Targeting the proteoglycan switch for lupus therapy
In lupus, a type of immune cell called plasmacytoid dendritic cells or pDCs produce an excess of a protein called type I interferon that fuels damaging inflammation and lupus. While a therapy like anifrolumab-fnia that blocks type I interferons can help relieve lupus symptoms, it may also lower the immune system’s ability to respond to infections. pDCs have a unique protein called Protein Tyrosine Phosphatase Receptor Type S or PTPRS that can reduce the production of damaging type I interferons. PTPRS can be turned “on” or “off” via a proteoglycan switch. Using this grant, Dr. Bottini aims to reduce lupus symptoms while leaving the important infection-fighting components of the immune system intact. He will repair the broken pDCs in lupus patients by targeting the proteoglycan switch that turns PTPRS “on” or “off.” Dr. Bottini’s research team will also test whether turning PTPRS “on” via the proteoglycan switch enhances the effectiveness of medications such as belimumab that is already approved to treat lupus.
What this study means for people with lupus
This work should pave the way for the development of new anti-lupus medications that inhibit the production of type I interferons with reduced risks of infections.
The objective of this grant is to validate a novel approach to normalize the excessive type 1 interferon production by plasmacytoid dendritic cells, which is a well-established pathogenic mechanism. Several therapeutic interventions for lupus based on plasmacytoid dendritic cell inactivation or depletion or on systemic blockage of type 1 interferon signaling are under development. Our idea is based on the finding that human plasmacytoid dendritic cells specifically express a transmembrane tyrosine phosphatase called PTPRS, which specifically controls their release of type 1 interferons. PTPRS is modulated by the interaction of its extracellular domain with surface proteoglycans in a process known as “the proteoglycan switch”. Our laboratory discovered that the proteoglycan switch can be pharmacologically targeted to achieve activation of the phosphatase and specifically inhibit release of type 1 interferons from plasmacytoid dendritic cells. Our goal is to validate PTPRS and its intracellular pathway in plasmacytoid dendritic cells as targets for novel treatments of lupus. PTPRS-modulating treatments would not operate through complete plasmacytoid dendritic inactivation or depletion or complete blockage of type 1 interferons, thus they could be less immunosuppressive and more amenable to combination with currently approved agents. In this grant we will complete the first three steps toward achieving our goal: 1) we will establish that PTPRS physiologically regulates type 1 interferon production by plasmacytoid dendritic cells of lupus patients, 2) we will show that modulation of the pathway improves the course of lupus in a mouse model if performed alone or 3) in combination with an analog of belimumab, an approved agent for lupus.