Molecular effects of interleukin-1ß on dorsal root ganglion neurons: prevention of ligand-induced internalization of the bradykinin 2 receptor and downregulation of G protein-coupled receptor kinase 2.

In dorsal root ganglion sections numerous small-to medium-sized neurons were found to exhibit extensive colocalization of the bradykinin receptor 2, the interleukin-1 receptor 1 and G protein-coupled receptor kinase 2. Application of bradykinin to cultured DRG neurons caused substantial internalization of the bradykinin 2 receptor which significantly reduced the responsiveness of DRG neurons to a second application of bradykinin. Such an internalization was not observed in DRG neurons which were exposed to long-term pretreatment with interleukin-1ß. The long-term incubation with interleukin-1ß on its own did neither change the proportion of neurons which expressed the bradykinin 2 receptor in the cytoplasma nor the proportion of neurons expressing the bradykinin 2 receptor in the membrane but it reduced the proportion of neurons expressing G protein-coupled receptor kinase 2, an enzyme which facilitates the internalization of G protein-coupled receptors. These results show that interleukin-1ß maintains the responsiveness of DRG neurons to bradykinin in the long-term range, and they suggest that the downregulation of G protein-coupled receptor kinase 2 could be a cellular mechanism involved in this interleukin-1ß effect.

Involvement of CD91 and scavenger receptors in Hsp70-facilitated activation of human antigen-specific CD4+ memory T cells.

Hsp70 plays several roles in the adaptive immune response. Based on the ability to interact with diverse peptides, extracellular Hsp70:peptide complexes exert profound effects both in autoimmunity and in tumor rejection by evoking potent T cell responses to the chaperoned peptide. The interaction with receptors on APC represents the basis for the immunological functions of Hsp70 and a critical point where the immune response can be regulated. Various surface proteins (e.g. CD91, scavenger receptors (SR)) have been implicated in binding of Hsp70. In this study, antigenic peptides from tetanus toxin and influenza hemagglutinin complexed to human stress-inducible Hsp70 were found to enhance the proliferation and cytokine production of human antigen-specific CD4(+) T cells. This was demonstrated in proliferation experiments using human monocytes as APC. Proliferated antigen-specific cells were detected combining HLA-DRB1*0401 or HLA-DRB1*1101 tetramer and CFSE staining. Treating monocytes with CD91 siRNA diminished these effects. Additional blocking of SR by the SR ligand fucoidan completely abolished enhanced proliferation and production of Th1 and Th2 cytokines. Taken together, our data indicate that in the human system, CD91 and members of the SR family efficiently direct Hsp70:peptide complexes into the MHC class II presentation pathway and thus enhance antigen-specific CD4(+) T cell responses.

HSV-pneumonitis in a patient with lung cancer receiving check point inhibitors - a case report.

BACKGROUND: Herpes simplex virus (HSV) is commonly associated with oro-facial and genital manifestations. It rarely causes encephalitis and even less commonly, in heavily immunosuppressed patients, visceral disease or bronchopneumonitis. We present a case of cytologically-proven, PCR-positive HSV-1 tracheobronchitis and pneumonitis in a patient with less severe immunocompromise. CASE PRESENTATION: A 64 year old white man with steroid-induced diabetes mellitus and progressive small-cell bronchial carcinoma despite chemo- and immunotherapy with two checkpoint inhibitors presented with symptoms of lower respiratory tract infection. Community-acquired pneumonia was suspected and empirical broad-spectrum antibacterial treatment was initiated. Chest CT-scan revealed ground-glass opacities and tree-in bud lesions. Cytology of BAL showed extensive cytopathic effects typically caused by infection with herpes virus and PCR confirmation of HSV-1. Acute phase HSV serology was positive for IgG and borderline for IgM. The patient deteriorated clinically due to tumor progress and infection despite high-dose acyclovir therapy and died 2 weeks after admission. CONCLUSIONS: We report an unusual case of fatal HSV-1 pneumonitis due to reactivation in a patient with lung cancer, steroid-induced diabetes and treatment with two checkpoint inhibitors. In immunosuppressed patients with non-improving pneumonia invasive diagnostic procedures are warranted including cytology and molecular diagnostics.

Necrotising coronaritis with fatal outcome.

A 56-year-old woman presented with acute onset of typical chest pain. She was diagnosed with acute coronary syndrome with ST-segment elevation myocardial infarction. Although significant obstructive coronary artery disease was ruled out by coronary angiography, cardiac MRI showed transmural necrosis of the lateral free wall with extensive microvascular obstruction consistent with ischaemic heart disease. Within 48 hours after initial presentation, the patient suddenly arrested due to pulseless electrical activity with futile resuscitation efforts. Autopsy revealed myocardial perforation with extensive haematothorax due to pericardial laceration, caused by the mechanical chest compressions. Eventually, histology identified diffuse necrotising coronary vasculitis as a rare cause of ischaemic heart disease.

Influence of a mutation in IFN-γ receptor 2 (IFNGR2) in human cells on the generation of Th17 cells in memory T cells.

The T cell subsets involved in inflammatory reactions are mainly the IFN-γ secreting Th1 cells and IL17-producing Th17 cells. Although Th17 cells are primed in the thymus, there is evidence that Th17 cells can be generated from effector memory CD4(+) T cells. Cytokines as IL-6, TGF-ß, IL-21 and IL-23 involved in development of Th17 cells are well described. Here we analyzed the impact of a mutation in the IFN-γ receptor 2 (IFN-γR2) on the induction of Th17 cells. By isolation of T cells and monocytes of a patient with this mutation we could demonstrate an inhibitory role of IFN-γ signaling as IFN-γR2-deficient monocytes induce a higher percentage of IL-17(+) cells from both healthy and IFN-γR2-deficient CD4(+) T cells. This data confirm the interference of these two T helper subsets and points to a balance of Th1 and Th17 cells obtained by their own cytokine production and their interplay with APCs.

Suicide announcement on Facebook.

BACKGROUND: The media and the Internet may be having an influence on suicidal behavior. Online social networks such as Facebook represent a new facet of global information transfer. The impact of these online social networks on suicidal behavior has not yet been evaluated. AIMS: To discuss potential effects of suicide notes on Facebook on suicide prevention and copycat suicides, and to create awareness among health care professionals. METHODS: We present a case involving a suicide note on Facebook and discuss potential consequences of this phenomenon based on literature found searching PubMed and Google. RESULTS: There are numerous reports of suicide notes on Facebook in the popular press, but none in the professional literature. Online social network users attempted to prevent planned suicides in several reported cases. To date there is no documented evidence of a copycat suicide, directly emulating a suicide announced on Facebook. CONCLUSIONS: Suicide notes on online social networks may allow for suicide prevention via the immediate intervention of other network users. But it is not yet clear to what extent suicide notes on online social networks actually induce copycat suicides. These effects deserve future evaluation and research.

One small scan for radiology, one giant leap for forensic medicine - Post-mortem imaging replaces forensic autopsy in a case of traumatic aortic laceration.

The questions of cause and manner of death are the most pressing ones in any forensic investigation. Traditionally, autopsy is the means to provide answers to these questions and despite the increasing use of CT and MR in the post-mortem setting, imaging has usually been an adjunct to forensic autopsy. Here we describe a case where post-mortem CT and MR were performed instead of autopsy, at the request of the responsible public prosecutor. The forensic conclusions derived from imaging, including cause and manner of death were accepted by the legal authorities, thereby setting precedence for future cases. This case represents a landmark in forensic medicine and is another step toward the full realization of minimally invasive forensic autopsy.

Experimental arthritis causes tumor necrosis factor-alpha-dependent infiltration of macrophages into rat dorsal root ganglia which correlates with pain-related behavior.

After peripheral nerve damage macrophages infiltrate the dorsal root ganglia (DRG) in which cell bodies of lesioned neurons are located. However, infiltration of macrophages into the DRGs was also reported in complete Freund's adjuvant (CFA)-induced inflammation raising the question whether CFA inflammation induces nerve cell damage or whether peripheral inflammation may also trigger macrophage infiltration into DRGs. Related questions are, first, which signals trigger macrophage infiltration into DRGs and, second, is macrophage infiltration correlated with pain-related behavior. Using the rat model of unilateral antigen-induced arthritis (AIA) in the knee we found a massive infiltration of ED1(+) macrophages into the ipsi- and contralateral lumbar DRGs but not into thoracic DRGs. At no time point of AIA DRG neurons showed expression of activating transcription factor-3 (ATF3) indicating that macrophage infiltration is not explainable by nerve cell lesions in this model. During AIA, lumbar but not thoracic DRGs exhibited a bilateral de novo expression of vascular cell adhesion molecule-1 (VCAM-1) which is known to be involved in macrophage infiltration. Tumor necrosis factor-alpha (TNF-alpha) neutralization with etanercept or infliximab treatment after induction of AIA significantly reduced both macrophage infiltration and VCAM-1 expression. It also decreased mechanical hyperalgesia at the inflamed joint although the joint inflammation itself was barely attenuated, and it reduced mechanical hyperalgesia at the non-inflamed contralateral knee joint. Thus, bilateral segment-specific infiltration of macrophages into DRGs is part of an unilateral inflammatory process in peripheral tissue and it may be involved in the generation of hyperalgesia in particular on the non-inflamed side.