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Abstract
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease whose pathogenesis can be conceptualized by a model based on a central role for immune complexes (ICs) between antinuclear antibodies and nucleic acids. According to this model, ICs can promote pathogenesis by two main mechanisms: deposition in the tissue to incite local inflammation and interaction with cells of the innate immune system to stimulate the production of cytokines, most prominently type 1 interferon. The latter stimulation results from the uptake of DNA and RNA in the form of ICs into cells and subsequent signaling by internal nucleic acid sensors for DNA and RNA. These sensors are likely important for the response to intracellular infection, although they may also be triggered during cell stress or injury by DNA or RNA aberrantly present in the cytoplasm. For IC formation, a source of extracellular DNA and RNA is essential. The current model of SLE posits that cell death is the origin of the nucleic acids in the ICs and that impairment of clearance mechanisms increases the amount of nuclear material in the extracellular space. This model of SLE is important since it points to new approaches to therapy; agents targeting interferon or the interferon receptor are examples of therapeutic approaches derived from this model. Future studies will explore novel biomarkers to monitor the operation of these mechanisms and to elucidate other steps in pathogenesis that can be targeted for therapy.
Highlights
Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease that primarily affects young women and causes highly variable clinical and serological manifestations[1,2]
Patients with mutations in DNase 1L3 present with a vasculitis-like condition, whereas mice with a knockout of the gene for DNase 1L3 develop a lupus-like illness with antiDNA production and a dramatic increase in DNA associated with MPs70–74
Historically, SLE has been conceptualized as a disease of immune complexes (ICs) composed of ANAs and their cognate nuclear antigens
Summary
Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease that primarily affects young women and causes highly variable clinical and serological manifestations[1,2]. Mutations in internal nucleic acid sensors and nucleases are rare causes of SLE in humans, these conditions suggest a mechanism by which nucleic acids can drive autoreactivity via the internal receptors In this schema, ANAs are critical effectors since they can form ICs that transport DNA and RNA into cells of the innate immune system. Patients with mutations in DNase 1L3 present with a vasculitis-like condition, whereas mice with a knockout of the gene for DNase 1L3 develop a lupus-like illness with antiDNA production and a dramatic increase in DNA associated with MPs70–74 These observations provide evidence for the relevance of particles as a source of extracellular DNA for IC formation and suggest the use of MP-ICs as biomarkers. Understanding of events in SLE will need fundamental investigation to elucidate the role of immune signaling by cytoplasmic nucleic acids in the context of infection
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