Article

Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med

Immunology and Inflammation Program, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
Journal of Experimental Medicine (Impact Factor: 13.91). 08/2008; 205(7):1551-7. DOI: 10.1084/jem.20080218
Source: PubMed

ABSTRACT Hyper-immunoglobulin E syndrome (HIES) is a primary immune deficiency characterized by abnormal and devastating susceptibility to a narrow spectrum of infections, most commonly Staphylococcus aureus and Candida albicans. Recent investigations have identified mutations in STAT3 in the majority of HIES patients studied. Despite the identification of the genetic cause of HIES, the mechanisms underlying the pathological features of this disease remain to be elucidated. Here, we demonstrate a failure of CD4+ T cells harboring heterozygous STAT3 mutations to generate interleukin 17-secreting (i.e., T helper [Th]17) cells in vivo and in vitro due to a failure to express sufficient levels of the Th17-specific transcriptional regulator retinoid-related orphan receptor t. Because Th17 cells are enriched for cells with specificities against fungal antigens, our results may explain the pattern of infection susceptibility characteristic of patients with HIES. Furthermore, they underscore the importance of Th17 responses in normal host defense against the common pathogens S. aureus and C. albicans.

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    • "In patients with hyper- IgE syndrome, a defect in signal transducer and activator of transcription-3 (STAT3) causes a failure to generate sufficient IL-17 releasing T-cells. The consequent lack of IL-17 has been linked with the high susceptibility of these patients to Staphylococcus aureus and Candida albicans infections [12] [13]. Whilst the release of IL-17 plays a key role in preventing infection and maintaining health, the deregulation of IL- 17 promotes disease, in particular inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease (IBD). "
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    • "Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of the skin, nails, oral and genital mucosae with Candida albicans, and sometimes by staphylococcal skin infections (Glocker and Grimbacher, 2010; Lilic, 2012; Puel et al., 2012; Alcais et al., 2010; Casanova and Abel, 2013). Patients with inherited or acquired T cell immunodeficiencies often suffer from CMC. Patients with autosomal dominant (AD) hyper-immunoglobulin E (IgE) syndrome (HIES) due to heterozygous loss-of-function mutations in STAT3 display CMC and a deficit of interleukin-17 (IL-17)-producing T cells (Chandesris et al., 2012; de Beaucoudrey et al., 2008; Ma et al., 2008; Milner et al., 2008; Minegishi et al., 2009; Renner et al., 2008). Biallelic mutations of IL12B or IL12RB1 in patients with Mendelian susceptibility to mycobacterial disease (MSMD) can also lead to mild CMC, due to low proportions of IL-17-pro- ducing circulating T cells (de Beaucoudrey et al., 2008; de Beaucoudrey et al., 2010; Prando et al., 2013; C. Rodríguez-Gallego, personal communication). "
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