No indication for a defect in toll-like receptor signaling in patients with hyper-IgE syndrome

• Published in: Journal of clinical immunology 2005-07, Vol.25 (4), p.321-328
• Main Authors: Renner, E D, Pawlita, I, Hoffmann, F, Hornung, V, Hartl, D, Albert, M, Jansson, A, Endres, S, Hartmann, G, Belohradsky, B H, Rothenfusser, S
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Candidiasis - immunology; Child; Child, Preschool; Cytokines - biosynthesis; Cytokines - blood; Female; Genetic Predisposition to Disease; Humans; Immunoglobulin E - biosynthesis; Immunoglobulin E - blood; Infant; Job Syndrome - blood; Job Syndrome - immunology; Job Syndrome - microbiology; Ligands; Listeria monocytogenes; Male; Signal Transduction - immunology; Staphylococcal Infections - immunology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Toll-Like Receptors - metabolism; Toll-Like Receptors - physiology
• ISSN: 0271-9142; 1573-2592
• DOI: 10.1007/s10875-005-4183-2

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-gamma, IL-2, and TNF-alpha 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-alpha, IL-6, IL-10, IFN-alpha, 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.