Abstract
BACKGROUND: IL-10-producing regulatory B cells (Bregs) are of great importance in autoimmunity, as they inhibit proinflammatory T cells. We have shown that IL-10-producing Bregs in psoriatic arthritis(PsA) were decreased and inversely correlated with IFNγ+T cells (TH1 cells) and IL-17+ T cells (TH17 cells). B cells with overexpression of CD39 have also inhibitory effects on proinflammatory T cells. PRELIMINARY RESULTS: Our preliminary data showed that Apremilast, a phosphodiesterase-4(PDE-4) inhibitor, used in the treatment of PsA and psoriasis (Ps) increased IL-10-producing Bregs and reduced IFNγ+CD3+ T cells and IL-17+CD3+ T cells. We also found reduced activation of p38MAP kinase and the transcription factor STAT3, two important signaling pathways of IL-10 production, in PsA. SPECIFIC AIMS: The aim of this research proposal is to study for the first time the immunomodulatory effect of Apremilast on signaling pathways in peripheral blood mononuclear cells (PBMCs) and CD39high B cells in PsA and Ps. METHODS: We will study CD39 expression in B cells from patients with PsA and Ps before and after Apremilast treatment and their relation to IFNγ+ and IL-17+ T cells. Activation of CREB (cAMP response element-binding protein), STAT3, and p38MAPK in PBMCs and CD39high B cells from patients with PsA and Ps before and after Apremilast. The effect of CD39high B cells on T cell IFNγ and IL-17 production will also be studied. SIGNIFICANCE: This study will elucidate the molecular pathways of Apremilast and better define Bregs in PsA and Ps.