Antigenic Function of 14-3-3ζ is a Novel Tool to Treat Rheumatoid Arthritis

Abstract

Abstract Autoantigens are an integral part of autoimmunity, but their role in health and disease are mostly unknown. We identified 14-3-3ζ as an autoantigen in patients with thoracic aortic aneurysm caused by large vessel vasculitis. Like others, neither the cause nor the consequence of newly-identified antigenic function of 14-3-3ζ protein is known. To address this, we investigated the antigenicity of 14-3-3ζ by studying ex vivo effects on human peripheral blood mononuclear cells (PBMC) polarization, and in vivo using a rat autoimmune disease model. Exogenous 14-3-3ζ promoted PBMC proliferation and T cell polarization towards increasing Th1 and Th17 populations. A specific increase in Th1 cells and IFN-γ production provided evidence for MHC class II presentation of 14-3-3ζ antigen. These 14-3-3ζ-induced responses of T cell polarization and cytokine secretion were inhibited by immunosuppressive agents. Our in-depth studies further revealed that 14-3-3ζ-induced phosphorylation of MAPK led to NF-kB activation in macrophages and PBMC. In vivo administration of recombinant 14-3-3ζ in rats triggered strong innate and adaptive immune responses with significant increases in IL-17, IFN-γ, and anti-14-3-3ζ antibody. Importantly, the immunization of Lewis rats with 14-3-3ζ protected them from rheumatoid arthritis in Pristane-Induced-Arthritis (PIA) model. These collectively demonstrate that the antigenic 14-3-3ζ by acting as a DAMP promotes IFN-γ and IL-17 levels, and confers an anti-arthritic effect. To the best of our knowledge, this is the first report describing the antigenic function of 14-3-3ζ and its physiologically relevant anti-arthritic role.