Transcriptomic and proteomic profiling reveals distinct pathogenic features of peripheral non-classical monocytes in systemic lupus erythematosus.

Peripheral blood monocytes propagate inflammation in systemic lupus erythematosus (SLE). Three major populations of monocytes have been recognized namely classical (CM), intermediate (IM) and non-classical monocytes (NCM). Herein, we performed a comprehensive transcriptomic, proteomic and functional characterization of the three peripheral monocytic subsets from active SLE patients and healthy individuals. Our data demonstrate extensive molecular disruptions in circulating SLE NCM, characterized by enhanced inflammatory features such as deregulated DNA repair, cell cycle and heightened IFN signaling combined with differentiation and developmental cues. Enhanced DNA damage, elevated expression of p53, G0 arrest of cell cycle and increased autophagy stress the differentiation potential of NCM in SLE. This immunogenic profile is associated with an activated macrophage phenotype of NCM exhibiting M1 characteristics in the circulation, fueling the inflammatory response. Together, these findings identify circulating SLE NCM as a pathogenic cell type in the disease that could represent an additional therapeutic target.

Antiviral Innate Immune Responses in Autoimmunity: Receptors, Pathways, and Therapeutic Targeting.

Innate immune receptors sense nucleic acids derived from viral pathogens or self-constituents and initiate an immune response, which involves, among other things, the secretion of cytokines including interferon (IFN) and the activation of IFN-stimulated genes (ISGs). This robust and well-coordinated immune response is mediated by the innate immune cells and is critical to preserving and restoring homeostasis. Like an antiviral response, during an autoimmune disease, aberrations of immune tolerance promote inflammatory responses to self-components, such as nucleic acids and immune complexes (ICs), leading to the secretion of cytokines, inflammation, and tissue damage. The aberrant immune response within the inflammatory milieu of the autoimmune diseases may lead to defective viral responses, predispose to autoimmunity, or precipitate a flare of an existing autoimmune disease. Herein, we review the literature on the crosstalk between innate antiviral immune responses and autoimmune responses and discuss the pitfalls and challenges regarding the therapeutic targeting of the mechanisms involved.