New mechanism of oral immunity to mucosal candidiasis in hyper-IgE syndrome

Abstract

Oropharyngeal candidiasis (OPC, thrush) is an opportunistic infection caused by the commensal fungus Candida albicans. An understanding of immunity to Candida has recently begun to unfold with the identification of fungal pattern-recognition receptors such as C-type lectin receptors, which trigger protective T-helper (Th)17 responses in the mucosa. Hyper-IgE syndrome (HIES/Job’s syndrome) is a rare congenital immunodeficiency characterized by dominant-negative mutations in signal transducer and activator of transcription 3, which is downstream of the Th17-inductive cytokines interleukin (IL)-6 and IL-23, and hence patients with HIES exhibit dramatic Th17 deficits. HIES patients develop oral and mucocutaneous candidiasis, supporting a protective role for Th17 cells in immunity to OPC. However, the Th17-dependent mechanisms of antifungal immunity in OPC are still poorly defined. An often unappreciated aspect of oral immunity is saliva, which is rich in antimicrobial proteins (AMPs) and exerts direct antifungal activity. In this study, we show that HIES patients show significant impairment in salivary AMPs, including β-defensin 2 and Histatins. This tightly correlates with reduced candidacidal activity of saliva and concomitantly elevated colonization with Candida. Moreover, IL-17 induces histatins in cultured salivary gland cells. This is the first demonstration that HIES is associated with defective salivary activity, and provides a mechanism for the severe susceptibility of these patients to OPC.

Le syndrome de Job-Buckley : à propos d’un cas et revue de la littérature

“…Ce gène est impliqué dans les mécanismes de cicatrisation et dans les mécanismes immunitaires. En effet, la mutation de ce gène va entraîner une intensification de la production des immunoglobulines E par les lymphocytes B, la perte de la capacité de modulation de leur production par l'IL 10 et l'IFN γ [13], et un défaut de chimiotactisme des polynucléaires neutrophiles [14].…”

Interplay between Candida albicans and the Mammalian Innate Host Defense

“…In humans, Th17 responses are severely defective in patients with chronic mucocutaneous candidiasis (107). Similarly, patients with hyper-IgE syndrome also suffer from oral and mucocutaneous candidiasis due to a defective Th17 response (21). Another line of evidence on the role of Th17 for antifungal defense as well as for the occurrence of chronic mucocutaneous candidiasis in patients with IL-17F or IL-17 receptor deficiencies comes from the dectin-1/CARD9/ Th17 pathway (89).…”

A Candida albicans Strain Expressing Mammalian Interleukin-17A Results in Early Control of Fungal Growth during Disseminated Infection

“…Moreover, the mechanisms by which IL-17 exerts its effects in the context of candidiasis are not fully understood. IL-17 is essential to control the neutrophil and antimicrobial peptide responses to candidiasis (31,(34)(35)(36). In addition, a recent study suggests that IL-17 may also be important for driving NK cell function in disseminated disease through a mechanism dependent on granulocyte-macrophage colony-stimulating factor (GM-CSF) (37).…”