Inherently inapt: the role of innate immunity in systemic lupus erythematosus pathogenesis

Recent advances in the understanding of the molecular and cellular basis of systemic lupus erythematosus (SLE) have challenged the classical view of SLE as the exemplary B cell and autoantibody-mediated disease. While much emphasis has been given to abnormalities on the humoral side of the immune response as essential to disease development, current findings suggest that mechanisms antedating B cell activation and autoantibody production are at the root of SLE initiation. In this review, we delineate key aspects involved with SLE pathogenesis, with a focus on how disturbances in cell death and metabolism may facilitate disease initiation and progression. We expound the relevance of disrupted cell death by non-programmed pathways, such as NETosis and ferroptosis, and of defective clearance of cellular debris, by complement factor and extracellular endonuclease deficiency, to the generation of damage-associated molecular patterns that will ultimately trigger interferon (IFN) production. We also describe how mitochondrial disturbances leading to reduced respiratory capacity, increased reactive oxygen species, and leakage of mitochondrial nucleic acids into the cytosol, underlie the dysfunctional behavior of multiple cell types involved in the immune response. Lastly, we outline the latest findings on how the IFN signature modulates the disease commencement, suggesting a primordial role of the skin stromal cells in producing several subtypes of IFN that will ultimately shape the behavior of infiltrating immune cells, thus constituting a paradigm shift on regards to the directionality of IFN effects between hematopoietic and non-hematopoietic cells. We advance the proposition that, in SLE, type I IFN plays a central role as an informational influence molecule, i.e., while IFN does not, in itself, act as an effector molecule driving SLE manifestations, it primes multiple cell types and misdirects immune responses, thus enabling autoreactivity.