Nicholas Van Bruaene

Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease

BACKGROUND Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by the accumulation of inflammatory cells; however, an eosinophil predominance is seen in white (Belgian), but not Asian (south Chinese), patients with polyps. OBJECTIVE We sought to investigate the association of inflammatory cell predominance with regulatory T-cell and T-effector cell patterns. METHODS Nasal mucosal tissue was obtained from 26 consecutive Belgian patients with CRSwNP and 21 Belgian control subjects and 29 south Chinese patients with CRSwNP and 29 south Chinese control subjects, who all underwent phenotyping, including nasal endoscopy and computed tomographic scanning. Tissues were investigated for granulocytes and their products and T-effector/regulatory T cells and related cytokines. RESULTS Both CRSwNP groups were comparable in terms of symptoms, computed tomographic scan results, and nasal endoscopy results, but asthma comorbidity was significantly higher in white patients. Tissue from white patients with CRSwNP was characterized by eosinophilic inflammation (eosinophil cationic protein/myeloperoxidase ratio > 2), whereas samples from Asian patients were biased toward neutrophilic inflammation (eosinophil cationic protein/myeloperoxidase ratio = 0.25). Both CRSwNP groups demonstrated significant upregulation of the T-cell activation marker soluble IL-2 receptor alpha and significant downregulation of Foxp3 expression and TGF-beta1 protein content versus their respective control groups. However, whereas white patients displayed a significant increase in T(H)2 cytokine and related marker levels versus control subjects and versus Asian patients, the latter showed a T(H)1/T(H)17 cell pattern versus control tissue. CONCLUSION Nasal polyps (CRSwNP) from white and Asian patients are both characterized by T-cell activation and impaired regulatory T-cell function; however, T-effector cells in the samples from white patients were T(H)2-biased, whereas samples from their Asian counterparts demonstrated a T(H)1/T(H)17 polarization.

Mepolizumab, a humanized anti–IL-5 mAb, as a treatment option for severe nasal polyposis

BACKGROUND Approximately 85% of nasal polyps (NPs) in white subjects are characterized by prominent eosinophilia. IL-5 is the key driver of eosinophilic differentiation and survival. OBJECTIVE We sought to investigate the therapeutic potential of inhibiting IL-5 with a humanized mAb as treatment for severe nasal polyposis. METHODS Thirty patients with severe nasal polyposis (grade 3 or 4 or recurrent after surgery) refractory to corticosteroid therapy were randomized in a double-blind fashion to receive either 2 single intravenous injections (28 days apart) of 750 mg of mepolizumab (n = 20) or placebo (n = 10). Change from baseline in NP score was assessed monthly until 1 month after the last dose (week 8). Computed tomographic scans were also performed at week 8. RESULTS Twelve of 20 patients receiving mepolizumab had a significantly improved NP score and computed tomographic scan score compared with 1 of 10 patients receiving placebo at week 8 versus baseline. CONCLUSION Mepolizumab achieved a statistically significant reduction in NP size for at least 1 month after dosing in 12 of 20 patients. IL-5 inhibition is a potential novel therapeutic approach in patients with severe eosinophilic nasal polyposis.

T-cell regulation in chronic paranasal sinus disease.

BACKGROUND Chronic rhinosinusitis is an inflammatory disease with distinct cytokine and remodeling patterns. Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a T(H)2-skewed eosinophilic inflammation, whereas chronic rhinosinusitis without nasal polyps (CRSsNP) represents a predominant T(H)1 milieu. OBJECTIVE We aimed to study the direct tissue expression of transcription factors for T-cell subpopulations, including T regulatory cells, in relation to the cytokine expression patterns in the different disease subgroups. METHODS The expression of forkhead box P3 (FOXP3), T-box transcription factor (T-bet), GATA-3, retinoid acid-related orphan receptor C (RORc), the suppressive cytokines TGF-beta1 and IL-10, and T(H)1/ T(H)2/ T(H)17 cytokines (IFN-gamma, IL-4, IL-5, IL-13, IL-17) were analyzed by means of RT-PCR in 13 CRSsNP, 16 CRSwNP, and 10 control samples. Additional protein measurements were performed for TGF-beta1 and IFN-gamma. RESULTS In CRSwNP, we observed a significantly lower FOXP3 mRNA and TGF-beta1 protein expression, but a significantly higher T-bet, GATA-3, IL-5, and IL-13 mRNA expression compared with controls, whereas RORc was not significantly different compared with controls. In CRSsNP, FOXP3, T-bet, GATA-3, and RORc expression was not significantly different from controls, whereas TGF-beta1 mRNA, IFN-gamma mRNA, and protein were significantly higher in CRSsNP compared with controls. For IL-17, no significant differences were noted among all groups. CONCLUSION We demonstrate for the first time a decreased FOXP3 expression accompanied by an upregulation of T-bet and GATA-3 and a downregulation of TGF-beta1 in CRSwNP versus controls and CRSsNP.

TGF-β signaling and collagen deposition in chronic rhinosinusitis

BACKGROUND Chronic rhinosinusitis is an inflammatory disease with distinct cytokine and remodeling patterns. OBJECTIVE The objective was to analyze the presence of TGF-beta isoforms, receptors, intracellular signaling, and collagen deposition in chronic rhinosinusitis. METHODS Sinonasal mucosal samples obtained from chronic rhinosinusitis with nasal polyps (CRSwNP; n = 13), chronic rhinosinusitis without nasal polyps (CRSsNP; n = 13), and controls (n = 10) were analyzed for TGF-beta isoforms 1 and 2 by means of ELISA and IHC, and for TGF-beta R1, 2, and 3 by RT-PCR and IHC. As downstream proteins, phospho-Smad 2 (pSmad 2) and collagen were analyzed by performing immunostaining and picrosirius red staining, respectively. RESULTS TGF-beta 1 and 2 protein concentrations, TGF-beta receptor (R) I and TGF-beta RIII mRNA expression, the number of pSmad 2-positive cells, and total collagen amount were significantly higher in CRSsNP versus controls. In CRSwNP, TGF-beta 1 protein concentration, TGF-beta RII and TGF-beta RIII mRNA expression, the number of pSmad 2-positive cells, and total collagen amount were significantly lower versus controls. Only TGF-beta 2 protein was found higher in CRSwNP versus controls. CONCLUSION A high TGF-beta 1 protein expression, increased TGF-beta RI expression, and a high number of pSmad 2-positive cells all indicate an enhanced TGF-beta signaling in CRSsNP, whereas a low TGF-beta 1 protein concentration, a decreased expression of TGF-beta RII, and a low number of pSmad 2-positive cells in CRSwNP indicate a low level of TGF-beta signaling in CRSwNP. These findings are compatible with the remodeling patterns observed, reflected by a lack of collagen in CRSwNP, and excessive collagen production with thickening of the collagen fibers in the extracellular matrix in CRSsNP.

Tissue remodeling in chronic rhinosinusitis.

Purpose of reviewTo summarize the current knowledge on remodeling in chronic sinus disease. Recent findingsChronic sinus disease is characterized by persistent inflammation of the nasal and paranasal mucosa and is currently classified into two major subgroups on the basis of the absence (CRSsNP) or presence (CRSwNP) of nasal polyps. Transforming growth factor-beta and matrix metalloproteinases are critical factors involved in the remodeling process. SummaryRemodeling is clearly present in chronic sinus disease. Transforming growth factor-beta has been implicated as an important factor in remodeling processes involved in chronic sinus disease, and serves as a main switch for different remodeling patterns in chronic sinus disease.

Pathophysiology of Chronic Rhinosinusitis

Chronic rhinosinusitis (CRS), a disease presenting with chronic symptoms such as nasal obstruction, rhinorrhea, hyposmia and facial pain, is highly prevalent and has a considerable impact on quality of life and health care expenditures. The disease is characterized by chronic inflammation of the sinonasal mucosa and can present with nasal polyps. Current consensus classifies CRS into CRS with nasal polyps and CRS without nasal polyps. This review illustrates the diversity of pathophysiological observations in CRS and highlights selected etiological hypotheses. A wide spectrum of alterations is described regarding histopathology, pattern of T cells and inflammatory effector cells, remodeling, immunoglobulin production, chemokine and eicosanoid production, and the role of microorganisms. The pathophysiological diversity observed in CRS seems to stand in contrast to its nonspecific clinical presentation, but is of the utmost importance in the development and application of highly individualized treatments. Identification of specific disease subgroups and their etiologies is an important and challenging task for future research.

Staphylococcus-aureus-derived Superantigens in Nasal Polyp Disease

Staphylococcus aureus (SA) secretes enterotoxins, small proteins that act as superantigens because of their potent effect on the immune system. The main mode of action of superantigens is the coupling of the major histocompatibility complex molecule with the T-cell receptor. The effect is a powerful stimulation of the adaptive immune system in a polyclonal (non-antigen-specific) way, resulting in a T-helper-2-biased inflammation. This superantigen mechanism is involved in the pathogenesis of nasal polyps (NP) in about 50% of the cases. The superantigenic effect is hallmarked by immunoglobulin changes in biopsies: high total IgE, polyclonal IgE to multiple allergens, and IgE specific to SA enterotoxins. Serum immunoglobulins coincide only partially with biopsy findings. Patients with this IgE pattern have an increased risk of asthma and aspirin-exacerbated respiratory disease (AERD). Future treatments with topical or systemic antibiotics and monoclonal antibodies to IgE and interleukin-5 (IL-5) are being studied.