoimmune phenotypes, including reduced body weight, enlarged spleen size, increased autoantibodies and immune complex deposition24."
SLE is a multiorgan condition of variable severity. Monogenic lupus includes autoimmune disorders caused by single-gene mutations with lupus-like phenotypes. Over 30 genes causing lupus have been identified. Intracellular nucleic-acid-sensing pathways defend against pathogens, tissue damage and aid repair. Endosomal TLR7 and TLR9 sense RNA and DNA and activate type I interferon, NF-κB and MAPK signalling when they recognize endogenous or exogenous nucleic acids. In plasmacytoid dendritic cells, TLR7/TLR9 activation triggers large interferon release, promoting autoantigen presentation and inflammation. In B cells, these pathways drive production of nucleic-acid autoantibodies. PLD4 is an endolysosomal 5′ exonuclease expressed in dendritic cells, monocytes and B cells that cleaves ssRNA and ssDNA to limit TLR7/TLR9 overactivation. Pld4-knockout mice display weight loss, splenomegaly, increased autoantibodies and immune complex deposition; combined Pld4/Pld3 loss causes early death. PLD4 deficiency has not yet been implicated in human disease.
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