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Allergic fungal rhinosinusitis linked to other hyper-IgE syndromes through defective TH17 responses
Hua Sun1, J Morgan Knight2, Yi-Dong Li1
1Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, McGovern Medical School of The University of Texas Health Science Center at Houston, Houston, Tex; Department of Otorhinolaryngology-Head and Neck Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Tex.
Background:
In a gene expression analysis comparing sinus mucosa samples from allergic fungal rhinosinusitis (AFRS) patients with samples from non-AFRS chronic rhinosinusitis with nasal polyp (CRSwNP) patients, the antimicrobial peptide (AMP) histatin 1 (HTN1) was found to be the most differentially downregulated gene in AFRS.
Objective:
We sought to identify the molecular etiology of the downregulated expression of HTN1.
Methods:
We used RT-PCR to compare the expression of AMPs and a fungistasis assay to evaluate the antifungal activity of sinus secretions. Using flow cytometry, we characterized the presence of TH17/TH22 cells and signal transducer and activator of transcription (STAT) signaling from AFRS patients, non-AFRS CRSwNP patients, and healthy controls.
Results:
We confirmed decreased expression of AMPs in AFRS sinus mucosa with concordant decrease in antifungal activity in sinus secretions. IL-22 and IL-22-producing T cells were deficient within sinus mucosa of AFRS patients. In vitro studies demonstrated a defect in IL-6/STAT3 signaling critical for TH17/TH22 differentiation. Epithelial cells from AFRS patients could express AMPs when stimulated with exogenous IL-22/IL-17 and circulating TH17 cell abundance was normal.
Conclusions:
Similar to other hyper-IgE syndromes, but distinct from CRSwNP, AFRS patients express a defect in STAT3 activation limited to IL-6-dependent STAT3 phosphorylation that is critical for TH17/TH22 differentiation. This defect leads to a local deficiency of IL-17/IL-22 cytokines and deficient AMP expression within diseased sinus mucosa of AFRS patients. Our findings support evaluation of therapeutic approaches that enhance airway AMP production in AFRS.
Insights
Allergic fungal rhinosinusitis (AFRS) involves downregulated antimicrobial peptides (AMPs) due to a defect in IL-6/STAT3 signaling, impacting T helper cell differentiation and leading to reduced antifungal defense.
Area of Science:
- Immunology
- Molecular Biology
- Otorhinolaryngology
Background:
- Allergic fungal rhinosinusitis (AFRS) shows significantly lower expression of histatin 1 (HTN1), a key antimicrobial peptide (AMP).
- This downregulation is a distinguishing genetic feature when comparing AFRS with chronic rhinosinusitis with nasal polyps (CRSwNP).
Purpose of the Study:
- To investigate the underlying molecular mechanisms responsible for the reduced expression of HTN1 in AFRS.
- To understand the role of T helper cell subsets and signaling pathways in AFRS pathogenesis.
Main Methods:
- Quantitative RT-PCR to measure AMP expression.
- Fungistasis assays to assess antifungal activity of sinus secretions.
- Flow cytometry to analyze T helper 17 (TH17)/T helper 22 (TH22) cells and signal transducer and activator of transcription (STAT) signaling.
Main Results:
- AFRS patients exhibit decreased AMP expression and reduced antifungal activity in sinus secretions.
- A deficiency in IL-22 and IL-22-producing T cells was observed in the sinus mucosa of AFRS patients.
- In vitro studies revealed a defect in IL-6/STAT3 signaling crucial for TH17/TH22 cell differentiation, although circulating TH17 cells were normal.
Conclusions:
- AFRS is characterized by a specific defect in IL-6-dependent STAT3 activation, impairing TH17/TH22 differentiation.
- This signaling defect results in localized deficiency of IL-17/IL-22 cytokines and reduced AMP expression in the sinus mucosa.
- Therapeutic strategies aimed at boosting airway AMP production may be beneficial for AFRS treatment.
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