Plasmacytoid dendritic cells promote the pathogenesis of Sjögren's syndrome

Abstract

Plasmacytoid dendritic cells (pDCs) produce type I interferons (IFNs) and promote pathogenesis of multiple autoimmune diseases. Autoimmune Sjögren's syndrome (SS) primarily affects salivary and lacrimal glands, causing their inflammation, destruction and dysfunction. pDCs and type I IFN activity are elevated in salivary glands of SS patients, and this study seeks to elucidate the in vivo actions of pDCs in SS pathogenesis using the non-obese diabetic (NOD) mouse model. We confirmed the type I IFN-dependency of SS development in female NOD mice and elevation of pDC-type I IFN in their submandibular glands (SMGs). We administered a pDC-depleting anti-BST2/CD317 antibody to female NOD mice from 4 to 7 weeks of age at the early stage of SS, and assessed SS pathologies at age 10 weeks, the time of disease onset. Depletion of pDCs impeded the development of SMG inflammation and secretory dysfunction. It drastically reduced the amount of type I IFN mRNA and the number of total leukocytes, and T- and B lymphocytes in SMGs. Gene expression analyses showed that pDC depletion markedly diminished SMG expression of IL-7, BAFF, TNF-α, IFN-γ, CXCL9, CXCL11, CD40, CD40L, Lt-α, Lt-β and NOS2. Hence, pDCs critically contribute to the development and onset of SS-like salivary gland exocrinopathy.