Increased mTORC1 activation in salivary gland B cells and T cells from patients with Sjögren’s syndrome: mTOR inhibition as a novel therapeutic strategy to halt immunopathology?

A hallmark feature of pSS is B cell hyperactivity, including formation of autoantibodies, elevated serum IgG levels, increased numbers of B cells and IgG+/IgM+ plasma cells in salivary glands, and formation of germinal centre-like structures in the salivary glands associated with an increased risk of lymphoma development.1 2 Th cells and in particular T follicular helper (Tfh) cells play an important role in activation of B cells and formation of germinal centre-like structures.1 The mammalian/mechanistic target of rapamycin (mTOR) pathway is essential for growth, survival and proliferation of T and B cells and integrates multiple signals from the immune microenvironment, including growth factors, nutrients,and T cell receptor (TCR)/B cell receptor (BCR) engagement.3 4 The serine/threonine kinase mTOR is the catalytic subunit of two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), characterised by the incorporation of the proteins Raptor and Rictor, respectively. mTORC1 is generally described to play a role in protein translation, cell growth, proliferation and metabolism, whereas mTORC2 regulates metabolism, cell survival, rearrangement of the cytoskeleton and cell cycle progression (figure 1A).4 Figure 1. [...]the biopsies of the immunofluorescence cohort were taken, EULAR Sjögren's Syndrome Disease Activity Index and EULAR Sjögren's Syndrome Patient Reported Index scores were not available.SP910.1136/rmdopen-2018-000701.supp9 Supplementary data Gene expression of isolated B cells CD19+ B cells were isolated from fresh peripheral blood mononuclear cells (PBMC) using magnetic-activated cell sorting. The remaining mTOR-related genes measured were not differentially expressed between the groups. Since RPTOR but not RICTOR was decreased, we further investigated the mTORC1 pathway. Magnification: 400×. nSS, non-Sjögren’s sicca; pSS, primary Sjögren’s syndrome; pS6, phosphorylated S6. mTOR inhibition robustly decreases B cell and T cell activation Activation of PBMCs with a combination of TCR cross-linking superantigen SEB and TLR9 ligand resulted in increased phosphorylation of S6 in CD4+ T helper (Th) cells and B cells (figure 3A), associated with Th cell and B cell proliferation (figure 3B) and production of IFN-γ and IgG (figure 3C,D) in both HC and pSS.