TLR9 independent interferon α production by neutrophils on NETosis in response to circulating chromatin, a key lupus autoantigen.

Objectives: Interferon (IFN) α is a key immunoregulatory cytokine secreted by activated plasmacytoid dendritic cells (PDC) that constitute less than 1% of leucocytes. IFNα plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Nevertheless, the natural IFNα inducers in SLE as well as the different IFNα secreting cell types are only partially characterised.

Primary blood neutrophils express a functional cell surface Toll-like receptor 9.

Polymorphonuclear leukocytes (PMNs) represent one of the first lines of defense against pathogens. TLR9 is normally expressed in endosomes/lysosomes where it is activated by pathogen-derived DNA. Here we show that freshly isolated human and mouse primary PMNs express TLR9 at the cell surface ex vivo.

The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells.

Myeloid-derived suppressor cells (MDSC) and regulatory T (Treg) cells are major components of the immune suppressive tumour microenvironment (TME). Both cell types expand systematically in preclinical tumour models and promote T-cell dysfunction that in turn favours tumour progression. Clinical reports show a positive correlation between elevated levels of both suppressors and tumour burden.

Immunocombination therapy for high-risk neuroblastoma.

Neuroblastoma (NBL) is an aggressive malignancy of the sympathetic nervous system. Advanced-stage NBLs prove fatal in approximately 50% of patients within 5 years. Therefore, new treatment modalities are urgently needed.

Simvastatin reduces tumor cell adhesion to human peritoneal mesothelial cells by decreased expression of VCAM-1 and β1 integrin.

Peritoneal carcinomatosis describes cancer metastasis onto the surface of the peritoneum. It is frequently caused by ovarian and colorectal cancer. Once a tumor has penetrated the peritoneum, cancer cells disseminate into the abdominal cavity.

Phagocytosis of dying tumor cells by human peritoneal mesothelial cells.

Peritoneal carcinomatosis is an advanced form of metastatic disease characterized by cancer cell dissemination onto the peritoneum. It is commonly observed in ovarian and colorectal cancers and is associated with poor patient survival. Novel therapies consist of cytoreductive surgery in combination with intraperitoneal chemotherapy, aiming at tumor cell death induction.

Nucleosome-induced neutrophil activation occurs independently of TLR9 and endosomal acidification: implications for systemic lupus erythematosus.

The nucleosome is a major autoantigen known to activate PMN in systemic lupus erythematosus (SLE). TLR9 recognizes bacterial and even mammalian DNA under certain circumstances. Nevertheless, the role of TLR9 in SLE development is still unclear.

Nph, DC and chromatin-mediated pathogenesis in systemic lupus erythematosus.

Nucleosomes (Nuc) are key lupus autoantigen and have been shown to activate several types of immune cells as well as the complement system, resulting in inflammation. The elevated concentrations and the immunostimulatory capacities of circulating Nuc may favour the break of peripheral tolerance in genetically predisposed individuals. Nevertheless, in most cases the signalling pathways involved are not elucidated yet, although Tir8/Sigirr deficiency has been recently shown to enhance cell activation upon exposure to Nuc-containing immune complexes.

Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology.

We have generated a novel transgenic mouse model on a C57BL/6J genetic background that coexpresses KM670/671NL mutated amyloid precursor protein and L166P mutated presenilin 1 under the control of a neuron-specific Thy1 promoter element (APPPS1 mice). Cerebral amyloidosis starts at 6-8 weeks and the ratio of human amyloid (A)beta42 to Abeta40 is 1.5 and 5 in pre-depositing and amyloid-depositing mice, respectively.

Production of recombinant RNase Ba and its application in downstream processing of plasmid DNA for pharmaceutical use.

The demand for new strategies in downstream processing of biopharmaceutical plasmid DNA has increased in response to the importance of nucleic acids as active pharmaceutical ingredients (API) in gene therapy and genetic vaccination. Led by the problematic usage of animal-derived proteins for producing reagents of clinical applications, we present an opportunity of removing RNA prior to chromatographic steps by using a recombinant RNase Ba (barnase of Bacillus amyloliquefaciens) as an alternative to bovine RNase A. An expression vector for RNase Ba production was constructed enabling periplasmic localization of the recombinant protein.