Regulation of type I interferons in health and autoimmune disease

Type I interferons (IFN) have a crucial role in the pathogenesis of a range of autoimmune diseases including systemic lupus erythematosus (SLE). Increased IFN activity is observed at preclinical stages and associated with disease progression, but the cause of this dysregulation remains unclear. Plasmacytoid dendritic cells (pDCs) produce large amounts of IFNs in viral infection, however their precise role in autoimmunity is still elusive. Peripheral blood and skin biopsies from different patient groups were used for gene expression assays, immunophenotyping, in vitro functional assays, transcriptomics and other assays to investigate the dysregulated IFN axis and the role of pDCs in preclinical autoimmunity and SLE. In preclinical autoimmunity and SLE, pDCs were found to exhibit an exhausted phenotype with: (i) loss of TLR-mediated IFN-α production; (ii) failure to induce T cell activation; (iii) transcriptional profile of cellular senescence; (iv) increased telomere erosion. In contrast, diffuse expression of type I IFNs was observed in the epidermis but not in leucocyte-infiltrating areas of patients with SLE as well as in non-lesional skin of individuals with preclinical autoimmunity. Additionally, keratinocytes isolated from non-lesional skin of patients with SLE and individuals with preclinical autoimmunity showed a significantly enhanced type I IFN expression in response to UV light and nucleic acids. Lastly, TNF-α regulates the function of pDCs by suppressing IFN-α production but enhancing a functional drift to antigen presentation and T cell activation. These findings revise our understanding of immune regulation in human autoimmunity. Non-haematopoietic tissue cells can perpetuate IFN responses; meanwhile the professional IFN-producing pDCs have lost their immunogenic properties. In patients with SLE, these insights may indicate potential therapeutic targets outside the conventional immune system, while knowledge of how IFN dysregulation initiates could allow disease prevention.