No Indication for a Defect in Toll-Like Receptor Signaling in Patients with Hyper-IgE Syndrome
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Hyper-IgE syndrome is a rare primary immunodeficiency of unknown etiology characterized by recurrent infections of the skin and respiratory system, chronic eczema, elevated total serum IgE, and a variety of associated skeletal symptoms. Recent reports about susceptibility to pyogenic bacterial infections and high IgE levels in patients and animals with defects in toll-like receptor (TLR) signaling pathways prompted us to search for TLR signaling defects as an underlying cause of hyper-IgE syndrome. Blood samples from six patients with hyper-IgE syndrome were analyzed for serum cytokine levels, intracellular cytokine production in T cells after stimulation with PMA/ionomycin, and cytokine production from peripheral blood mononuclear cells stimulated by TLR ligands and bacterial products including LPS (TLR4), peptidoglycan (TLR2), PolyIC (TLR3), R848 (TLR7/8), CpG-A, and CpG-B (TLR9), zymosan and heat killed Listeria monocytogenes. All results were compared to data from healthy controls. A reduction in IFN-γ, IL-2, and TNF-α producing T cells after PMA stimulation suggested a reduced inflammatory T cell response in patients with hyper-IgE syndrome. Increased serum levels of IL-5 indicated a concomitant Th2 shift. However, normal production of cytokines (TNF-α, IL-6, IL-10, IFN-α, IP-10) and upregulation of CD86 on B cells and monocytes after TLR stimulation made a defect in TLR signaling pathways highly unlikely. In summary, our data confirmed an imbalance in T cell responses of patients with hyper-IgE syndrome as previously described but showed no indication for an underlying defect in toll-like receptor signaling.
Key WordsHyper-IgE syndrome toll-like receptor signaling cytokine pattern interferon-γ interleukin-4 innate immunity
peripheral blood mononuclear cells; IRAK, IL-1-receptor-associated kinase; MyD88, myeloid differentiation factor 88; IP-10, γ-interferon inducible protein 10; NFκ-B, nuclear factor kappa B; ODN, oligodeoxynucleotide; IRF, interferon regulatory factor; PMA, phorbol 12-myristate 13-acetate.
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