Bradykinin B2 receptors of dendritic cells, acting as sensors of kinins proteolytically released by Trypanosoma cruzi, are critical for the development of protective type-1 responses
Ana Carolina Monteiro
Luciana Barros de Arruda
João B. Pesquero
Herbert B. Tanowitz
- Although the concept that dendritic cells (DCs) recognize pathogens through the engagement of Toll-like receptors is widely accepted, we recently suggested that immature DCs might sense kinin-releasing strains of Trypanosoma cruzi through the triggering of G-protein-coupled bradykinin B2 receptors (B2R). Here we report that C57BL/6.B2R-/- mice infected intraperitoneally with T. cruzi display higher parasitemia and mortality rates as compared to B2R+/+ mice. qRT-PCR revealed a 5-fold increase in T. cruzi DNA (14 d post-infection [p.i.]) in B2R-/- heart, while spleen parasitism was negligible in both mice strains. Analysis of recall responses (14 d p.i.) showed high and comparable frequencies of IFN-gamma-producing CD4+ and CD8+ T cells in the spleen of B2R-/- and wild-type mice. However, production of IFN-gamma by effector T cells isolated from B2R-/- heart was significantly reduced as compared with wild-type mice. As the infection continued, wild-type mice presented IFN-gamma-producing (CD4+CD44+ and CD8+CD44+) T cells both in the spleen and heart while B2R-/- mice showed negligible frequencies of such activated T cells. Furthermore, the collapse of type-1 immune responses in B2R-/- mice was linked to upregulated secretion of IL-17 and TNF-alpha by antigen-responsive CD4+ T cells. In vitro analysis of tissue culture trypomastigote interaction with splenic CD11c+ DCs indicated that DC maturation (IL-12, CD40, and CD86) is controlled by the kinin/B2R pathway. Further, systemic injection of trypomastigotes induced IL-12 production by CD11c+ DCs isolated from B2R+/+ spleen, but not by DCs from B2R-/- mice. Notably, adoptive transfer of B2R+/+ CD11c+ DCs (intravenously) into B2R-/- mice rendered them resistant to acute challenge, rescued development of type-1 immunity, and repressed TH17 responses. Collectively, our results demonstrate that activation of B2R, a DC sensor of endogenous maturation signals, is critically required for development of acquired resistance to T. cruzi infection. Author Summary: Antibodies and IFN-gamma-producing effector T cells are essential for the immune control of infection by Trypanosoma cruzi, the intracellular protozoa that causes human Chagas disease. Despite the potency of anti-parasite immunity, the parasites are not cleared from their intracellular niches. Instead, a low grade chronic infection prevails, provoking severe immunopathology in the myocardium. Although it is well established that innate sentinel cells sense T. cruzi through receptors for microbial structures, such as Toll-like receptors, it remained unclear whether endogenous inflammatory signals also contribute to the development of adaptive immunity. The present study was motivated by awareness that T. cruzi trypomastigotes (extracellular infective forms) are equipped with proteases that liberate the pro-inflammatory bradykinin peptide from an internal segment of kininogens. Here we demonstrate that splenic dendritic cells (DCs), the antigen-presenting cells that coordinate the adaptive branch of immunity in lymphoid tissues, are potently activated via G-protein-coupled bradykinin B2 receptors (B2R). Analysis of the outcome of infection in B2R-knockout mice revealed that the mutant mice developed a typical susceptible phenotype, owing to impaired development of IFN-gamma-producing effector T cells. Notably, the immune dysfunction of B2R-knockout mice was corrected upon cell transfer of wild-type DCs, thus linking development of protective T cells to DCs' sensing of endogenous danger signals (kinins) released by trypomastigotes.
High-energy dileptons from an anisotropic quark-gluon plasma
- We calculate leading-order dilepton yields from a quark-gluon plasma which has a time-dependent anisotropy in momentum space. Such anisotropies can arise during the earliest stages of quark-gluon plasma evolution due to the rapid longitudinal expansion of the created matter. A phenomenological model for the proper time dependence of the parton hard momentum scale, p_hard, and the plasma anisotropy parameter, xi, is proposed. The model describes the transition of the plasma from a 0+1 dimensional collisionally-broadened expansion at early times to a 0+1 dimensional ideal hydrodynamic expansion at late times. We find that high-energy dilepton production is enhanced by pre-equilibrium emission up to 50% at LHC energies, if one assumes an isotropization/thermalization time of 2 fm/c. Given sufficiently precise experimental data this enhancement could be used to determine the plasma isotropization time experimentally.
QPRT: a potential marker for follicular thyroid carcinoma including minimal invasive variant : a gene expression, RNA and immunohistochemical study
- Background The differential diagnosis between follicular thyroid adenoma and minimal invasive follicular thyroid carcinoma is often difficult for several reasons. One major aspect is the lack of typical cytological criteria in well differentiated specimens. New marker molecules, shown by poly- or monoclonal antibodies proved helpful. Methods We performed global gene expression analysis of 12 follicular thyroid tumours (4 follicular adenomas, 4 minimal invasive follicular carcinomas and 4 widely invasive follicular carcinomas), followed by immunohistochemical staining of 149 cases. The specificity of the antibody was validated by western blot analysis Results In gene expression analysis QPRT was detected as differently expressed between follicular thyroid adenoma and follicular thyroid carcinoma. QPRT protein could be detected by immunohistochemistry in 65% of follicular thyroid carcinomas including minimal invasive variant and only 22% of follicular adenomas. Conclusion Consequently, QPRT is a potential new marker for the immunohistochemical screening of follicular thyroid nodules.
Ribes x nidigrolaria R. &. A. Bauer und Fragaria x vescana R. & A. Bauer - Beschreibung zweier Hybridarten
Heinrich E. Weber
- Zwei von Rudolf Bauer künstlich erzeugte Hybriden werden als neue Nothospecies beschrieben: Ribes x nidigrolaria Rudolf & Annelise Bauer (=[R. nigrum x divaricatum] x [R. nigrum x uva-cripa]) and Fragaria x vescana Rudolf & Annelise Bauer (= [Fragaria vesca f. semperflorens x F. x ananassa] x F. x ananassa). Diese wirtschaftlich wichtigen Kulturarten sind bereits allgemein bekannt als „Jostabeere“ (cv. „Josta“) und als Vescana mit den Kultursorten „Spadeka“ und „Florika“. Die Hybridarten sind taxonomisch beschrieben, ihre Holotypen sind abgebildet, außerdem werden Einzelheiten zur Entstehung, zu den Eigenschaften und zur Kultur mitgeteilt.
Zwergformen bei Brombeeren ("Rubus" L. subgen. "Rubus")
Heinrich E. Weber
- Der Beitrag behandelt die in Europa nachgewiesenen Zwergformen der Gattung Rubus L. Sechzehn Arten (alle nur Sekt. Rubus) bilden solche offensichtlich genetisch fixierten Abwandlungen aus, die als Varietäten der betreffenden Arten eingestuft werden. Neu beschrieben werden R. marssonianus H. E. WEBER var. pusillus H. E. WEBER, R. muenteri T. MARSS. var. pusillus H. E. WEBER und R. senticosus KÖHLER ex WEIHE var. pusillus H. E. WEBER & KIESEWETTER. Einen status novus erhalten R. gracilis J. & C. PRESL var. parvulus (HÜLSEN) H. E. WEBER, R. pyramidalis KALT. var. parvifolius (K. FRID. & GELERT) H. E. WEBER und R. silvaticus WEIHE & NEES var. microphyllus (K. FRID. ex ERICHSEN) H. E. WEBER. – Zwergformen sind meist etwa nur halb so groß wie die Normalform und weisen weitere charakteristische Merkmale auf. Ihre Häufigkeit nimmt von Norden nach Süden ab. Die meisten Zwergformen wachsen in Dänemark (13), es folgen Norddeutschland (9) und Mitteleuropa bis zur Donau (4). Weiter südlich und in Südeuropa fehlen sie. Von den Britischen Inseln sind vier Zwergformen bekannt.
Taurolidine reduces the tumor stimulating cytokine interleukin-1beta in patients with resectable gastrointestinal cancer : a multicentre prospective randomized trial
Carsten Nils Gutt
Joachim M. Müller
Christoph A. Jacobi
- Background The effect of additional treatment strategies with antineoplastic agents on intraperitoneal tumor stimulating interleukin levels are unclear. Taurolidine and Povidone-iodine have been mainly used for abdominal lavage in Germany and Europe. Methods In the settings of a multicentre (three University Hospitals) prospective randomized controlled trial 120 patients were randomly allocated to receive either 0.5% taurolidine/2,500 IU heparin (TRD) or 0.25% povidone-iodine (control) intraperitoneally for resectable colorectal, gastric or pancreatic cancers. Due to the fact that IL-1beta (produced by macrophages) is preoperatively indifferent in various gastrointestinal cancer types our major outcome criterion was the perioperative (overall) level of IL-1beta in peritoneal fluid. Results Cytokine values were significantly lower after TRD lavage for IL-1beta, IL-6, and IL-10. Perioperative complications did not differ. The median follow-up was 50.0 months. The overall mortality rate (28 vs. 25, p = 0.36), the cancer-related death rate (17 vs. 19, p = .2), the local recurrence rate (7 vs. 12, p = .16), the distant metastasis rate (13 vs. 18, p = 0.2) as well as the time to relapse were not statistically significant different. Conclusion Reduced cytokine levels might explain a short term antitumorigenic intraperitoneal effect of TRD. But, this study analyzed different types of cancer. Therefore, we set up a multicentre randomized trial in patients undergoing curative colorectal cancer resection. Trial registration : ISRCTN66478538
Heinrich E. Weber
- Besprochen werden die beiden folgenden Werke: "Die Naturschutzgebiete Westfalens und des früheren Regierungsbezirks Osnabrück", 3. verbesserte und erweiterte Auflage, von Fritz Runge (1978), sowie "Moosflora von Westfalen", Fotomechanischer Neudruck, von Fritz Koppe (1978).
T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers
- Introduction Lymphocyte infiltration (LI) is often seen in breast cancer but its importance remains controversial. A positive correlation of human epidermal growth factor receptor 2 (HER2) amplification and LI has been described, which was associated with a more favorable outcome. However, specific lymphocytes might also promote tumor progression by shifting the cytokine milieu in the tumor. Methods Affymetrix HG-U133A microarray data of 1,781 primary breast cancer samples from 12 datasets were included. The correlation of immune system-related metagenes with different immune cells, clinical parameters, and survival was analyzed. Results A large cluster of nearly 600 genes with functions in immune cells was consistently obtained in all datasets. Seven robust metagenes from this cluster can act as surrogate markers for the amount of different immune cell types in the breast cancer sample. An IgG metagene as a marker for B cells had no significant prognostic value. In contrast, a strong positive prognostic value for the T-cell surrogate marker (lymphocyte-specific kinase (LCK) metagene) was observed among all estrogen receptor (ER)-negative tumors and those ER-positive tumors with a HER2 overexpression. Moreover ER-negative tumors with high expression of both IgG and LCK metagenes seem to respond better to neoadjuvant chemotherapy. Conclusions Precise definitions of the specific subtypes of immune cells in the tumor can be accomplished from microarray data. These surrogate markers define subgroups of tumors with different prognosis. Importantly, all known prognostic gene signatures uniformly assign poor prognosis to all ER-negative tumors. In contrast, the LCK metagene actually separates the ER-negative group into better or worse prognosis.
Das Schmalblättrige Kreuzkraut (Senecio inaequidens DC.), eine aus Südafrika stammende Art, nun auch im Raum Osnabrück : mit 1 Tabelle
Heinrich E. Weber
- Senecio inaequidens De., ein in Natal und Transvaal beheimateter, sich im westlichen Europa zunehmend ausbreitender Neophyt, ist seit 1985 auch bei Osnabrück nachgewiesen. Die pflanzensoziologische Situation des 1986 noch vorhandenen Standorts in einem fragmentarischen Echino-Melilotatum Tx. 42 bei Bramsche-Achmer ist durch eine Vegetationstabelle veranschaulicht.
Tfg (Trk fused gene) is a Carma-1/IKKgamma interacting protein involved in CD40-induced canonical NF-KB signaling
- Carma-1 is required for B cell receptor-/CD40- and T cell receptor-/CD28-induced B- and T-cell activation via JNK and NF-betaB. In B cells, Carma-1 becomes phosphorylated by PKCbeta, leading to its oligomerization. Subsequent Bcl10 binding induces IKKbeta-activation and, thereby, canonical NF-KB signalling. Despite these findings it is still unknown how exactly Carma-1 is connected to the plasma membrane and to the IKK-complex. Therefore, we purified Carma-1 complexes from mouse CH12 B cells using anti-Carma-1 affinity columns. Mass spectrometric analyses of the column eluates demonstrated the presence of Carma-1 as well as three previously uncharacterized adaptor proteins in B cells, one of which was the Trk-fused gene (Tfg), an adaptor protein containing PB1 and coiledcoil domains. Whereas Tfg was originally identified as fusion partner of oncogenic Trk tyrosine kinase mutants, the normal cellular homologue of Tfg has so far not been described in B cells. However, Tfg has been shown in other systems to interact with IKKgamma and to enhance TNFinduced NF-KB activation. Tfg and Carma-1 co-localized at the plasma membrane and perinuclear structures in B cells. We further corroborated the interactions of Tfg, IKKgamma and Carma-1 by Blue Native gel electrophoresis, where Carma-1 and Tfg formed a 0.7–1 MDa complex. Ectopic expression of Tfg increased the molecular mass of IKKgamma complexes, fused IKKgamma, Bcl10 and Carma-1 complexes to a ~2 MDa complex, and increased basal and CD40-induced canonical activity of NF-KB and IKKbeta. In contrast, shRNA-mediated silencing of Tfg decreased CD40-induced IKKbeta activity. Very interestingly, in primary B cells, highest expression of Tfg was detected in marginal zone and B1 B cells, and Carma-1 and Tfg formed complexes in these B cells. Since Carma-1 is required for marginal zone B cell and B1 B cell development, we suggest that a functional interaction between Carma-1 and Tfg contributes to development and maintenance of these cells by means of canonical NF-KB signals.