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. 2019 Jul 10;10:1601. doi: 10.3389/fimmu.2019.01601

Figure 1.

Figure 1

Cellular and molecular responses to extracellular and intracellular DNA. The schematic shows involvement of extracellular DNases in anti-DNA responses/ SLE pathogenesis and intracellular DNases in interferonopathies. The major molecular pathways of autoantibody and autoinflammatory responses are highlighted in different colors as described below. Yellow: Primary cellular and molecular pathways of anti-DNA Ab production. DNase1L3-deficiency increases availability and uptake of cfDNA (naked DNA, NET-DNA, cell-free chromatin, and microparticle-associated chromatin), along with associated proteins potentially through self-reactive BCRs or through cell-surface TLRs. Internalized self-DNA causes TLR-MyD88 dependent B cell activation, differentiation, IFN production, and presentation of cfDNA-associated peptides to T cells. Blue: T cells help in anti-DNA Ab production. Costimulatory and cognate MHC-TCR interactions between DNA-reactive B and T cells stimulate activation, proliferation, and differentiation of B cells into anti-DNA Ab secreting cells. Purple: Amplification of anti-DNA Abs through myeloid cell help. Anti-DNA antibodies accumulate and form immune complexes with cfDNA which are internalized through Fc-receptors on myeloid cells i.e., DCs, pDCs, macrophages, further inducing IFN production through TLR-MyD88 pathway. Myeloid cells also present self-antigen to T cells further amplifying the B-T cell interaction loop and anti-DNA Ab production. Red: Undigested DNA promotes IC formation and deposition in target organs. DNase1 expressed in kidneys digests locally produced apoptotic cell-derived DNA. IC-formation is enhanced in the presence of extracellular DNA. ICs deposit in kidneys causing immune complex-mediated tissue damage. Green: DNases and signaling pathways regulating interferonopathies. DNase2 cleaves endocytosed apoptotic cell-derived DNA while TREX1 cleaves cytosolic DNA. Absence of DNase2 and TREX1 trigger activation of cGAS-STING pathway causing IFN production leading to interferonopathies. DNase2 and TREX1 do not directly contribute to anti-DNA antibody production.