Blockade but not overexpression of the junctional adhesion molecule C influences virus-induced type 1 diabetes in mice

Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing beta-cells in the pancreas. Recruitment of inflammatory cells is prerequisite to beta-cell-injury. The junctional adhesion molecule (JAM) family proteins JAM-B and JAM–C are involved in polarized leukocyte transendothelial migration and are expressed by vascular endothelial cells of peripheral tissue and high endothelial venules in lympoid organs. Blocking of JAM-C efficiently attenuated cerulean-induced pancreatitis, rheumatoid arthritis or inflammation induced by ischemia and reperfusion in mice. In order to investigate the influence of JAM-C on trafficking and transmigration of antigen-specific, autoaggressive T-cells, we used transgenic mice that express a protein of the lymphocytic choriomeningitis virus (LCMV) as a target autoantigen in the β-cells of the islets of Langerhans under the rat insulin promoter (RIP). Such RIP-LCMV mice turn diabetic after infection with LCMV. We found that upon LCMV-infection JAM-C protein was upregulated around the islets in RIP-LCMV mice. JAM-C expression correlated with islet infiltration and functional beta-cell impairment. Blockade with a neutralizing anti-JAM-C antibody reduced the T1D incidence. However, JAM-C overexpression on endothelial cells did not accelerate diabetes in the RIP-LCMV model. In summary, our data suggest that JAM-C might be involved in the final steps of trafficking and transmigration of antigen-specific autoaggressive T-cells to the islets of Langerhans

3He in the Bransfield Strait waters: indication for local injection from back-arc rifting

Helium data from the waters of the Bransfield Strait, the southern Drake Passage and the northwestern shelf of the Weddell Sea are presented. The 3He profiles from the eastern and central basins of the Bransfield Strait show maxima (δ3He ≈ 7%) below the sill depths that separate the strait from the surrounding open ocean. The 3He excess is interpreted as a local injection of a 3He-rich helium component into the deep waters of the Bransfield Strait from backarc rifting. Tritiogenic 3He and excess 3He from mixing with Circumpolar Deep Water are excluded as possible sources. The estimated 3He/4He ratio of the injected helium component (2.4–5.0 × 10−6) is less than that of pure mantle helium and may contain radiogenic helium from continental crustal material which underlies the Bransfield Strait

Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection

Autoimmune liver diseases, such as autoimmune hepatitis (AIH) and primary biliary cirrhosis, often have severe consequences for the patient. Because of a lack of appropriate animal models, not much is known about their potential viral etiology. Infection by liver-tropic viruses is one possibility for the breakdown of self-tolerance. Therefore, we infected mice with adenovirus Ad5 expressing human cytochrome P450 2D6 (Ad-2D6). Ad-2D6–infected mice developed persistent autoimmune liver disease, apparent by cellular infiltration, hepatic fibrosis, “fused” liver lobules, and necrosis. Similar to type 2 AIH patients, Ad-2D6–infected mice generated type 1 liver kidney microsomal–like antibodies recognizing the immunodominant epitope WDPAQPPRD of cytochrome P450 2D6 (CYP2D6). Interestingly, Ad-2D6–infected wild-type FVB/N mice displayed exacerbated liver damage when compared with transgenic mice expressing the identical human CYP2D6 protein in the liver, indicating the presence of a stronger immunological tolerance in CYP2D6 mice. We demonstrate for the first time that infection with a virus expressing a natural human autoantigen breaks tolerance, resulting in a chronic form of severe, autoimmune liver damage. Our novel model system should be instrumental for studying mechanisms involved in the initiation, propagation, and precipitation of virus-induced autoimmune liver diseases

The temporal evolution of the tracer signal in the Deep Western Boundary Current, Tropical Atlantic

Four World Ocean Circulation Experiment (WOCE) repeat cruises (October 1990 to March 1994) in the tropical Atlantic off Brazil are used to study the spatial and temporal evolution of the chlorofluorocarbon (CFC) (components CFC-11 and CFC-12) and tritium signal in the upper North Atlantic Deep Water (NADW). Its shallowest part, located in the tropical Atlantic around 1600-m depth, is the shallow upper North Atlantic Deep Water (SUNADW). It is characterized by a distinct tracer maximum, which is presumably received through winter time convection in the subpolar North Atlantic. Here we discuss the tracer fields and the temporal evolution of the tracer signal of the SUNADW in the tropical Atlantic along two meridional sections at 44 degrees and 35 degrees W and two zonal sections at 5 degrees and 10 degrees S off Brazil. The spatial and temporal development of the tracer field in the tropical Atlantic as well as the correlation with hydrographic parameters show that the temporal tracer change being due to the arrival of "younger" water is disturbed by other processes. In particular, the impact of variable mixing and spreading pathways on the observed tracer variability in the SUNADW is evident in the observations

Staphylococcus aureus α-Toxin Triggers the Synthesis of B-Cell Lymphoma 3 by Human Platelets

The frequency and severity of bacteremic infections has increased over the last decade and bacterial endovascular infections (i.e., sepsis or endocarditis) are associated with high morbidity and mortality. Bacteria or secreted bacterial products modulate platelet function and, as a result, affect platelet accumulation at sites of vascular infection and inflammation. However, whether bacterial products regulate synthetic events in platelets is not known. In the present study, we determined if prolonged contact with staphylococcal α-toxin signals platelets to synthesize B-cell lymphoma (Bcl-3), a protein that regulates clot retraction in murine and human platelets. We show that α-toxin induced αIIbβ3-dependent aggregation (EC50 2.98 µg/mL ± 0.64 µg/mL) and, over time, significantly altered platelet morphology and stimulated de novo accumulation of Bcl-3 protein in platelets. Adherence to collagen or fibrinogen also increased the expression of Bcl-3 protein by platelets. α-toxin altered Bcl-3 protein expression patterns in platelets adherent to collagen, but not fibrinogen. Pretreatment of platelets with inhibitors of protein synthesis or the mammalian Target of Rapamycin (mTOR) decreased Bcl-3 protein expression in α-toxin stimulated platelets. In conclusion, Staphylococcus aureus-derived α-toxin, a pore forming exotoxin, exerts immediate (i.e., aggregation) and prolonged (i.e., protein synthesis) responses in platelets, which may contribute to increased thrombotic events associated with gram-positive sepsis or endocarditis