Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis.

IL-17 and IL-23 are known to be absolutely central to psoriasis pathogenesis because drugs targeting either cytokine are highly effective treatments for this disease. The efficacy of these drugs has been attributed to blocking the function of IL-17-producing T cells and their IL-23-induced expansion. However, we demonstrate that mast cells and neutrophils, not T cells, are the predominant cell types that contain IL-17 in human skin. IL-17(+) mast cells and neutrophils are found at higher densities than IL-17(+) T cells in psoriasis lesions and frequently release IL-17 in the process of forming specialized structures called extracellular traps. Furthermore, we find that IL-23 and IL-1ß can induce mast cell extracellular trap formation and degranulation of human mast cells. Release of IL-17 from innate immune cells may be central to the pathogenesis of psoriasis, representing a fundamental mechanism by which the IL-23-IL-17 axis mediates host defense and autoimmunity.

Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus.

An abnormal neutrophil subset has been identified in the PBMC fractions from lupus patients. We have proposed that these low-density granulocytes (LDGs) play an important role in lupus pathogenesis by damaging endothelial cells and synthesizing increased levels of proinflammatory cytokines and type I IFNs. To directly establish LDGs as a distinct neutrophil subset, their gene array profiles were compared with those of autologous normal-density neutrophils and control neutrophils. LDGs significantly overexpress mRNA of various immunostimulatory bactericidal proteins and alarmins, relative to lupus and control neutrophils. In contrast, gene profiles of lupus normal-density neutrophils do not differ from those of controls. LDGs have heightened capacity to synthesize neutrophils extracellular traps (NETs), which display increased externalization of bactericidal, immunostimulatory proteins, and autoantigens, including LL-37, IL-17, and dsDNA. Through NETosis, LDGs have increased capacity to kill endothelial cells and to stimulate IFN-α synthesis by plasmacytoid dendritic cells. Affected skin and kidneys from lupus patients are infiltrated by netting neutrophils, which expose LL-37 and dsDNA. Tissue NETosis is associated with increased anti-dsDNA in sera. These results expand the potential pathogenic roles of aberrant lupus neutrophils and suggest that dysregulation of NET formation and its subsequent responses may play a prominent deleterious role.

Intraoperative pathologic examination: cost effectiveness and clinical value in patients with cytologic diagnosis of cellular follicular thyroid lesion.

OBJECTIVE: Routine use of intraoperative pathologic examination (IOPE), including frozen section (FS) and scrape preparation cytology (SPC), during diagnostic thyroid lobectomy continues to be a source of controversy. We sought to better delineate the usefulness and cost-benefit ratio of IOPE in the context of cytologically diagnosed cellular follicular lesion (CFL) or follicular neoplasm (FN). DESIGN: Records of 205 patients who underwent thyroidectomy for cytologically diagnosed FN or CFL between 1997 and 2005 were retrospectively reviewed. IOPE results, patient demographics, and tumor characteristics were correlated to final histopathologic diagnoses. Sensitivity, specificity, predictive values, accuracy, and costs of IOPE were calculated. MAIN OUTCOME: IOPE correctly identified 3 of 16 follicular carcinomas and 9 of 36 papillary carcinomas. Sensitivity, specificity, and accuracy were 23%, 99%, and 78%, respectively. On univariate analysis, malignancy risk among follicular nodules did not correlate with age, gender, or nodule size. On multivariate analysis, nodule size was predictive of malignancy (p < 0.05). Over the entire patient series, routine IOPE resulted in a net cost savings of $74,304.33. CONCLUSIONS: IOPE reduced costs and limited the number of completion thyroidectomies necessary. IOPE is specific, cost effective, and of minimal additional risk when performed routinely for patients with CFL or FN.

Resveratrol decreases noise-induced cyclooxygenase-2 expression in the rat cochlea.

OBJECTIVE: Our previous studies have demonstrated the efficacy of resveratrol, a grape constituent noted for its antioxidant and anti-inflammatory properties, in reducing temporary threshold shifts and decreasing cochlear hair cell damage following noise exposure. This study was designed to identify the potential protective mechanism of resveratrol by measuring its effect on cyclooxygenase-2 (COX-2) protein expression and reactive oxygen species (ROS) formation following noise exposure. STUDY DESIGN: Controlled animal intervention study. SETTING: Otology Laboratory, Henry Ford Health System. SUBJECTS AND METHODS: Twenty-two healthy male Fischer 344 rats (2-3 months old) were exposed to acoustic trauma of variable duration with or without intervention. An additional 20 healthy male rats were used to study COX-2 expression at different time points during and following treatment of 24 hours of noise exposure. Cochlear harvest was performed at various time intervals for measurement of COX-2 protein expression via Western blot analysis and immunostaining. Peripheral blood was also obtained for ROS analysis using flow cytometry. RESULTS: Acoustic trauma exposure resulted in a progressive up-regulation of COX-2 protein expression, commencing at 8 hours and peaking at 32 hours. Similarly, ROS production increased after noise exposure. However, treatment with resveratrol reduced noise-induced COX-2 expression as well as ROS formation in the blood as compared with the controls. CONCLUSION: COX-2 levels are induced dramatically following noise exposure. This increased expression may be a potential mechanism of noise-induced hearing loss (NIHL) and a possible mechanism of resveratrol's ability to mitigate NIHL by its ability to reduce COX-2 expression.

Anti-intercellular adhesion molecule-1 antibody's effect on noise damage.

OBJECTIVES/HYPOTHESIS: The purpose of this study was to investigate possible preventive effects of anti-intercellular adhesion molecule-1 antibody (anti-ICAM-1 Ab) on noise-induced cochlear damage as assessed by changes in auditory thresholds and cochlear blood flow. STUDY DESIGN: A controlled animal study. Pretreated rats with anti-ICAM-1 Ab or saline control, followed with exposure to 72 continuous hours of broad band noise (107 dB SPL), and 24 hours after noise exposure treated again with anti-ICAM-1 Ab or saline. METHODS: Eighteen healthy male Fischer rats (200-250 g) were used. Sixteen were randomly selected to study noise-induced temporary threshold shifts. The remaining two rats were used to study cochlear blood flow (CBF), using laser Doppler flowmetry and blood pressure measurements. RESULTS: Rats treated with anti-ICAM-1 Ab (1.875 mg/kg, intravenously) showed attenuated temporary threshold shifts (TTS) compared to controls. Both groups showed a partial threshold recovery 72 hours following noise exposure, normal for this noise exposure paradigm. Comparisons of baseline and post-treatment measurements of CBF and mean arterial blood pressure revealed no significant changes. Anti-ICAM-1 Ab animals displayed significantly lower mean auditory threshold shifts at all five test frequencies (P < .05) when compared to control. CONCLUSIONS: Blocking the cascade of reactive oxygen species (ROS) generation by using anti-ICAM-Ab protects against noise-induced hearing loss.