Sources of Pathogenic Nucleic Acids in Systemic Lupus Erythematosus

• Main Authors: Tomas Mustelin, Christian Lood, Natalia V. Giltiay
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2019-05-01
• Series: Frontiers in Immunology
• Subjects: lupus; interferon; nucleic acid sensors; mitochondria; reverse transcriptase
• Online Access: https://www.frontiersin.org/article/10.3389/fimmu.2019.01028/full

A hallmark of systemic lupus erythematosus (SLE), and several related autoimmune diseases, is the presence of autoantibodies against nucleic acids and nucleic acid-binding proteins, as well as elevated type I interferons (IFNs), which appear to be instrumental in disease pathogenesis. Here we discuss the sources and proposed mechanisms by which a range of cellular RNA and DNA species can become pathogenic and trigger the nucleic acid sensors that drive type I interferon production. Potentially SLE-promoting DNA may originate from pieces of chromatin, from mitochondria, or from reverse-transcribed cellular RNA, while pathogenic RNA may arise from mis-localized, mis-processed, ancient retroviral, or transposable element-derived transcripts. These nucleic acids may leak out from dying cells to be internalized and reacted to by immune cells or they may be generated and remain to be sensed intracellularly in immune or non-immune cells. The presence of aberrant DNA or RNA is normally counteracted by effective counter-mechanisms, the loss of which result in a serious type I IFN-driven disease called Aicardi-Goutières Syndrome. However, in SLE it remains unclear which mechanisms are most critical in precipitating disease: aberrant RNA or DNA, overly sensitive sensor mechanisms, or faulty counter-acting defenses. We propose that the clinical heterogeneity of SLE may be reflected, in part, by heterogeneity in which pathogenic nucleic acid molecules are present and which sensors and pathways they trigger in individual patients. Elucidation of these events may result in the recognition of distinct “endotypes” of SLE, each with its distinct therapeutic choices.