Invariant Natural Killer T Cell Deficiency and Functional Impairment in Sleep Apnea: Links to Cancer Comorbidity.

STUDY OBJECTIVES: Emerging evidence links obstructive sleep apnea (OSA) with increased cancer incidence and mortality. Invariant natural killer T (iNKT) cells play an important role in cancer immunity. We hypothesized that patients with OSA have low number of circulating invariant natural killer T (iNKT) cells, which may also be functionally impaired. This study aims to evaluate the frequency of circulating iNKT cells in OSA. DESIGN: We evaluated the frequency of circulating iNKT cells by flow cytometry in 33 snorers being assessed for possible OSA. Using iNKT cell lines, we also evaluated the effect of exposure to hypoxia over 24 hours on apoptosis, cytotoxicity, and cytokine production. SETTING: Teaching hospital based sleep unit and research laboratory. PATIENTS: Thirty-three snorers were evaluated: 9 with no OSA (apnea-hypopnea frequency [AHI] < 5/h), 12 with mild-moderate OSA (AHI 5-30) and 12 with severe OSA (AHI > 30). MEASUREMENTS AND RESULTS: Patients with severe OSA had considerably fewer iNKT cells (0.18%) compared to patients with mild-moderate (0.24%) or no OSA (0.35%), P = 0.0026. The frequency of iNKT cells correlated negatively with apnea-hypopnea index (r = -0.58, P = 0.001), oxygen desaturation index (r = -0.58, P = 0.0003), and SpO2% < 90% (r = -0.5407, P = 0.005). The frequency of iNKT cells increased following 12 months of nCPAP therapy (P = 0.015). Hypoxia resulted in increased apoptosis (P = 0.016) and impaired cytotoxicity (P = 0.035). CONCLUSION: Patients with obstructive sleep apnea (OSA) have significantly reduced levels of circulating invariant natural killer T (iNKT) cells and hypoxia leads to impaired iNKT cell function. These observations may partly explain the increased cancer risk reported in patients with OSA.

Effects of adenoid/tonsillectomy on inflammatory response in snoring children with witnessed apnoea.

OBJECTIVE: The aim of this study was to investigate the clinical significance of preoperative serum C-reactive protein (CRP), interleukin-6 (IL-6), fetuin-A, cystatin C, adiponectin and tumour necrosis factor-alpha (TNF-α) levels in children with adenoid/tonsillar hypertrophy and compare these results with postoperative values. STUDY DESIGN: Prospective clinical trial. SETTING: Single tertiary care centre. PARTICIPANTS: Thirty-five children (14 boys and 21 girls) participated in this study. MAIN OUTCOME MEASURES: The operations were performed with the indication of sleep-disordered breathing (SDB). Blood samples were taken preoperatively and at 6 months postoperatively to determine the changes in serum high-sensitivity CRP (hs-CRP), IL-6, fetuin-A, cystatin C, adiponectin and TNF-α levels. Pre- and postoperative values of body weights and heights of the participants were recorded preoperatively and at postoperative 6 months. RESULTS: Patients underwent adenoidectomy (n = 21) or adenotonsillectomy (n = 21). The mean age at surgery was 8.74 ± 3.33 years (range 3-16 years). Mean serum levels of parameters measured preoperatively and at postoperative 6 months. The observed differences between pre- and postoperative values were statistically significant (P < 0.05), excluding cystatin C levels (P > 0.05). CONCLUSION: High levels of IL-6, hs-CRP and TNF-α and low levels of fetuin-A in serum might have a clinical significance in patients with sleep-disordered breathing. Levels of cytokines in children with sleep-disordered breathing because of adenotonsillar disease decreased after surgical treatment. The risks of development of cardiovascular disease are decreased in association with lower levels of cytokines, which are also closely associated with many disease states.

Salivary cytokines and the association between obstructive sleep apnea syndrome and periodontal disease.

BACKGROUND: A higher prevalence of periodontal disease has been reported in patients with obstructive sleep apnea syndrome (OSAS), and these two chronic conditions may be linked via inflammatory pathways. The aim of the present study is to evaluate the salivary interleukin (IL)-1ß, IL-6, IL-21, IL-33, and pentraxin-3 (PTX3) concentrations in patients with and without OSAS. METHODS: A total of 52 patients were included in the study. Thirteen individuals were in the control (non-OSAS) group, 17 were in the mild/moderate OSAS group, and 22 were in the severe OSAS group. Clinical periodontal measurements were recorded, and saliva samples were obtained before initiation of periodontal intervention. Enzyme-linked immunosorbent assay was used to determine salivary cytokine concentrations. Data were statistically analyzed using D'Agostino-Pearson omnibus normality, Spearman ρ rank, Kruskal-Wallis, and Dunn tests. RESULTS: Salivary IL-6 and IL-33 concentrations were similar in the two OSAS groups (P >0.05), which were statistically higher than the control group (P <0.05). IL-1ß, IL-21, and PTX3 concentrations were similar in the study groups. The only significant correlation between clinical periodontal parameters and salivary cytokines was found between clinical attachment level (CAL) and IL-21 (P = 0.02). Highly significant correlations were found between probing depth, CAL measures, and indicators of OSAS severity (P <0.01). CONCLUSIONS: The present findings suggest that OSAS may have an increasing effect on salivary IL-6 and IL-33 concentrations regardless of OSAS severity. Additional investigation is required to elucidate a potential bidirectional relationship between OSAS and periodontal disease.

Hypoxemia and obesity modulate plasma C-reactive protein and interleukin-6 levels in sleep-disordered breathing.

C-reactive protein (CRP) and interleukin-6 (IL-6) are pro-inflammatory proteins and important risk factors for atherosclerosis. Plasma CRP levels in snoring children may or may not be elevated. Since obesity is prevalent among snoring children and is associated with elevated CRP levels, we aimed to investigate the relative contributions of sleep-disordered breathing (SDB) and obesity to the inflammatory processes in snoring children in this prospective study. Two hundred forty-four children (mean age 8.9 +/- 3.4 years) underwent polysomnographic evaluation. CRP was measured the following morning, and plasma IL-6 levels from 111 randomly selected children were also examined. Plasma CRP and IL-6 levels were elevated in children with SDB. Log plasma CRP levels were higher in the moderate-severe SDB group (apnea/hypopnea index, AHI > or = 5) compared to the mild SDB group (AHI > or = 1 and <5; p < 0.0001) or the control group (AHI < 1; p = 0.0001). Log plasma CRP levels correlated with AHI, arousal index, relative BMI, and SpO(2) nadir (r = 0.30, p < 0.0001; r = 0.21, p = 0.002; r = 0.39, p < 0.0001, r = -0.36, p < 0.0001, respectively). Log plasma CRP levels were lower in children with SpO(2) nadir > or =90 (p < 0.0001). Sub-analysis of the 116 non-obese children in the cohort revealed similar findings. Log plasma IL-6 levels were increased in children with moderate-severe SDB compared to controls (p = 0.03) and correlated with AHI (r = 0.28, p = 0.003) and SpO(2) nadir (r = -0.24, p = 0.02). Children with SDB display significant severity-dependent increases in plasma CRP and IL-6 levels independent of obesity.

Neutrophil migration in tonsils.

Recent studies have indicated the existence of an active cellular defence in the secretion on the tonsillar surface. This defence seems to consist partly of physiologically active neutrophils and is present in health and during disease. The present study was undertaken to examine the migration of these neutrophils to the secretion on the mucosal surface. Tonsils from 6 patients with acute tonsillitis and 5 patients with snoring problems were removed and sectioned. Sections were stained immunohistochemically against CD15 to visualise neutrophils. Other sections were stained with acridine orange to detect bacteria. Clusters of neutrophils were frequently seen in tonsils both from patients with acute tonsillitis and from snorers. They were observed to be accumulated within the tonsillar epithelial layer. Streaks of neutrophils could be observed running not only from vessels mainly near or within the epithelium to the epithelial surface, but also from vessels far from the epithelium through the extrafollicular areas to the epithelial surface. Bacteria were not present in the epithelium. We consider that the findings indicate an active physiological migration of neutrophils to the tonsillar surface.