{"id":4921,"date":"2020-01-07T19:17:37","date_gmt":"2020-01-07T10:17:37","guid":{"rendered":"http:\/\/163.180.4.222\/lab\/?p=4921"},"modified":"2020-01-07T19:17:37","modified_gmt":"2020-01-07T10:17:37","slug":"mitochondrial-dna-promotes-autoimmunity","status":"publish","type":"post","link":"https:\/\/biochemistry.khu.ac.kr\/lab\/?p=4921","title":{"rendered":"Mitochondrial DNA promotes autoimmunity"},"content":{"rendered":"

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The immune system provides essential protection from microbial infection but can damage tissue when its functions are excessive, sustained, or insufficiently regulated. In autoimmune disease, T lymphocytes and autoantibodies (antibodies directed to \u201cself\u201d-antigens) target the immune response to host tissue. But innate immunity, the first response to infection or cell stress, is also important in orchestrating pathologic immune responses in autoimmune diseases. The type I interferon (IFN) family of innate immune cytokines contributes to the aberrant immune functions of systemic lupus erythematosus (SLE) and several other autoimmune diseases (1<\/em><\/a>). Self\u2013nucleic acids induce type I IFN in SLE, but the mechanisms are not clear. On page 1531 of this issue, Kim\u00a0et al.<\/em>\u00a0(2<\/em><\/a>) show that pores formed by oligomerization of the mitochondrial voltage-dependent anion channel (VDAC) allow short mitochondrial DNA (mtDNA) fragments from stressed mitochondria to enter the cytosol, which may then induce type I IFN production.<\/p>\n

In SLE, autoantibody-containing immune complexes promote tissue damage and variable symptoms that include rash, arthritis, kidney disease, and cardiovascular disease. White blood cells from SLE patients demonstrate a type I IFN \u201csignature\u201d characterized by increased expression of hundreds of IFN-regulated genes (1<\/em><\/a>). Sustained activation of the IFN pathway supports differentiation of T follicular helper cells, development of autoantibody-producing plasma cells, and recruitment of inflammatory cells that produce tissue damage. Candidate cellular pathways that could induce type I IFN in SLE include the endosomal Toll-like receptors (TLRs), particularly TLR7, which recognizes single-stranded RNA in lupus immune complexes (3<\/em><\/a>), and cytosolic sensors of DNA or RNA that engage the adapter STING (stimulator of interferon genes) (4<\/em><\/a>). RNA-containing immune complexes are found in sera from many patients with SLE and have a well-established role in TLR7-dependent production of type I IFN by plasmacytoid dendritic cells, robust producers of the type I IFN-\u03b1 cytokine (3<\/em><\/a>,\u00a05<\/em><\/a>). The relevance of the cytosolic pathways and their nucleic acid triggers in SLE pathogenesis is less well established.<\/p>\n

Conditions of oxidative stress that generate mitochondrial reactive oxygen species (mROS) can cause mtDNA damage and single-stranded breaks, which can lead to mtDNA degradation. The resulting fragments might be a stimulus for type I IFN production (6<\/em><\/a>). In contrast to nuclear DNA, mtDNA includes CpG sequences that are less methylated, is packaged into DNA-protein complexes (nucleoids) rather than associated with histones, and may have less robust DNA repair mechanisms. Release of mtDNA might stimulate cytosolic DNA sensors, including cyclic guanosine monophospate (GMP)\u2013adenosine monophosphate (AMP) synthase (cGAS), and activate the downstream kinase TANK-binding kinase 1 (TBK1) and the transcription factor interferon regulatory factor 3 (IRF3) after engaging STING, an inducer of type I IFN production. mtDNA that has been modified by ROS or other cell stressors is a particularly effective inducer of type I IFN (7<\/em><\/a>). Thus, mtDNA could be an initiator of SLE by providing a trigger for innate immune system activation. If mtDNA leakage persisted over time, it could amplify established autoimmunity through effects of type I IFN on T and B lymphocytes and neutrophils, inducing clinically important disease flares.<\/p>\n

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