No Indication for a Defect in Toll-Like Receptor Signaling in Patients with Hyper-IgE Syndrome

Abstract

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.

Toll-Like Receptor Stimulation Induces Higher TNF-α Secretion in Peripheral Blood Mononuclear Cells from Patients with Hyper IgE Syndrome

“…Given the different requirements of TLR signaling for cytokine production, the higher levels of pro-inflammatory cytokines in HIES might be due to an accessory pathway, as previously suggested [10]. …”

“…We then attempted to perform a meta-analysis on TNF-α response with the data from previous studies [9, 10]. However, due to differences in the study design, only data from the study by Hawn et al [9] could be compared with our data.…”

“…To date, 2 reports on a limited number of patients have failed to reveal defects in TLR signaling in HIES patients [9, 10]. In addition, both studies showed that in HIES patients pro-inflammatory cytokines are secreted at least in similar amounts compared to normal controls, a finding somewhat surprising given that the hallmark of HIES is the absence of inflammation (lack of warmth of abscesses and fevers in severely ill patients).…”

Toll-like receptor heterodimer variants protect from childhood asthma

“…Freshly isolated PBMCs were stimulated for 24 hours with specific TLR1/ 2/6 ligands, according to methods previously described. 12 After the incubation period, the PBMCs were separated by means of centrifugation, and the secretion of IL-6, TNF-a, IL-12, IFN-g, IL-10, and IL-4 was measured in triplicate in culture supernatants by using ELISA kits according to the manufacturer's instructions (R&D Systems, Minneapolis, Minn). All SNP data were based on the results of the National Institute of Health mutation screening program of innate immunity genes 13 performed in a standard set of immortalized human samples from the Coriell Institute for Medical Research, Camden, New Jersey (ccr.coriell.org).…”

RARE PRIMARY IMMUNODEFICIENCY – HYPER-IgE-SYNDROME: CASE REPORT AND LITERATURE REVIEW

“…Установлено, что TLR2 кератиноцитов и эпителиаль-ных клеток бронхов у больных с гипер-IgE-синдромом в ответ на лиганды способны синтезировать антибактери-альные факторы, но их количество меньше 10% уровня тех клеток, которые получали двойной стимул: от цито-кинов Th17 лимфоцитов и цитокинов классического каскада [41,42].…”