Immunopathogenesis of schistosomiasis Wynn, Thomas A.; Thompson, Robert W.; Cheever, Allen W. ...
Immunological reviews,
October 2004, Letnik:
201, Številka:
1
Journal Article
Recenzirano
In schistosomiasis mansoni, the chronic egg‐induced granulomatous response in the liver and intestines may eventually cause extensive tissue scarring and development of portal hypertension. Indeed, ...much of the morbidity and mortality associated with this disease is directly attributable to the deposition of connective tissue elements in affected tissues. Elucidating the mechanisms that regulate the severity of schistosomiasis has been a major research objective over the past several years. Research conducted with DNA microarrays as well as investigations with a variety of gene knock‐out mice have been particularly helpful in achieving this goal. A notable accomplishment in the past few years was the identification of interleukin‐13 (IL‐13) and the IL‐13 receptor complex as central regulators of disease progression in schistosomiasis. Liver fibrogenesis is severely decreased in infected IL‐13‐deficient mice as well as in wildtype animals treated with IL‐13 antagonists. In contrast, IL‐13 effector function increases dramatically in IL‐13 receptor α2 (IL‐13Rα2)‐deficient mice. These mice develop severe hepatic fibrosis, fail to downregulate granuloma formation in the chronic phase of S. mansoni infection, and succumb to the disease at an accelerated rate; thus, identifying the ‘decoy’ IL‐13 receptor as a critical life sustaining ‘off’ switch for tissue damaging egg‐induced inflammation.
Secondary CLIQ is a quench protection method for protecting high-field accelerator magnets that involves charged capacitors into secondary normal-conducting coils that are magnetically coupled to the ...superconducting coils. The resulting coupling losses quickly brings the magnet to normal state and safely discharges it. No direct electrical or thermal link is required between the primary and secondary coils, and robust insulation is placed in between them. The two secondary circuits per magnet are galvanically insulated from the primary circuit, so that the tens to hundreds of CLIQ units needed to protect an accelerator circuit are galvanically insulated from one-another and from the superconducting magnets. The two secondary circuits per magnet each feature a CLIQ unit, and each CLIQ unit discharge is sufficient to bring the magnet to normal state over the entire operational current range. The coil geometry is such that the CLIQ discharge does not raise the voltage over the half-turns of the superconducting coils. After the superconducting coils develop resistance, a significant fraction of the stored magnetic energy is inductively transferred to and dissipated in the secondary coils. The resulting favourable adiabatic hot-spot temperature and voltage-to-ground enables the magnet designer to reduce the copper content of the superconducting coils, and thus lower the overall cost of the magnet. Secondary CLIQ quench simulations were performed on a hypothetical 14 m variant of the HD2 Nb3Sn dipole with a bore field of 16 T. It is demonstrated that the Secondary CLIQ method protects the magnet over its entire operational current range even in the case where one of the two CLIQ units fails to discharge with an adiabatic hotspot temperature of 248 K and voltage-to-ground of 610 V under nominal protection conditions, and a worst-case adiabatic hot-spot temperature of 263 K and voltage-to-ground of 840 V under fault conditions.
Macrophage-specific expression of Arginase-1 is commonly believed to promote inflammation, fibrosis, and wound healing by enhancing L-proline, polyamine, and Th2 cytokine production. Here, however, ...we show that macrophage-specific Arg1 functions as an inhibitor of inflammation and fibrosis following infection with the Th2-inducing pathogen Schistosoma mansoni. Although susceptibility to infection was not affected by the conditional deletion of Arg1 in macrophages, Arg1(-/flox);LysMcre mice died at an accelerated rate. The mortality was not due to acute Th1/NOS2-mediated hepatotoxicity or endotoxemia. Instead, granulomatous inflammation, liver fibrosis, and portal hypertension increased in infected Arg1(-/flox);LysMcre mice. Similar findings were obtained with Arg1(flox/flox);Tie2cre mice, which delete Arg1 in all macrophage populations. Production of Th2 cytokines increased in the infected Arg1(-/flox);LysMcre mice, and unlike alternatively activated wild-type macrophages, Arg1(-/flox);LysMcre macrophages failed to inhibit T cell proliferation in vitro, providing an underlying mechanism for the exacerbated Th2 pathology. The suppressive activity of Arg1-expressing macrophages was independent of IL-10 and TGF-beta1. However, when exogenous L-arginine was provided, T cell proliferation was restored, suggesting that Arg1-expressing macrophages deplete arginine, which is required to sustain CD4(+) T cell responses. These data identify Arg1 as the essential suppressive mediator of alternatively activated macrophages (AAM) and demonstrate that Arg1-expressing macrophages function as suppressors rather than inducers of Th2-dependent inflammation and fibrosis.
Screening currents are field-induced dynamic phenomena which occur in superconducting materials, leading to persistent magnetization. Such currents are of importance in ReBCO tapes, where the large ...size of the superconducting filaments gives rise to strong magnetization phenomena. In consequence, superconducting accelerator magnets based on ReBCO tapes might experience a relevant degradation of the magnetic field quality in the magnet aperture, eventually leading to particle beam instabilities. Thus, persistent magnetization phenomena need to be accurately evaluated. In this paper, the 2D finite element model of the Feather-M2.1-2 magnet is presented. The model is used to analyze the influence of the screening current-induced magnetic field on the field quality in the magnet aperture. The model relies on a coupled field formulation for eddy current problems in time-domain. The formulation is introduced and verified against theoretical references. Then, the numerical model of the Feather-M2.1-2 magnet is detailed, highlighting the key assumptions and simplifications. The numerical results are discussed and validated with available magnetic measurements. A satisfactory agreement is found, showing the capability of the numerical tool in providing accurate analysis of the dynamic behavior of the Feather-M2.1-2 magnet.
Immunopathology of schistosomiasis Wilson, Mark S; Mentink-Kane, Margaret M; Pesce, John T ...
Immunology and cell biology,
February/March 2007, Letnik:
85, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Waterborne parasitic diseases plague tropical regions of the world with the development of water resources often increasing transmission. Skin-penetrating cercariae (infectious stages of schistosome ...parasites) mature within their mammalian host, form sexual pairs and produce several hundred eggs per day. Many eggs are swept within the circulation and in the case of Schistosoma mansoni and S. japonicum, become lodged within hepatic sinusoids, invoking a fibrotic granulomatous response. Animal studies have identified a moderate type 1 helper (Th1) response to parasite antigens; however, a robust Th2 response to egg-derived antigens dominates and propagates fibrogenesis within the liver. Elegant T helper cell polarization studies have highlighted that critical control of Th1, Th2 and interleukin (IL)-17-secreting lymphocytes is necessary to prevent severe liver pathology. Alternatively activated macrophages develop in the Th2 milieu and upregulate Fizz1, Ym-1 and Arg-1. The possible contribution of macrophages to fibrogenesis and their role in immune regulation are discussed. Within the liver, natural (CD4(+)CD25(+) Forkhead box protein 3 (Foxp3)(+)) and inducible (CD4(+)Foxp3(-)) Treg's are recruited, providing an essential regulatory arm to stabilize the immune response and limit immunopathology. This review ties together current thinking of how the granulomatous response develops, causing much of the associated immunopathology, with extensive discussions on how regulatory cells and cytokine decoy receptors serve to limit the extent of immune-mediated pathology during schistosomiasis.
As part of the European Strategy for Particle Physics there is an ongoing development towards a Future Circular Collider (FCC-ee) where electron-positron collisions could be used to study the entire ...electro-weak sector in a low background environment. Particle detectors are used to study these collisions and a strong magnetic field is required to measure the particles' momenta. Currently, two detector concepts are being studied: the Innovative Detector for Electron-positron Accelerators (IDEA) and the CLIC-Like Detector (CLD). Both these detectors include a superconducting solenoid magnet with a central field of <inline-formula><tex-math notation="LaTeX">2 \,\mathrm{T}</tex-math></inline-formula> of which the designs are presented here. The IDEA magnet has an stored magnetic energy density of 14 kJ/kg and in CLD this is 12 kJ/kg. Taking into account their respective free-bore diameters of <inline-formula><tex-math notation="LaTeX">4.2 \,\mathrm{m}</tex-math></inline-formula> for IDEA and <inline-formula><tex-math notation="LaTeX">7.2 \,\mathrm{m}</tex-math></inline-formula> for CLD this results in very challenging designs for which the mechanical and quench studies are presented. Their results are promising, but extensive R&D on these magnets would be needed in the future to reach the goals set out in the Conceptual Design Report (CDR).
Particle physics experiments make use of magnetic fields up to <inline-formula><tex-math notation="LaTeX">4 \,\mathrm{T}</tex-math></inline-formula> to bend electrically charged particles such that ...their charge and momentum can be determined. The particle energy measurement requires a low amount of material, or material that is highly transparent to particles inside the calorimeter volume. The conflict between the small volume of space reserved for a magnet and having a field of several teslas inside the detector is often resolved by using superconducting magnets. Up to now, large particle physics detector magnets have been constructed with low temperature superconductors, but there are clear benefits from using high temperature superconductors in future particle physics detector designs, such as allowing for an elevated operating temperature and the reduced amount of superconductor needed. In addition to the HTS material itself, additional material is needed to support the Lorentz forces, and to temporarily carry the current in case of a quench since these magnets are always one-of-a-kind and they need to operate reliably and without damage in case of a failure scenario. The stabilizer has to be a low-density material for high particle transparency, such as aluminium. Since the density of the superconductor is a factor of 4 higher than the density of aluminium, a reduction of superconducting material also means an improvement of the particle transparency: the density of a material is directly related to its particle transparency. This paper presents a conceptual design for high temperature superconducting detector magnets and a study of the type of aluminium stabilizer used.
Background & Aims The cytokine interleukin (IL)-10 is required to maintain immune homeostasis in the gastrointestinal tract. IL-10 null mice spontaneously develop colitis or are more susceptible to ...induction of colitis by infections, drugs, and autoimmune reactions. IL-13 regulates inflammatory conditions; its activity might be compromised by the IL-13 decoy receptor (IL-13Rα2). Methods We examined the roles of IL-13 and IL-13Rα2 in intestinal inflammation in mice. To study the function of IL-13Rα2, il10 −/− mice were crossed with il13r α 2 −/− to generate il10 −/− il13r α 2 −/− double knockout (dKO) mice. Colitis was induced with the gastrointestinal toxin piroxicam or Trichuris muris infection. Results Induction of colitis by interferon (IFN)-γ or IL-17 in IL-10 null mice requires IL-13Rα2. Following exposure of il10 −/− mice to piroxicam or infection with T muris , production of IL-13Rα2 increased, resulting in decreased IL-13 bioactivity and increased inflammation in response to IFN-γ or IL-17A. In contrast to il10 −/− mice, dKO mice were resistant to piroxicam-induced colitis; they also developed less severe colitis during chronic infection with T muris infection. In both models, resistance to IFN-γ and IL-17–mediated intestinal inflammation was associated with increased IL-13 activity. Susceptibility to colitis was restored when the dKO mice were injected with monoclonal antibodies against IL-13, confirming its protective role. Conclusions Colitis and intestinal inflammation in IL10 −/− mice results from IL-13Rα2–mediated attenuation of IL-13 activity. In the absence of IL-13Rα2, IL-13 suppresses proinflammatory Th1 and Th17 responses. Reagents that block the IL-13 decoy receptor IL-13Rα2 might be developed for inflammatory bowel disease associated with increased levels of IFN-γ and IL-17.
T helper 1 responses are typically proinflammatory, while Th2 responses have been considered regulatory. Interestingly, Th2 responses characterize a number of pulmonary diseases, many of which ...terminate in tissue remodeling and fibrosis. We developed a mouse model using Schistosoma mansoni eggs and cytokine-deficient mice to induce highly polarized Th1- or Th2-type inflammation in the lung. In this study, we examined the pathology and cytokine profiles in Th1- and Th2-polarized environments and used oligonucleotide microarray analysis to decipher the genes responsible for these effects. We further elaborated on the results using IL-10- and IL-13-deficient mice because these cytokines are believed to be the central regulators of Th2-associated pathology. We found that the Th1-polarized mice developed small granulomas with less fibrosis while expressing genes characteristic of tissue damage. Th2-polarized mice, in contrast, formed large granulomas with massive collagen deposition and up-regulated genes associated with wound healing, specifically, arginase, collagens, matrix metalloproteinases (MMPs), and tissue inhibitors of MMP. In addition, several members of the chitinase-like family were up-regulated in the lung following egg challenge. We also developed a method of defining the net collagen deposition using the expression profiles of several collagen, MMP, and tissue inhibitors of MMP genes. We found that Th1-polarized mice did not elaborate collagens or MMPs and therefore did not have a significant capacity for repair in this model. Thus, Th1-mediated inflammation is characterized by tissue damage, while Th2 directs wound healing and fibrosis.
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