Repeated sensitization of mice with microfilariae of Litomosoides sigmodontis induces pulmonary eosinophilia in an IL-33-dependent manner

Background Eosinophilia is a hallmark of helminth infections and eosinophils are essential in the protective immune responses against helminths. Nevertheless, the distinct role of eosinophils during parasitic filarial infection, allergy and autoimmune disease-driven pathology is still not sufficiently understood. In this study, we established a mouse model for microfilariae-induced eosinophilic lung disease (ELD), a manifestation caused by eosinophil hyper-responsiveness within the lung. Methods Wild-type (WT) BALB/c mice were sensitized with dead microfilariae (MF) of the rodent filarial nematode Litomosoides sigmodontis three times at weekly intervals and subsequently challenged with viable MF to induce ELD. The resulting immune response was compared to non-sensitized WT mice as well as sensitized eosinophil-deficient dblGATA mice using flow cytometry, lung histology and ELISA. Additionally, the impact of IL-33 signaling on ELD development was investigated using the IL-33 antagonist HpARI2. Results ELD-induced WT mice displayed an increased type 2 immune response in the lung with increased frequencies of eosinophils, alternatively activated macrophages and group 2 innate lymphoid cells, as well as higher peripheral blood IgE, IL-5 and IL-33 levels in comparison to mice challenged only with viable MF or PBS. ELD mice had an increased MF retention in lung tissue, which was in line with an enhanced MF clearance from peripheral blood. Using eosinophil-deficient dblGATA mice, we demonstrate that eosinophils are essentially involved in driving the type 2 immune response and retention of MF in the lung of ELD mice. Furthermore, we demonstrate that IL-33 drives eosinophil activation in vitro and inhibition of IL-33 signaling during ELD induction reduces pulmonary type 2 immune responses, eosinophil activation and alleviates lung lacunarity. In conclusion, we demonstrate that IL-33 signaling is essentially involved in MF-induced ELD development.</p

Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID)

Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting. Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm). Conclusions: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies

The invisible meydan. The discourse on public space in Istanbul and Brussels, 1830-2000

This dissertation proposes to apply Henri Lefebvre s approach of the production of space to the analysis of public space. A thus historically informed socio-economic analysis of public space does prevent research from falling into the trap of orientalism, rehearsing only the age-old argument that public space in the so-called Orient did not exist due to a lack of democracy, the lack of women moving in public space, the dominance of Islam and indeed the mere physical lack of the square. A historical discourse analysis of the term meydan (square) and publicspace in Istanbul between 1830-2000 uncovered the genealogy of this knowledge. The comparison with Brussels (a city where nobody would question the existence of public space) in the same period and with relatively similar material, showed not only that the discourse about public space in the two cities followed similar logics and were influenced by similar models, it also helped to single out their characteristics. The emergence of private ownership of urban land during the nineteenth century, interestingly, appears as an important condition to expropriate and demolish the existing urban fabric in order to open up public space.1. Theoretical considerations............................................ 5 1.1. Why again public space? .......................................................... 5 Normative definitions ............................................................................................................ 6 Topographical Approaches to Public Space .......................................................... 8 Space matters – the geographic intervention............................................. 12 1.2. Literature Review ......................................................... 14 Public space as an Orientalist Trope ...................................................................................... 14 Ideas that travel................................................................................................................... 17 1.3. A spatial production approach to public space ............................................................... 19 Space of the past ................................................................................................................. 21 Actors in the Production of Public Space ............................................................................... 24 2. Methodological considerations ................................................................................................ 26 3. Meydan in Istanbul .................................................................................................................. 35 3.1. Ottoman Istanbul.............................................................................................................. 35 The meydan of representative emptiness .............................................................................. 35 Metropolitan meydan .......................................................................................................... 50 The meydan of the other ...................................................................................................... 59 The Paradox of Public Space and Vakıf Space......................................................................... 61 The Role of Actors in the Production of Meydan .................................................................... 62 3.2. Republican Istanbul........................................................................................................... 66 Meydan as Açık Mekân ........................................................................................................ 68 Meydan of identity .............................................................................................................. 89 Meydan as nostalgia ...........................................................................................................108 The alan .............................................................................................................................112 The meydan of the other .....................................................................................................115 4. Place publique in Brussels ...................................................................................................120 Place publique of identity ....................................................................................................122 Place publique of metropolitanism.......................................................................................127 Espace libre and the car ......................................................................................................136 From place publique to espace public ..................................................................................138 5. Conclusion .............................................................................................................................144nrpages: 242status: publishe

Süleymaniye- 19. yüzyıl boyunca İstanbul'da sur- içi bir mahalle'de bir örnek olay incelemesi

With the concept of mahalle as the key concept to grasp everyday life in the Ottoman Empire, this thesis tries to understand ordinary life in a not very ordinary neighbourhood, the Süleymaniye mahalle in Istanbul. Süleymaniye, once inhabitedby religious, military and educational elites, in the contemporary discourse advancedto a symbol for the riches of the lost Empire without examining, however, the nineteenth century. This case-study on the mahalle focusses on the turbulent years1815 to 1885 with an attempt to observe change in the institutional structure of thecity, the social make-up of the mahalle and its built environment.It offers insights into the ways these three aspects – institutional, social and builtchange – mutually influence each other and gives hints to the question, which of these changes actually affected the micro-scale. In the process of this undertaking,the concept of the mahalle as a distinct and identity-generating community with poorand rich living side by side is juxtaposed with mahalle borders in flux and a clear socioeconomic segregation. An unexpected picture of a mahalle emerges with a high share of female property and illicit activities in a neighbourhood that at least until 1885 is still one of the principal areas in Istanbul

Renal fibrosis is attenuated by targeted disruption of K(Ca)3.1 potassium channels

Proliferation of interstitial fibroblasts is a hallmark of progressive renal fibrosis commonly resulting in chronic kidney failure. The intermediate-conductance Ca2+-activated K+ channel (K(Ca)3.1) has been proposed to promote mitogenesis in several cell types and contribute to disease states characterized by excessive proliferation. Here, we hypothesized that K(Ca)3.1 activity is pivotal for renal fibroblast proliferation and that deficiency or pharmacological blockade of K(Ca)3.1 suppresses development of renal fibrosis. We found that mitogenic stimulation up-regulated K(Ca)3.1 in murine renal fibroblasts via a MEK-dependent mechanism and that selective blockade of K(Ca)3.1 functions potently inhibited fibroblast proliferation by G(0)/G(1) arrest. Renal fibrosis induced by unilateral ureteral obstruction (UUO) in mice was paralleled by a robust up-regulation of K(Ca)3.1 in affected kidneys. Mice lacking K(Ca)3.1 (K(Ca)3.1(-/-)) showed a significant reduction in fibrotic marker expression, chronic tubulointerstitial damage, collagen deposition and alpha SMA(+) cells in kidneys after UUO, whereas functional renal parenchyma was better preserved. Pharmacological treatment with the selective K(Ca)3.1 blocker TRAM-34 similarly attenuated progression of UUO-induced renal fibrosis in wild-type mice and rats. In conclusion, our data demonstrate that K(Ca)3.1 is involved in renal fibroblast proliferation and fibrogenesis and suggest that K(Ca)3.1 may represent a therapeutic target for the treatment of fibrotic kidney disease

Lung eosinophils are highly activated during ELD.

Geometric mean of the fluorescence intensity (gMFI) of (A) CD11b, (B) Siglec-F, (C) CD86 and (D) ST2/IL-33R of lung eosinophils isolated from wild-type ELD mice, mice solely challenged with MF (MF) or naïve animals ten days after MF challenge. (E-H) Representative histograms comparing eosinophils from naïve (grey) and ELD mice (red). (A-D) Data is pooled from 1–3 independent experiments with n = 5–13 mice per group. Data is shown as median with interquartile range. Statistical analysis was performed with Kruskal-Wallis followed by Dunn´s multiple comparison test. p values ≤ 0.05 are shown.</p

IL-33 serum levels are elevated in ELD mice.

Serum levels of (A) total IgE, (B) parasite-specific IgE, (C) IL-33, and (D) IL-4 ten days after the MF challenge in naïve, MF-only challenged, ELD and dblGATA ELD mice. (E) DNA quantification of 20 μl BAL fluid of MF-challenged, ELD and dblGATA ELD mice. One experiment with n = 5–8 mice per group. Data is shown as median with interquartile range. Statistical analysis was performed with Kruskal-Wallis followed by Dunn´s multiple comparison test. p values ≤ 0.05 are shown.</p

ELD mice have increased levels of eosinophil-associated mediators as well as markers of tissue remodeling activity.

Serum (A) IL-5, (B) IFN-y, (C) total IgE and (D) parasite-specific IgE levels from wild-type ELD mice, dblGATA ELD mice, mice challenged with MF (MF) or naïve animals one day after MF challenge. (E) EPO, (F) MBP, (G) CCL5, (H) CCL11 and (I) amphiregulin levels in lung tissue homogenates. (J) MMP activity assay from lung homogenates. Data is pooled from 1–3 independent experiments with n = 4–18 animals per group and shown as median with interquartile range. Statistical analysis was performed with Kruskal-Wallis followed by Dunn´s multiple comparison test. p values ≤ 0.05 are shown.</p

S4 Fig -

Serum (A) IFNγ and (B) IL-5 levels of naïve, and 10 days after the final challenge of MF-challenged, ELD and dblGATA ELD mice. Data from one experiment, n = 5–8, median with interquartile range. Kruskal-Wallis test followed by Dunn´s multiple comparison. p values ≤ 0.05 are shown. (TIF)</p

Gating strategies for neutrophils, eosinophils, ILC2s, and alternatively activated macrophages.

Gating strategies for neutrophils, eosinophils, ILC2s, and alternatively activated macrophages.</p