Julius Renne

Interleukin-1 from epithelial cells fosters T cell-dependent skin inflammation

Background  Chronic inflammatory skin diseases such as atopic dermatitis and psoriasis are characterized by the infiltration of lymphocytes into the epidermal compartment. Several studies point to an active role of skin epithelial cells in the pathophysiology of such diseases.

IL-18 and skin inflammation.

IL-18 belongs to the IL-1 family of cytokines and has recently regained interest in the context of inflammasome activation. The inflammasome dependent caspase 1 cleaves pro-IL-18 into the active form - similar to what is known for IL-1ss. Still, the action and importance of IL-18 are not completely understood. There are several indications that it plays a pathogenetically important role in chronic inflammatory conditions of epithelial organs (such as skin, gut, kidney) and importantly also in responses against self. Here, we summarise current knowledge on the role of IL-18 in human skin inflammation with a focus on its role in Cutaneous Lupus Erythematosus (CLE). There is evidence that IL-18 plays a role in CLE upstream of TNFalpha. In CLE but not normal keratinocytes IL-18 strongly induces TNFalpha release, which then results in apoptosis. Blocking TNFalpha in vitro prevents apoptosis of keratinocytes but anti-TNFalpha therapy is not applicable in LE conditions. We will discuss potential approaches to control IL-18 in skin inflammation.

Primary human keratinocytes efficiently induce IL-1-dependent IL-17 in CCR6+ T cells.

Abstract:  Keratinocytes and activated T cells interact in skin inflammation by virtue of chemokines and cytokines. T cell‐derived IL‐17 has been described to play an important role in the course of psoriatic inflammation. In this study, we addressed how keratinocytes influence the secretion of IL‐17 in autologous T cell subsets. We found that a co‐culture of autologous keratinocytes and T cell‐receptor‐stimulated T cells markedly enhanced the production of IL‐17. Besides the importance of direct cell contact, this effect was mainly mediated by IL‐1 and could be blocked by the IL‐1 antagonist anakinra. An additional increase in IL‐17 production by IL‐23 was only seen in the presence of IL‐1, which thus plays a permissive role for the action of IL‐23. Importantly, co‐culture of keratinocytes with CCR6+ CD4+ T cells that are enriched for Th17 cells resulted in significantly higher IL‐17 production compared to co‐culture with CD4+ T cells.

Performance of perfusion-weighted Fourier decomposition MRI for detection of chronic pulmonary emboli

To evaluate the test performance of perfusion‐weighted Fourier‐decomposition (pw‐FD) magnetic resonance imaging (MRI) in comparison to dynamic contrast‐enhanced (DCE)‐MRI as a reference standard in patients with known or suspected chronic pulmonary embolism (PE).

Quantification of Pulmonary Inflammation after Segmental Allergen Challenge Using Turbo-Inversion Recovery-Magnitude Magnetic Resonance Imaging

RATIONALE There is a need to develop novel noninvasive imaging biomarkers that help to evaluate antiinflammatory asthma treatments. OBJECTIVES To investigate whether the extent of the segmental lung edema measured noninvasively using turbo-inversion recovery-magnitude magnetic resonance imaging (TIRM MRI) corresponds to the severity of the regional allergic reaction determined by the percentage of eosinophils in bronchoalveolar lavage fluid (BAL) 24 hours after segmental allergen challenge in patients with asthma compared with normal control subjects. METHODS Eleven volunteers with allergic asthma and five healthy volunteers underwent segmental challenges with different allergen doses by two bronchoscopies 24 hours apart. They had lung MRI at baseline and 6 and 24 hours after segmental challenge. MRI TIRM scores were correlated with the eosinophilic response at 24 hours. MEASUREMENTS AND MAIN RESULTS In patients with asthma, there were significant differences of eosinophil percentages in BAL at 24 hours from segments given standard-dose, low-dose, or no allergen (saline) (P < 0.001). Correspondingly significant differences between the TIRM score in allergen standard-dose, low-dose, and saline-treated segments were observed at 24 hours post-challenge (P < 0.001). With increasing TIRM score at 24 hours the percent eosinophils per segment 24 hours post-challenge also increased accordingly (P < 0.001). There was interobserver agreement for TIRM score grading (kappa = 0.72 for 24-h time point). CONCLUSIONS The MRI-based noninvasive TIRM score is a promising biomarker for the noninvasive detection of the inflammatory response after segmental allergen challenge in patients with asthma and may serve to monitor the therapeutic effectiveness of novel antiinflammatory drugs in future human trials.

MR Imaging–derived Regional Pulmonary Parenchymal Perfusion and Cardiac Function for Monitoring Patients with Chronic Thromboembolic Pulmonary Hypertension before and after Pulmonary Endarterectomy

Purpose To evaluate surgical success after pulmonary endarterectomy (PEA) by means of cardiopulmonary magnetic resonance (MR) imaging. Materials and Methods In this institutional review board-approved study, 20 patients with chronic thromboembolic pulmonary hypertension were examined at 1.5 T with a dynamic contrast material-enhanced three-dimensional fast low-angle shot sequence before and 12 days after PEA (25th-75th percentile range, 11-16 days). Lung segments were evaluated visually before PEA for parenchymal hypoperfused segments. Pulmonary blood flow (PBF), first-pass bolus kinetic parameters, and biventricular mass and function were determined. Mean pulmonary artery pressure (mPAP) and 6-minute walking distance were measured before and after PEA. The Shapiro-Wilk test, paired two-sided Wilcoxon rank sum test, Spearman ρ correlation, and multiple linear regression analysis were performed. Results Two weeks after PEA, regional PBF increased 66% in the total lung from 32.7 to 54.2 mL/min/100 mL (P = .0002). However, after adjustment for cardiac output, this change was not evident anymore (increase of 7% from 7.03 to 7.54 mL/min/100 mL/L/min, P = .1). Only in the lower lobes, a significant increase in PBF after cardiac output adjustment remained: a 16% increase in the right lower lobe from 7.53 to 8.71 mL/min/100 mL (P = .01) and a 14% increase in the left lower lobe from 7.42 to 8.47 mL/min/100 mL/L/min (P < .05). Right ventricular mass and function also improved. mPAP decreased from 46 to 24 mm Hg (P < .0001). Six-minute walking distance increased from 390 to 467 m (P = .02) 5 months after PEA. Percentage change of mPAP and PBF in the lower lobe tended to be significant predictors of percentage change in 6-minute walking distance (β = -1.79 [P = .054] and β = 0.45 [P = .076], respectively) in multiple linear regression analysis. Conclusion Improvement of PBF after PEA was observed predominantly in the lower lungs, and the magnitude of improvement of PBF in the lower lobes correlated with the improvement in exercise capacity, reflecting surgical success. (©) RSNA, 2016.

Chronic Lung Allograft Dysfunction: Oxygen-enhanced T1-Mapping MR Imaging of the Lung

PURPOSE To evaluate oxygen-enhanced T1-mapping magnetic resonance (MR) imaging of the lungs for detection of chronic lung allograft dysfunction (CLAD) in patients who have undergone double lung transplantation. MATERIALS AND METHODS The local ethics committee approved this study. Seventy-six recipients of double lung allografts who underwent MR imaging of the lungs during an outpatient visit between 2011 and 2013 were included in this study after they provided written informed consent. Patients were classified as having CLAD on the basis of spirometric results and were divided into three groups: no CLAD (bronchiolitis obliterans syndrome level 0 [BOS 0]), early CLAD (BOS 0p), and late-stage CLAD (BOS 1-3). Coronal T1 maps of the lungs were acquired with the patient breathing room air and 100% oxygen by using an inversion-recovery snapshot fast low-angle shot sequence at 1.5 T. The median and interquartile range of T1 values at room air and at 100% oxygen and the oxygen transfer function were calculated. Statistical analysis was performed with analysis of variance and the Tukey honestly significant difference test or the Kruskal-Wallis test and the Mann-Whitney U test (α = 0.05). Bonferroni correction was applied for multiple comparisons. RESULTS The oxygen transfer function was significantly lower in patients in the BOS 0p (P = .025) and BOS 1-3 groups (P = .003) than it was in the patients with BOS 0. Absolute T1 values (room air, P = .66; 100% oxygen, P = .67) did not differ significantly among the groups. The heterogeneity of T1 values, measured by using the interquartile range, showed a strong trend toward higher values in patients with BOS (room air, P = .06; 100% oxygen, P = .08). CONCLUSION Oxygen transfer function may serve as an early marker for detection of CLAD.

High frequency of vitamin D deficiency among patients with cutaneous lupus erythemathosus

1998; 29:193–5. 8 Harris SL, Levine AJ. The p53 pathway: positive and negative feedback loops. Oncogene 2005; 24:2899–908. 9 Leone G, Mele L, Pulsoni A et al. The incidence of secondary leukemias. Haematologica 1999; 84:937–45. 10 van Leeuwen FE, Stiggelbout AM, van den Belt-Dusebout AW et al. Second cancer risk following testicular cancer: a follow-up study of 1,909 patients. J Clin Oncol 1993; 11:415–24.

Noninvasive Quantification of Airway Inflammation Following Segmental Allergen Challenge with Functional MR Imaging: A Proof of Concept Study

PURPOSE To evaluate oxygen-enhanced T1-mapping magnetic resonance (MR) imaging as a noninvasive method for visualization and quantification of regional inflammation after segmental allergen challenge in asthmatic patients compared with control subjects. MATERIALS AND METHODS After institutional review board approval, nine asthmatic and four healthy individuals gave written informed consent. MR imaging (1.5 T) was performed by using an inversion-recovery snapshot fast low-angle shot sequence before (0 hours) and 6 hours and 24 hours after segmental allergen challenge by using either normal- or low-dose allergen or saline. The volume of lung tissue with increased relaxation times was determined by using a threshold-based method. As a biomarker for oxygen transfer from the lungs into the blood, the oxygen transfer function ( OTF oxygen transfer function ) was calculated. After the third MR imaging examination, eosinophils in bronchoalveolar lavage fluid were counted. Differences between times and segments were analyzed with nonparametric Wilcoxon matched-pairs test and Spearman correlation. RESULTS In lung segments treated with the standard dose of allergen, the OTF oxygen transfer function was decreased at 6 hours in asthmatic patients, compared with saline-treated segments (P = .0078). In asthmatic patients at 24 hours, the volume over threshold was significantly increased in normal allergen dose-treated segments compared with saline-treated segments (P = .004). In corresponding lung segments, the volume over threshold at 24 hours in the asthmatic group showed a positive correlation (r = 0.65, P = .0001) and the OTF oxygen transfer function at 6 hours showed an inverse correlation (r = -0.67, P = .0001) with the percentage of eosinophils in the bronchoalveolar lavage fluid. CONCLUSION OTF oxygen transfer function and volume over threshold are noninvasive MR imaging-derived parameters to visualize and quantify the regional allergic reaction after segmental endobronchial allergen challenge.

Clinical use of oxygen-enhanced T1 mapping MRI of the lung: Reproducibility and impact of closed versus loose fit oxygen delivery system

To evaluate the reproducibility of oxygen‐enhanced magnetic resonance imaging (MRI), and the influence of different gas delivery methods, in a clinical environment.