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An unexpected source of antigens
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that can affect multiple organs. Antibodies against DNA have been found in the blood of patients with SLE; however, the sources of autoantigens have not been completely elucidated. Here, Melki et al. described the capacity of platelets to extrude mitochondrial DNA (mtDNA) through the stimulation of FcγRIIA. In lupus-prone transgenic mice, triggering FcγRIIA by immune complexes leads to platelets activation and release of mtDNA, which further accelerates and aggravates the lupus phenotype, providing a rationale for the role of mtDNA in SLE.
Abstract
The accumulation of DNA and nuclear components in blood and their recognition by autoantibodies play a central role in the pathophysiology of systemic lupus erythematosus (SLE). Despite the efforts, the sources of circulating autoantigens in SLE are still unclear. Here, we show that in SLE, platelets release mitochondrial DNA, the majority of which is associated with the extracellular mitochondrial organelle. Mitochondrial release in patients with SLE correlates with platelet degranulation. This process requires the stimulation of platelet FcγRIIA, a receptor for immune complexes. Because mice lack FcγRIIA and murine platelets are completely devoid of receptor capable of binding IgG-containing immune complexes, we used transgenic mice expressing FcγRIIA for our in vivo investigations. FcγRIIA expression in lupus-prone mice led to the recruitment of platelets in kidneys and to the release of mitochondria in vivo. Using a reporter mouse with red fluorescent protein targeted to the mitochondrion, we confirmed platelets as a source of extracellular mitochondria driven by FcγRIIA and its cosignaling by the fibrinogen receptor α2bβ3 in vivo. These findings suggest that platelets might be a key source of mitochondrial antigens in SLE and might be a therapeutic target for treating SLE.
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