Neutrophil proteases degrade autoepitopes of NET-associated proteins

Neutrophils can form neutrophil extracellular traps (NETs) to capture microbes and facilitate their clearance. NETs consist of decondensed chromatin decorated with anti-microbial proteins. Here, we describe the effect of neutrophil proteases on the protein content of NETs. We show that the neutrophil serine proteases degrade several neutrophil proteins associated with NETs. Interestingly, the anti-bacterial proteins associated with NETs, such as myeloperoxidase, calgranulin B and neutrophil elastase (NE), seem to be less susceptible to proteolytic degradation than other NET proteins, such as actin and MNDA. NETs have been proposed to play a role in autoimmune reactions. Our data demonstrate that a large number of the autoepitopes of NET proteins that are recognized by autoantibodies produced by systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients are also removed by the proteases. In conclusion, neutrophil serine proteases have a major impact on the NET proteome and the proteolytic changes of NET-associated proteins may counteract autoimmune reactions to NET components.     

Human herpesvirus type 6 reactivation after haematopoietic stem cell transplantation

Human herpesvirus type 6 (HHV6) is known to reactivate after hematopoetic stem cell transplantation (HSCT) and has been suggested to be associated with increased mortality and severe clinical manifestations, including graft versus host disease (GvHD). The exact etiological role of HHV6 reactivation in increased morbidity and mortality after HSCT remains unclear. This review will focus on the current available evidence of HHV6 reactivation after HSCT and its immuno-modulatory capacities, with particular emphasis on the severe complication GvHD. At present, no effective specific antiviral treatment for HHV6 reactivation has been identified. The currently available antiviral agents are outlined, as well as possible future strategies for the treatment of HHV6 reactivation. Non-toxic, specific treatment or prevention of HHV6 reactivation might improve the safety and efficacy of the HSCT procedure.     

Block Copolymer Micelles with an Intermediate Star‐/Flower‐Like Structure Studied by 1H NMR Relaxometry

¹H NMR relaxation is used to study the self‐assembly of a double thermoresponsive diblock copolymer in dilute aqueous solution. Above the first transition temperature, at which aggregation into micellar structures is observed, the trimethylsilyl (TMS)‐labeled end group attached to the shell‐forming block shows a biphasic T₂ relaxation. The slow contribution reflects the TMS groups located at the periphery of the hydrophilic shell, in agreement with a star‐like micelle. The fast T₂ contribution corresponds to the TMS groups, which fold back toward the hydrophobic core, reflecting a flower‐like micelle. These results confirm the formation of block copolymer micelles of an intermediate nature (i.e., of partial flower‐like and star‐like character), in which a part of the TMS end groups folds back to the core due to hydrophobic interactions.

     

Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients

Alpha-mannosidosis is a rare lysosomal storage disease. Hematopoietic SCT (HSCT) is usually recommended as a therapeutic option though reports are anecdotal to date. This retrospective multi institutional analysis describes 17 patients that were diagnosed at a median of 2.5 (1.1-23) years and underwent HSCT at a median of 3.6 (1.3-23.1) years. In all, 15 patients are alive (88%) after a median follow-up of 5.5 (2.1-12.6) years. Two patients died within the first 5 months after HSCT. Of the survivors, two developed severe acute GvHD (>=grade II) and six developed chronic GvHD. Three patients required re-transplantation because of graft failure. All 15 showed stable engraftment. The extent of the patients' developmental delay before HSCT varied over a wide range. After HSCT, patients made developmental progress, although normal development was not achieved. Hearing ability improved in some, but not in all patients. We conclude that HSCT is a feasible therapeutic option that may promote mental development in alpha-mannosidosis.     

Differential expression and distribution of epithelial adhesion molecules in non-small cell lung cancer and normal bronchus

BACKGROUND: Changes in epithelial cell interactions have been implicated in carcinogenesis, tumour invasion and metastasis. AIM: To screen for altered expression of epithelial adhesion genes in lung cancer development. METHODS: Gene expression profiles were assessed with cDNA expression arrays in eight non-small cell lung cancer (NSCLC) and eight normal bronchi obtained from the same patient. Immunohistochemistry (IHC) and RNA in situ hybridisation (ISH) were used to confirm the most prominently expressed adhesion molecules and to investigate their distribution at protein and mRNA levels. RESULTS: 43 differentially expressed cancer-related genes were identified in adenocarcinoma, squamous cell carcinoma (SCC) and normal bronchus. Five of these genes are related to epithelial adhesion-that is, integrin alpha3 (ITGA3), integrin beta4 (ITGB4), desmoplakin I and II (DSP), plakoglobin, and desmocollin 3 (DSC3). ITGA3 and ITGB4, showing predominantly cell-matrix staining, were up regulated in adenocarcinoma and SCC, respectively. ITGB4 also showed strong staining in SCC with IHC and ISH. Components of the desmosome adhesion complex DSP, plakoglobin and DSC3 were strongly up regulated in SCC and showed a distinct cell-cell staining pattern. DSP and plakoglobin were predominantly present at central, more differentiated tumour cells, whereas DSC3 showed a stronger staining in the peripheral basal cells of SCC tumour areas. CONCLUSIONS: Lack of cellular adhesion may have an important role in the metastatic potency of a primary tumour. A possible association of strong presence and normal-distributed desmosomal molecules in SCC with the less frequent and late pattern of metastasis in SCC as compared with adenocarcinoma is suggested.