Advances in understanding the role of type I interferons in systemic lupus erythematosus

Abstract

Purpose of review: Advances in understanding the genetic and molecular basis of innate immune system activation and function have supported the hypothesis that type I interferons (IFN-I), the essential mediators of antiviral host defense, are central contributors to the pathogenesis of systemic lupus erythematosus (SLE). This review addresses the recent data that support the rationale for therapeutic targeting of the IFN-I pathway in SLE.

Recent findings: New insights into the mechanisms of cell-intrinsic innate immune system activation, driven by endogenous virus-like nucleic acids and potentially modified by environmental stressors, provide a model for the induction of IFN-I that may precede the clinically apparent autoimmunity in patients with lupus. Further amplification of IFN-α production, induced by nucleic-acid-containing immune complexes that activate endosomal Toll-like receptors, augments and sustains immune system activation, autoimmunity and tissue damage.

Summary: As demonstrated in the murine studies of persistent virus infection accompanied by sustained production of IFN-I, blockade of the IFN-I pathway may reverse the immune dysregulation and tissue damage that are the essential features of the immunopathogenesis of SLE. Recent research progress has identified numerous therapeutic targets, and specific candidate therapeutics relevant to the IFN-I pathway are under investigation.

Figure 1. Induction of type I interferon in lupus pathogenesis

Recent data from studies of cytoplasmic sensors of RNA and DNA, including RIG-I, MDA5 and cGAS, suggest that in addition to exogenous microbes, endogenous triggers can activate signaling pathways that induce IFN-I, with IFN-β the dominant product. Stimulatory cytoplasmic RNA or DNA, in some cases enriched in endogenous retrotransposon sequences, may result from impaired regulation of genome integrity or altered nucleic acid degradation. Cell-intrinsic induction of IFN-I may represent a primary mechanism that primes the immune system for development of autoimmunity. Once autoantibodies have formed, nucleic acid-containing immune complexes, including those derived from products of apoptosis, necrosis, NETosis, or extrusion of mitochondria, can access endosomal TLR7 or TLR9 and induce high level production of IFN-α by plasmacytoid dendritic cells, amplifying and sustaining immune dysregulation and promoting inflammation and tissue damage. Free chromatin might be a cell-extrinsic inducer IFN-I production by neutrophils, contributing to lupus pathology.