Milner JD, Brenchley JM, Laurence A et al.Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452:773-776

Laboratory of Immunology, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature (Impact Factor: 41.46). 05/2008; 452(7188):773-6. DOI: 10.1038/nature06764
Source: PubMed


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 tissue. 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-gamma and tumour-necrosis factor by T cells, diminished memory T-cell populations, decreased delayed-type-hypersensitivity responses and decreased in vitro lymphoproliferation in response to specific antigens 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 failed to produce IL-17, but not IL-2, tumour-necrosis factor or interferon-gamma, on mitogenic stimulation with staphylococcal enterotoxin B or on antigenic stimulation with Candida albicans or streptokinase. Purified naive T cells were unable to differentiate into IL-17-producing (T(H)17) T helper cells in vitro and had lower expression of retinoid-related orphan receptor (ROR)-gammat, which is consistent with a crucial role for STAT3 signalling in the generation of T(H)17 cells. T(H)17 cells have emerged as an important subset of helper T cells that are believed to be critical in the clearance of fungal and extracellular bacterial 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.

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Available from: Brenna Hill, Apr 10, 2014
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    • "No clinical characteristics of previous or current allergies were found through the retrospective analysis of clinical records of all the patients included in this study (data not shown). Consistent with the potential protective role of Th17 cells against the development of allergies are the negative correlation between IgE and Th17 cells in atopic dermatitis (Hayashida et al. 2011) and the report of an impaired Th17 cell differentiation in autosomal dominant hyper IgE syndrome (Milner et al. 2008). Thus, the possibility to extrapolate to functional role of IL-17 depending on its values during HAV infection in patients with allergies deserves additional investigation. "
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    ABSTRACT: We determined the serum IgE levels and T-helper (Th)17-related cytokines during distinct hepatitis A virus (HAV)-induced clinical courses in children. A significantly higher concentration of macrophage inflammatory protein 3α, interleukin (IL)-17E and IL-17F in HAV-infected children with intermediate liver injury compared with those with minor liver damage was found. A reduction in the IgE levels in those patients who showed the highest levels of IL-17F in the group of intermediate liver injury was found. The data suggested that the Th17-related profile is associated with the severity of HAV infection and might play a role on the modulation achieved by HAV during allergies.
    Memórias do Instituto Oswaldo Cruz 03/2015; 110(2). DOI:10.1590/0074-02760140309 · 1.59 Impact Factor
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    • "IL-17A plays a central role in multiple facets of the immune response of the lung. Its activity is critical for host defense against extracellular bacteria including Haemophilus influenzae [1], [2] and Staphylococcus aureus [3], [4], [5]. For example, in patients with Hyper-IgE syndrome, who lack ThIL-17 cells, Sa skin and lung infections are common [5]. "
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    ABSTRACT: The epithelium plays an active role in the response to inhaled pathogens in part by responding to signals from the immune system. Epithelial responses may include changes in chemokine expression, increased mucin production and antimicrobial peptide secretion, and changes in ion transport. We previously demonstrated that interleukin-17A (IL-17A), which is critical for lung host defense against extracellular bacteria, significantly raised airway surface pH in vitro, a finding that is common to a number of inflammatory diseases. Using microarray analysis of normal human bronchial epithelial (HBE) cells treated with IL-17A, we identified the electroneutral chloride-bicarbonate exchanger Pendrin (SLC26A4) as a potential mediator of this effect. These data were verified by real-time, quantitative PCR that demonstrated a time-dependent increase in Pendrin mRNA expression in HBE cells treated with IL-17A up to 48 h. Using immunoblotting and immunofluorescence, we confirmed that Pendrin protein expression is increased in IL-17 treated HBE cells and that it is primarily localized to the mucosal surface of the cells. Functional studies using live-cell fluorescence to measure intracellular pH demonstrated that IL-17A induced chloride-bicarbonate exchange in HBE cells that was not present in the absence of IL-17A. Furthermore, HBE cells treated with short interfering RNA against Pendrin showed substantially reduced chloride-bicarbonate exchange. These data suggest that Pendrin is part of IL-17A-dependent epithelial changes and that Pendrin may therefore be a therapeutic target in IL-17A-dependent lung disease.
    PLoS ONE 08/2014; 9(8):e103263. DOI:10.1371/journal.pone.0103263 · 3.23 Impact Factor
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    • "The protective effects of IL-17-producing cells have been demonstrated in patients with hyper-immunoglobulin E syndrome, who suffer from recurrent infections with Candida albicans (C. albicans) and Staphylococcus aureus (S. aureus) due to the impairment in Th17 development (Milner et al., 2008; Puel et al., 2011). In addition to their protective effect, Th17 have also been reported to be pathogenic. "
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    ABSTRACT: Propionibacterium acnes is a Gram-positive commensal bacterium thought to be involved in the pathogenesis of acne vulgaris. While the ability of P. acnes in the initiation of pro-inflammatory responses is well documented, little is known about adaptive immune responses to this bacterium. The observation that infiltrating immune cells consist mainly of CD4(+) T cells in the perifollicular space of early acne lesions suggests that helper T cells may be involved in immune responses caused by the intra-follicular colonization of P. acnes. A recent report showing that P. acnes can induce IL-17 production by T cells suggests that acne might be a Th17-mediated disease. In line with this, we show in this work that, in addition to IL-17 A both Th1 and Th17 effector cytokines, transcription factors and chemokine receptors are strongly upregulated in acne lesions. Furthermore, we found that, in addition to Th17, P. acnes can promote mixed Th17/Th1 responses by inducing the concomitant secretion of IL-17 A and IFNγ from specific CD4(+) T cells in vitro. Finally, we show that both P. acnes-specific Th17 and Th17/Th1 cells can be found in the peripheral blood of patients suffering from acne and, at lower frequencies, in healthy individuals. We therefore identified P. acnes-responding Th17/Th1 cells as previously unreported CD4(+) sub-population involved in inflammatory acne.Journal of Investigative Dermatology accepted article preview online, 10 July 2014; doi:10.1038/jid.2014.290.
    Journal of Investigative Dermatology 07/2014; DOI:10.1038/jid.2014.290 · 7.22 Impact Factor
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