Systemic lupus erythematosus (SLE) is a common autoimmune disorder in which the body’s immune system mistakenly attacks healthy tissues, it can affect the skin, joints, kidneys, brain, and other organs. Though the initial trigger for the disease remains unknown, it is characterized by a misdirected immune response in people who are genetically susceptible. A normal immune system makes antibodies that protect against pathogens such as viruses and bacteria. Lupus is characterized by the presence of antibodies directed against a person’s own proteins; these are most commonly anti-nuclear antibodies, which are autoantibodies that target normal proteins within the nucleus of a cell. Currently there is no cure for SLE.
Now, a study from researchers at The Baylor Institute for Immunology Research (BIIR) shows that the neutrophils, a type of immune cell, of SLE patients release oxidized DNA from their mitochondria that can stimulate an unwanted immune response. The team states that their findings suggest targeting the pathways that lead to the accumulation of this DNA, or facilitating its removal, could be a new way to treat this chronic autoimmune disease. The study is published in The Journal of Experimental Medicine.
Previous studies show though the initial trigger for the disease remains unknown, it is characterized by the generation of autoantibodies that recognize the patient’s own DNA or RNA-protein complexes and the excessive production of type I interferons, signaling proteins which activate the body’s immune response. Earlier studies from the lab showed that SLE patient neutrophils respond to certain autoantibodies by extruding some of their DNA, which subsequently stimulates another type of immune cell, called plasmacytoid dendritic cells, to produce type I interferons. The current study shows that neutrophils do not complete selective degradation of mitochondria upon induction of mitochondrial damage, rather, they extrude mitochondrial components, including DNA (mtDNA), devoid of oxidized residues.
The current study shows that SLE neutrophils accumulate oxidized DNA within their mitochondria and eventually extrude it from the cell to stimulate the production of interferons by plasmacytoid dendritic cells. The group explain that mitochondria are the cell’s energy-generating organelles, and they contain their own DNA packaged up into structures called nucleoids. They go on to add that to safely rid themselves of oxidized mitochondrial DNA, neutrophils usually disassemble their nucleoids and transfer the oxidized DNA to the cell’s lysosomes for degradation.
Results show, in contrast, that when SLE neutrophils are exposed to certain autoantibodies, nucleoid disassembly is impaired, and the oxidized DNA is retained inside mitochondria before eventually being extruded from the cell to stimulate interferon production. Data findings show that SLE patients also generated antibodies against the extruded, oxidized mitochondrial DNA.
The team surmise that oxidized mitochondrial DNA released from neutrophils therefore induces an immune response and may contribute to SLE pathogenesis. For the future, the researchers state that therapeutic efforts to enhance pathways involved in oxidized mitochondrial DNA degradation should be explored in human SLE, a disease for which only one new drug has been approved in the past 50-years.
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