title: 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.
authors.affiliation: Department of Oral Biology, University at Buffalo, SUNY, Buffalo, New York, USA.
authors.forename: H R
authors.initials: HR
authors.lastname: Conti
authors.forename: O
authors.initials: O
authors.lastname: Baker
authors.forename: A F
authors.initials: AF
authors.lastname: Freeman
authors.forename: W S
authors.initials: WS
authors.lastname: Jang
authors.forename: S M
authors.initials: SM
authors.lastname: Holland
authors.forename: R A
authors.initials: RA
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Edgerton
authors.forename: S L
authors.initials: SL
authors.lastname: Gaffen
mesh_terms: D000249:Adenosine Monophosphate / Q000276:immunology / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002176:Candida albicans / Q000276:immunology; D002177:Candidiasis / Q000150:complications* / Q000276:immunology*; D002648:Child; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D054808:Histatins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018928:Immunity, Mucosal; D007589:Job Syndrome / Q000150:complications* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa / Q000276:immunology* / Q000382:microbiology*; D012463:Saliva / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D055815:Young Adult; D023083:beta-Defensins / Q000276:immunology / Q000378:metabolism
chemical_list: D054808:Histatins; D023083:beta-Defensins; D000249:Adenosine Monophosphate