Systemic Lupus Erythematosus and DNA Degradation and Elimination Defects

Abstract

Introduction: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by the production of autoantibodies specific for components of the cell nucleus and that causes damage to body tissues and organs. The pathogenesis of SLE remains unclear, with numerous studies pointing to a combination of genetic and environmental factors. A critical stage in SLE development is cell necrosis, in which undegraded chromatin and nucleoproteins are released into the blood, resulting in circulating cell-free DNA and serum nucleoproteins that trigger anti-dsDNA autoantibody production. This systematic literature review aimed to examine whether SLE stems from a DNA degradation and elimination defect. Materials and Methods: An advanced literature search was conducted in PubMed using the following keywords: [(“SLE” OR “Systemic Lupus Erythematosus” OR “Lupus”)] AND [(“DNA” OR “DNA Degradation”)] AND [(“Defect Elimination”)]. More articles were obtained from the references of the identified articles and basic Google searches. Twenty-five peer-reviewed articles published within the past 10 years (2007–2018) were included for review. Results: The findings of each study are summarized in Tables 1 , 2 . Discussion and Conclusion: The etiopathogenesis of SLE remains controversial, which limits therapeutic inventions for this disease. However, SLE is a DNA degradation and elimination disorder caused by uncleared histones and nuclear material that leak into the extracellular space and form cell-free DNA, triggering an immune response that destroys tissues and organs. Under normal conditions, apoptosis allows DNA and other nuclear material to be efficiently cleared through degradation and additional complex mechanisms such that this material does not trigger the immune system to produce nuclear autoantibodies.

In vivo evidence for extracellular DNA trap formation

“…Systemic lupus erythematosus (SLE) is considered to be a prototypic systemic autoimmune disease and is characterized by loss of tolerance to self-antigens, abnormal T-and B-cell responses, and autoantibody production [66][67][68][69][70] . Its pathogenesis involves defective clearance of immune complexes and debris containing nucleic acids, excessive innate immune activation involving Toll-like receptors (TLR) and type I interferons, as well as aberrant lymphocyte activation 71 .…”

Emerging roles of Toll-like receptor 9 in cardiometabolic disorders

“…For example, circulating cfDNA level is higher in systemic sclerosis [ 43 ], experimental pulmonary thromboembolism [ 44 ], end-stage renal disease [ 45 ], and sepsis [ 46 ]. Of note, the role of cfDNA has attracted much attention in the pathogenesis of autoimmune diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis [ 47 – 52 ]. In fact, autoantibodies against dsDNA and nucleosomes represent a feature of SLE [ 39 , 53 , 54 ].…”

Sustained high expression of multiple APOBEC3 cytidine deaminases in systemic lupus erythematosus

“…Sustained oxidative stress and mtDNA lesions lead to DNA leakage into the cytosol and induce potent IFN-I responses. Other hallmarks of SLE are profound lymphopenia, improper clearance of apoptotic and necrotic cells and circulating auto-antibodies against DNA and nuclear components 37 – 41 . The pathogenesis of SLE is multifactorial, involving genetic, immunological and environmental factors 41 .…”

“…Other hallmarks of SLE are profound lymphopenia, improper clearance of apoptotic and necrotic cells and circulating auto-antibodies against DNA and nuclear components 37 – 41 . The pathogenesis of SLE is multifactorial, involving genetic, immunological and environmental factors 41 . There is currently no licensed drug targeting IFN-I or the IFN-I receptor in SLE 42 .…”