Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome

Abstract

The autosomal dominant hyper-IgE syndrome (HIES, 'Job's syndrome') is characterized by recurrent and often severe pulmonary infections, pneumatoceles, eczema, staphylococcal abscesses, mucocutaneous candidiasis, and abnormalities of bone and connective tissue1,2. Mutations presumed to underlie HIES have recently been identified in stat3, the gene encoding STAT3 (signal transducer and activator of transcription 3) (refs 3, 4). Although impaired production of interferon-γ and tumour-necrosis factor by T cells5, diminished memory T-cell populations, decreased delayed-type-hypersensitivity responses and decreased in vitro lymphoproliferation in response to specific antigens6 have variably been described, specific immunological abnormalities that can explain the unique susceptibility to particular infections seen in HIES have not yet been defined. Here we show that interleukin (IL)-17 production by T cells is absent in HIES individuals. We observed that ex vivo T cells from subjects with HIES is consistent with a crucial role for STAT3 signalling in the generation of T H 17 cells7-14. T H 17 cells have emerged as an important subset of helper T cells15 that are believed to be critical in the clearance of fungal16 and extracellular bacterial17 infections. Thus, our data suggest that the inability to produce T H 17 cells is a mechanism underlying the susceptibility to the recurrent infections commonly seen in HIES. HHS Public AccessWe studied three groups of subjects: healthy controls with no apparent immunological defects, HIES individuals with defined mutations in stat3, and individuals (termed 'HIESlike') with some combination of elevated IgE, atopic dermatitis, skeletal abnormalities and susceptibility to infection, but without recurrent staphylococcal abscesses or candidiasis or stat3 mutations (Table 1).We observed that IL-17-producing T cells were barely detectable among peripheral blood mononuclear cells (PBMCs) from subjects with HIES on stimulation with staphylococcal enterotoxin B (SEB) (Fig. 1a). The frequency of SEB-induced interferon (IFN)-γ-producing CD4 T cells from PBMCs of subjects with HIES was similar to that of healthy controls, whereas the frequency of cells producing IL-2 and/or tumour-necrosis factor (TNF) was slightly reduced. Fewer of the IFN-γ-producing CD4 T cells from subjects with HIES also produced TNF and/or IL-2 compared with healthy controls (Fig. 1b). IL-17-producing T cells were present in PBMCs from the HIES-like cohort with no mutations in stat3,suggesting that the lack of IL-17 production in HIES has a critical function in susceptibility to the specific infections seen in HIES, and also that elevated serum IgE, atopic dermatitis or low frequency of memory T cells (data not shown) are not independently associated with severe defects in the T H 17 axis (Fig. 1a). The production of IL-21 and IL-22, which have been described as both T H 1 and T H 17 cytokines9,10,18, was not significantly lower in subjects with HIES than in healthy controls. Additionally, among subjects with ...

Targeting Th17 cells in immune diseases

“…These results indicate an essential function of STAT3 in the global regulation of Th17-cell gene expression programs, possibly through the induction of lineage-specific transcription factors. Consistently, in human hyper-IgE patients with STAT3 mutation, Th17 differentiation was found to be defective [3].…”

Curative treatment of autosomal-recessive hyper-IgE syndrome by hematopoietic cell transplantation

“…4 Classical hyperIgE syndrome is caused by mutations in STAT3, occurs either sporadic or with autosomal-dominant inheritance and is characterized by mainly bacterial infectious complications, as well as by nonimmunological abnormalities, including skeletal and dental abnormalities. [5][6][7] These latter abnormalities were not observed in DOCK8-deficient patients, whereas persistent lymphocytopenia, due to low CD4 þ and CD8 þ T cells, as well as diminished lymphocyte functions, were prominent findings. Although these immunological abnormalities likely are causative for the profound susceptibility to viral infections, a direct role of DOCK8 deficiency in the etiology of the exceptional susceptibility to cutaneous viral disease is not ruled out.…”

TLR2‐activated human langerhans cells promote Th17 polarization via IL‐1β, TGF‐β and IL‐23

“…IL-17 mRNA was detected in skin cells of sensitized mice and in T cells of psoriatic human skin [10,11]. However, naive T cells from patients suffering from hyper-IgE syndrome lost the potential to differentiate into Th17 cells [12]. In human donors suffering from Langerhans cell (LC) histiocytosis, IL-17A was found in skin LC, CD3/CD28-activated T cells, and monocyte-derived DC (MoDC), but not in MoDC from healthy donors [13].…”