A regulatory network of type I interferon

What is it about?

Type I interferons are cytokines with an essential role in immune defense against pathogens. However, inappropriate production of these cytokines may harm the host by promoting an inflammatory response, ultimately leading to the development of autoimmune or chronic inflammatory diseases. Plasmacytoid dendritic cells (pDCs), a subset of dendritic cells, produce type I interferon after sensing pathogenic nucleic acids through toll-like receptors 7 and 9, and have been implicated in autoimmune diseases. To regulate the production of type I interferons, pDCs possess regulatory receptors such as blood dendritic cell antigen 2 (BDCA-2), capable of inhibiting the production of type I interferon.

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Photo by Clint Adair on Unsplash

Photo by Clint Adair on Unsplash

Why is it important?

This study demonstrates that both commercial and human plasma–derived heparin bind to BDCA-2, resulting in the inhibition of type I interferons in human pDCs. Moreover, upon activation of the cells by DNA, a soluble form of BDCA-2 (referred to as solBDCA-2) is released, which neutralizes heparin in the environment and enhances the production of type I interferon by pDCs. This discovery sheds light on how pDCs in circulation are tightly regulated for type I interferon production due to the presence of heparin in plasma, with this regulation being lifted once the cells exit circulation and migrate to tissues. Within tissues, pDC activation by pathogenic nucleic acids leads to the production of solBDCA-2, which neutralizes heparin and facilitates the production of type I interferon. These molecular components (heparin, the receptor BDCA-2, and soluble BDCA-2) form a regulatory network modulating type I interferon production. Of particular importance, scrub typhus, an acute infectious disease caused by the bacterium Orientia tsutsugamushi, has been linked to an increased risk of developing Systemic Lupus Erythematosus (SLE). In this study, we observed elevated solBDCA-2 levels in the serum of patients with scrub typhus compared to healthy controls, which positively correlated with anti-double-stranded DNA antibodies (a marker for SLE). This suggests an increased activation of pDCs during infection and dysregulation of the regulatory network modulating type I interferon in infection-related autoimmune diseases. Understanding the function and regulation of pDCs may hold implications for the treatment of pDC-related autoimmune disorders.