Circulating Free DNA and Its Emerging Role in Autoimmune Diseases

Abstract

Liquid biopsies can be used to analyse tissue-derived information, including cell-free DNA (cfDNA), circulating rare cells, and circulating extracellular vesicles in the blood or other bodily fluids, representing a new way to guide therapeutic decisions in cancer. Among the new challenges of liquid biopsy, we found clinical application in nontumour pathologies, including autoimmune diseases. Since the discovery of the presence of high levels of cfDNA in patients with systemic lupus erythaematosus (SLE) in the 1960s, cfDNA research in autoimmune diseases has mainly focused on the overall quantification of cfDNA and its association with disease activity. However, with technological advancements and the increasing understanding of the role of DNA sensing receptors in inflammation and autoimmunity, interest in cfDNA and autoimmune diseases has not expanded until recently. In this review, we provide an overview of the basic biology of cfDNA in the context of autoimmune diseases as a biomarker of disease activity, progression, and prediction of the treatment response. We discuss and integrate available information about these important aspects.

Keywords: autoimmune diseases; cfDNA; inflammatory bowel disease; liquid biopsy; rheumatoid arthritis; systemic lupus erythaematosus.

Figure 1

Mechanisms involved in the release of cell-free DNA.

Figure 2

Potential mechanisms involving synovial fluid circulating-free DNA and the development of rheumatoid arthritis (RA). Release of cfDNA could increase in conditions including trauma, infections, or other mechanisms that we do not know (a). In addition, synovial fluid cfDNA seems to be enriched with specific hypomethylated CpG motif-rich sequences, with capacity to induce severe inflammatory responses independently. CfDNA and mtDNA can bind with LL-37, HMGB1, auto-Ig, and other proteins to form immunocomplexes that can be recognized by pattern recognition receptors (TLR-9 or STING) (b). This would facilitate the induction of cytokine overexpression, TNF-α and IL-6, that are critical for RA pathogenesis (c). Abbreviations: cfDNA, circulating-free DNA; HMGB1, high mobility group box chromosomal protein 1; IG, immunoglobulins; IL-6, interleukin 6; LL-37, human cathelicidin LL-37; mtDNA, mitochondrial DNA; STING, stimulator of interferon genes; TLR-9, toll-like receptor 9; TNF-α, tumor necrosis factor alpha.