Type I interferons and autoimmunity

The cytokine family of type I interferons plays a crucial role in antimicrobial, most importantly antiviral, immunity. Through signaling of a cognate IFN α/β ?receptor, type I IFNs induce a multitude of genes called IFN-stimulated genes (ISGs) which play critical roles in conveying direct and broad-spectrum anti-viral protection to the cells. During viral infection, transiently produced type I IFNs also help bridge the innate and the adaptive immune responses for effective viral clearance. Surprisingly, persistent systemic IFN signature has been observed in several autoimmune diseases such as systemic lupus erythematosus (SLE), Sjögren syndrome or systemic sclerosis, which at times correlates with the severity of disease, suggesting that abnormal production of type I IFNs may function as a key component of the etiopathology of autoimmunity. In this chapter we first review the essential role of type I IFNs in antiviral immune response, then present clinical and experimental evidence that lead to the association of abnormal production of type I IFNs to various autoimmune diseases. Plasmacytoid dendritic cells (pDCs) are unique immune cells specialized in the rapid and robust production of all type I IFN subtypes in responding to viral nucleic acids via endosomal TLR activation. Under autoimmune conditions, several host-derived factors, complexed to self-nucleic acids, can trigger the activation of pDCs and release of type I IFNs. Aberrant type I IFN production potently promotes the development of autoimmunity through their pluripotent effects on almost all immune cell populations that participate in autoantibody production as well as tissue injury. Last, we discuss the questions remaining to be addressed on the precise role of type I IFNs in autoimmunity and briefly touch the effort of developing therapeutic agents targeting type I IFNs and components along the signaling pathway leading to IFN production for the treatment of autoimmune diseases.