A missense single-nucleotide polymorphism in the PTPN22 gene causing an R620W substitution in the PTPN22 protein is one of the strongest genetic risk factors for rheumatoid arthritis. No consensus model has yet emerged on how PTPN22 increases risk of rheumatoid arthritis. As PTPN22 is a negative regulator of signaling through the T cell receptor, most studies to date have focused on the effect of the polymorphism on adaptive immune cell signaling. Here we wish to explore the concept that PTPN22-W620 impinges on the pathogenesis of rheumatoid arthritis through an action on myeloid cell signaling as well. Recent studies from our laboratory revealed a novel function of PTPN22 as a promoter of type 1 interferon release after engagement of myeloid cell toll-like receptors. Within this pathway, rheumatoid arthritis- predisposing PTPN22-W620 behaves as a loss-of-function variant, and macrophages and dendritic cells expressing PTPN22-W620 display a defect in toll-like receptor-induced type 1 interferon production. Type 1 interferon production by myeloid cells triggers several immunosuppressive mechanisms that protect from rheumatoid arthritis in mouse models. These include IL-27-mediated inhibition of arthritogenic Th17 cell differentiation and IL-1Ra-mediated suppression of inflammation in the rheumatoid joint. Here we hypothesize that loss of function of PTPN22 in dendritic cells and macrophages predisposes to rheumatoid arthritis by reducing type 1 interferon-dependent immunosuppressive mechanism. We will test our hypothesis by exploring whether loss of function of PTPN22 promotes myeloid cell-dependent differentiation of arthritogenic Th17 cells (Aim 1) and IL-1 mediated joint inflammation (Aim 2).
In Aim 3 we will assess whether loss-of-function of PTPN22 or carriage of PTPN22-W620 impairs the immunoregulatory ability of human myeloid cells. By defining immunological mechanisms that are defective in carriers of the PTPN22-W620 variant, our study will suggest new strategies for personalized therapy of rheumatoid arthritis in genetically predisposed individuals.
Variations in several rheumatoid arthritis genes are responsible for arthritis recurrence in families and differences in disease course among individuals. The objective of this grant is to elucidate a novel mechanism of action of one of the most potent human arthritis genes called PTPN22. Our goal is to identify anomalies of PTPN22-regulated immune functions that increase risk of disease and thus can be targeted by new personalized therapies.
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