Background Plasmacytoid dendritic cells (pDCs) are dendritic cells characterized by their unique ability to produce large amounts of type I interferon (IFNalpha/beta) upon Toll-like receptor (TLR) 7/9 triggering. Blood type I interferon signature is the hallmark of several autoimmune diseases including systemic lupus erythematosus (SLE) and pDCs have been shown to play a central role. pDCs express surface regulatory receptors, BDCA2 and ILT7, involved in negative regulation of IFNalpha secretion1. Both receptors use the gamma chain of high affinity Fc receptor for immunoglobulin E (IgE), FcepsRI. We hypothesized that IgE engagement of FcepsRI on pDCs may have an effect on IFNalpha production and other functions, in SLE patients.
Objectives Our objective is to investigate, in the context of SLE, the effects of IgE treatment on pDCs. We look at IFNalpha secretion by pDCs, and pDC function as Antigen Presenting Cell (APC) in the orientation of CD4+ T lymphocyte (LT4) response.
Methods Serum levels of total IgE were measured by immunoCAP Phadiatop, in healthy volunteers, SLE and allergic patients. FcepsRI expression on pDCs (CD123+ BDCA2+) was evaluated by flow cytometry in SLE patients. SLE disease activity was defined using SLEDAI score: <6 for quiescent disease and ≥6 for active disease. In vitro, surface markers expressed on pDCs were assessed by flow cytometry. IFNalpha production by pDCs after TLR and immune complexes triggering was detected by quantitative RT-PCR and ELISA. Intracellular cytokines expressed by LT4 after 7 days of coculture with pDCs were analysed by flow cytometry.
Results First, we observed significantly higher IgE levels (independently of allergy or parasitic infection) in SLE patients with quiescent disease than with active disease and healthy donors (p<0.005 and p<0.05, respectively). In SLE patients, IgE levels were inversely correlated to anti-DNA antibodies and disease activity (SLEDAI) (r = -0.4; p<0.05). In vitro, blood purified pDCs treated during 24h with monoclonal IgE upregulate the surface expression of FcepsRI in an IgE dose-dependent manner (p<0.005). IgE-treated pDCs significantly downregulate CCR7 expression and decrease IFNalpha secretion upon TLR7, 9 and immune complexes triggering (p<0.05). Interestingly, no significant decrease of IFNalpha production is observed when pDCs do not upregulate FcepsRI expression after IgE treatement. Finally, the coculture of IgE pretreated pDCs with allogeneic LT4 promotes their differentiation into IL-10 -secreting-Tcells (p<0.05).
Conclusions All together, these data suggest a role for IgE in modulating the inflammatory response by pDCs and promoting a tolerance induction. Recently, use of parasitic worms as a therapy in autoimmune disease has been proposed. Our results highlight a complementary mechanism that could be involved in the protective effect of worm infection in SLE.
Gilliet, et al. Nat Rev Immunol, 2008
Disclosure of Interest None declared