Abstract
Endogenous DNA is primarily found intracellularly in nuclei and mitochondria. However, extracellular, cell-free (cf) DNA, has been observed in several pathological conditions, including autoimmune diseases, prompting the interest of developing cfDNA as a potential biomarker. There is an upsurge in studies considering cfDNA to stratify patients, monitor the treatment response and predict disease progression, thus evaluating the prognostic potential of cfDNA for autoimmune diseases. Since the discovery of elevated cfDNA levels in lupus patients in the 1960s, cfDNA research in autoimmune diseases has mainly focused on the overall quantification of cfDNA and the association with disease activity. However, with recent technological advancements, including genomic and methylomic sequencing, qualitative changes in cfDNA are being explored in autoimmune diseases, similar to the ones used in molecular profiling of cfDNA in cancer patients. Further, the intracellular origin, e.g., if derived from mitochondrial or nuclear source, as well as the complexing with carrier molecules, including LL-37 and HMGB1, has emerged as important factors to consider when analyzing the quality and inflammatory potential of cfDNA. The clinical relevance of cfDNA in autoimmune rheumatic diseases is strengthened by mechanistic insights into the biological processes that result in an enhanced release of DNA into the circulation during autoimmune and inflammatory conditions. Prior work have established an important role of accelerated apoptosis and impaired clearance in leakage of nucleic acids into the extracellular environment. Findings from more recent studies, including our own investigations, have demonstrated that NETosis, a neutrophil cell death process, can result in a selective extrusion of inflammatory mitochondrial DNA; a process which is enhanced in patients with lupus and rheumatoid arthritis. In this review, we will summarize the evolution of cfDNA, both nuclear and mitochondrial DNA, as biomarkers for autoimmune rheumatic diseases and discuss limitations, challenges and implications to establish cfDNA as a biomarker for clinical use. This review will also highlight recent advancements in mechanistic studies demonstrating mitochondrial DNA as a central component of cfDNA in autoimmune rheumatic diseases.
Highlights
In 1948, Mandel and Metais were the first to report on the presence of cfDNA in human plasma [1]
We have shown that neutrophil cell death i.e., NETosis in response to ribonucleoprotein-containing immune complex (IC) (RNP ICs), is dependent on mitochondrial reactive oxygen species (ROS) and the released neutrophil extracellular traps (NETs) are enriched in oxidized interferogenic mitochondrial DNA (mtDNA) [38]
There are many factors that needs to be addressed in order to establish cfDNA as a biomarker for systemic lupus erythematosus (SLE) from a clinical standpoint. cfDNA quantification as a diagnostic marker for SLE is promising but lacks clinical specificity since it is detected in other diseases albeit at lower levels
Summary
In 1948, Mandel and Metais were the first to report on the presence of cfDNA in human plasma [1]. It was used as a liquefaction agent to treat disease conditions associated with exudative responses to inflammation and infection [136] These studies by Johnson et al, [135, 136] laid basis for the first therapeutic application of bovine DNase I to treat SLE where patients injected with DNase I showed improvement in clinical symptoms, including a rapid fall in the ESR and in the levels of autoantibodies specific to DNA-containing antigens but not in other autoantibodies. A higher sera-to-plasma cfDNA ratio suggests that white blood cells from SLE patients are fragile and/or damaged and are prone to undergo disruption during coagulation releasing DNA These studies strengthened the view that cfDNA levels from serum samples should be interpreted with caution especially when employing sensitive detection methods and if possible, should be replaced by carefully collected plasma samples. Koffler et al [4] in a TABLE 1 | Cell-free DNA research in Systemic lupus erythematosus and Rheumatoid arthritis
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