Abstract
Human lupus is strongly associated with a gene expression signature characterized by over-expression of Type I interferon-regulated genes. A strong interferon signature generally is not seen in the standard mouse models of lupus, despite considerable evidence for the involvement of toll-like receptor-driven interferon production. In contrast, pristane-induced lupus exhibits a prominent TLR7-dependent interferon signature. Importantly, genetic disorders with dysregulated interferon production in both human beings and mice cause severe autoinflammatory diseases but not the typical manifestations of lupus, suggesting that interferon over-production is insufficient to cause systemic lupus erythematosus itself. Single-gene models in mice suggest that lupus-like disease may result from abnormalities in B-cell activation and the clearance of dead cells. Pristane may mimic human systemic lupus erythematosus by causing synergistic abnormalities in interferon production along with defective clearance of apoptotic cells and over-active B-cell signaling.
Highlights
Reviewed by: Ching Chen, University of Maryland School of Medicine, USA Dwight Kono, The Scripps Research Institute, USA
It has become increasingly clear that over-production of Type I interferon (IFN-I) is strongly associated with Systemic lupus erythematosus (SLE) and that this cytokine is involved in disease pathogenesis
This review focuses on the suitability of mouse models for studying the interferon signature positive subset of SLE, which as noted above is characterized clinically by the production of specific autoantibodies with an increased prevalence of nephritis and possibly cutaneous manifestations
Summary
A strong interferon signature generally is not seen in the standard mouse models of lupus, despite considerable evidence for the involvement of toll-like receptor-driven interferon production. Despite the strong association of IFN-I over-production with SLE and evidence that the severity of lupus-like disease usually is attenuated in mice lacking the Type I interferon receptor (IFNAR) [12, 13], our understanding of the relationship of IFN-I to SLE pathogenesis is incomplete. [5] Why do Stimulator of IFN Genes (STING)-deficient lupus mice paradoxically develop more severe lupus-like disease than controls, despite the fact that human gain-of-function mutations are associated with inflammatory disease and a high interferon signature [18, 19]? Animal models of lupus induce lupus-like manifestations, whereas IFNβ generally does not [10]? [3] Why does treatment with neutralizing antibodies against IFNα (e.g., rontalizumab) lead to improvement of lupus in the interferon signature negative subset but not in the interferon signature high subset [15]? [4] Why do children with “interferonopathies,” who are identified by the presence of a strong interferon signature, develop vasculopathy, nervous system disease, and other inflammatory manifestations but only rarely lupus [16, 17]? [5] Why do Stimulator of IFN Genes (STING)-deficient lupus mice paradoxically develop more severe lupus-like disease than controls, despite the fact that human gain-of-function mutations are associated with inflammatory disease and a high interferon signature [18, 19]? [6] Why does IFN-I protect MRL/lpr mice from lupus, while exacerbating it in other strains [20]? [7] How is IFN-I linked to the production of lupus-specific autoantibodies?
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
