IgE Inhibits Toll‐like Receptor 7– and Toll‐like Receptor 9–Mediated Expression of Interferon‐α by Plasmacytoid Dendritic Cells in Patients With Systemic Lupus Erythematosus

Abstract

Objective Plasmacytoid dendritic cells (PDCs) play a central role in pathogenesis of systemic lupus erythematosus (SLE) through their unique ability to produce large amounts of type I interferon (IFN) upon Toll‐like receptor 7 (TLR‐7) and TLR‐9 triggering. PDCs express specific surface regulatory receptors involved in negative regulation of IFNα secretion. These receptors use the γ‐chain of high‐affinity Fc receptor (FcR) for IgE, FcɛRI. We undertook this study to test our hypothesis that IgE engagement of FcɛRI on PDCs may impact IFNα production in SLE patients. Methods Serum levels of total IgE were measured in healthy volunteers, SLE patients, and patients with IgE‐dependent allergic disorders. FcɛRI expression on PDCs from SLE patients was evaluated by flow cytometry. Purified PDCs were incubated with monoclonal IgE for 24 hours, then stimulated for 18 hours with TLR agonists or immune complexes (ICs). IFNα production by PDCs was detected by quantitative real‐time polymerase chain reaction (PCR) and enzyme‐linked immunosorbent assay. Expression of TLR‐7, TLR‐9, and IFN regulatory factor 7 (IRF‐7) in PDCs was quantified by quantitative real‐time PCR. Results We observed significantly higher IgE levels in SLE patients with quiescent disease than in those with active disease. In SLE patients, IgE levels correlated inversely with disease activity. IgE levels were not associated with the presence of antinuclear IgE. Purified PDCs treated for 24 hours with monoclonal IgE up‐regulated FcɛRI expression in an IgE dose–dependent manner. IgE‐treated PDCs significantly decreased IFNα secretion and down‐regulated CCR7 expression upon stimulation with TLR‐7 and TLR‐9 ligands and ICs from lupus patients. IgE treatment down‐regulated expression of TLR‐9 and IRF‐7. Conclusion Our results support the notion that IgE plays a protective role in SLE pathogenesis through the modulation of inflammatory response by PDCs.

Elevated total serum IgE in vitiligo might be protective for other autoimmune diseases

“…Autoimmune diseases have a higher prevalence in Western societies than in developing countries, where a high prevalence of parasitic infections associated with high levels of IgE and T‐helper 2 (Th2) response are found . IgE has been found to dampen the production of type I interferons, involved in chronic inflammatory conditions and vitiligo . These findings are also in accordance with results of previous studies demonstrating a lower prevalence of atopy in type 1 diabetes or rheumatoid arthritis .…”

“…6 IgE has been found to dampen the production of type I interferons, involved in chronic inflammatory conditions and vitiligo. 7 These findings are also in accordance with results of previous studies demonstrating a lower prevalence of atopy in type 1 diabetes or rheumatoid arthritis. 8 The positive correlation between elevated total IgE levels and KP type 1 could suggest that the proinflammatory Th2 immune response that characterizes atopy may predispose toward melanocyte loss.…”

Interferon α2 and interferon γ induce the degranulation independent production of VEGF‐A and IL‐1 receptor antagonist and other mediators from human mast cells

“…These include hypoxic tissue microenvironments, complement receptors, toll‐like receptors and other innate immune recognition receptors 2. IgE mediated activation of dendritic cells has been associated with enhanced IFN production in systemic lupus but limits IFN expression following TLR‐mediated activation 54, 55, 56. These findings suggest a potentially complex relationship between IgE, dendritic cells, mast cells, and IFNs in disease.…”

Toll-like receptors in lupus nephritis

“…Interestingly, the gene product of the ITGAM gene, CD11b, is an endogenous negative regulator of TLR7 signaling and gene variants in the ITGAM gene affect the risk for SLE in humans [ 23 ]. Intrinsic IgE seems to be another endogenous inhibitor of TLR7-mediated IFN-α induction in dendritic cells isolated from SLE patients [ 64 ]. In summary, TLR7 is involved in the pathogenesis of murine and human SLE and LN by sensing endogenous ribonucleoprotein antigens for the activation of antigen presenting cells such as B cells and dendritic cells [ 10 , 65 , 66 ].…”

“…B cell TLR9 expression is associated with serum creatinine levels in SLE patients [ 25 ]. Intrinsic IgE inhibits also TLR9-mediated IFN-α induction in dendritic cells isolated from SLE patients [ 64 ]. Together, TLR has a complex role in SLE as it promotes DNA autoantibody production as an important component of lupus nephritis.…”