Systemic Lupus Erythematosus Pathogenesis: Interferon and Beyond

Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. The partial success of drugs targeting these pathways, however, supports heterogeneity in upstream mechanisms contributing to disease pathogenesis. In this review, we focus on recent insights from genetic and immune monitoring studies of patients that are refining our understanding of these basic mechanisms. Among them, novel mutations in genes affecting intrinsic B cell activation or clearance of interferogenic nucleic acids have been described. Mitochondria have emerged as relevant inducers and/or amplifiers of SLE pathogenesis through a variety of mechanisms that include disruption of organelle integrity or compartmentalization, defective metabolism, and failure of quality control measures. These result in extra- or intracellular release of interferogenic nucleic acids as well as in innate and/or adaptive immune cell activation. A variety of classic and novel SLE autoantibody specificities have been found to recapitulate genetic alterations associated with monogenic lupus or to trigger interferogenic amplification loops. Finally, atypical B cells and novel extrafollicular T helper cell subsets have been proposed to contribute to the generation of SLE autoantibodies. Overall, these novel insights provide opportunities to deepen the immunophenotypic surveillance of patients and open the door to patient stratification and personalized, rational approaches to therapy.

Automated summary

Autoreactive B cells and interferons play important roles in the development of systemic lupus erythematosus (SLE). Recent studies on genetics and immune monitoring of SLE patients have provided new insights into the underlying mechanisms, including novel gene mutations affecting B cell activation and clearance of interferogenic nucleic acids. Mitochondria have been identified as inducers or amplifiers of SLE through various mechanisms, leading to the release of interferogenic nucleic acids and activation of immune cells. Specific autoantibodies associated with monogenic lupus or triggering interferogenic amplification loops have been discovered. Additionally, atypical B cells and novel T helper cell subsets have been proposed to contribute to the generation of SLE autoantibodies. These findings offer opportunities for improved monitoring and personalized therapy for SLE patients.