Terminal complement activation is increased and associated with disease severity in CIDP

Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common chronic autoimmune neuropathy. While both cell-mediated and humoral mechanisms contribute to its pathogenesis, the rapid clinical response to plasmapheresis implicates a circulating factor responsible for peripheral nerve injury. We report that treatment-naïve patients with CIDP show increased serum and CSF levels of the anaphylatoxin C5a and the soluble terminal complement complex (sTCC). Systemic terminal complement activation correlates with clinical disease severity as determined by the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale. These data indicate that complement activation contributes to peripheral nerve injury and suggest that complement inhibition should be explored for its potential therapeutic merit in CIDP

EBV-specific immune responses in patients with multiple sclerosis responding to IFNβ therapy

Background: Symptomatic primary infection with the human γ-herpesvirus Epstein-Barr virus (EBV) and elevated immune responses to EBV are associated with the development and progression of multiple sclerosis (MS). Interferon-beta (IFNβ), first-line treatment for relapse-onset MS, exhibits complex immunoregulatory and antiviral activities. Objective: To determine EBV-specific immune responses in patients with MS during IFNβ therapy. Methods: We evaluated cellular and humoral immune responses to EBV- and human cytomegalovirus (HCMV)-encoded antigens in patients with MS before and 1 year after IFNβ treatment by ELISA and flow cytometry. Twenty-eight patients with MS who showed a clinical response to IFNβ as defined by the absence of relapses and lack of progression on the Expanded Disability Status Scale score during the first 2 years of treatment were included. Results: Clinically effective IFNβ-therapy was associated with a downregulation of proliferative T cell responses to the latent EBV nuclear antigen-1 (EBNA1). EBNA1-specific IgG responses as well as cellular and humoral immune responses to MHC class I restricted EBV antigens expressed during lytic replication and viral B cell transformation were similar before and after IFNβ therapy. Although HCMV-specific IgG levels slightly decreased, proliferative T-cell responses towards HCMV antigens remained unchanged during IFNβ therapy. Conclusion: Clinically effective IFNβ therapy is associated with a reduction of proliferative T-cell responses to EBNA1

Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination

Over recent years, human autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG Ab) have been associated with monophasic and relapsing central nervous system demyelination involving the optic nerves, spinal cord, and brain. While the clinical relevance of MOG Ab detection is becoming increasingly clear as therapeutic and prognostic differences from multiple sclerosis are acknowledged, an in-depth characterization of human MOG Ab is required to answer key challenges in patient diagnosis, treatment, and prognosis. Herein, we investigated the epitope, binding sensitivity, and affinity of MOG Ab in a cohort of 139 and 148 MOG antibody-seropositive children and adults (n = 287 patients at baseline, 130 longitudinal samples, and 22 cerebrospinal fluid samples). MOG extracellular domain was also immobilized to determine the affinity of MOG Ab. MOG Ab response was of immunoglobulin G1 isotype, and was of peripheral rather than intrathecal origin. High affinity MOG Ab were detected in 15% paediatric and 18% adult sera. More than 75% of paediatric and adult MOG Ab targeted a dominant extracellular antigenic region around Proline42. MOG Ab titers fluctuated over the progression of disease, but affinity and reactivity to Proline42 remained stable. Adults with a relapsing course intrinsically presented with a reduced immunoreactivity to Proline42 and had a more diverse MOG Ab response, a feature that may be harnessed for predicting relapse. Higher titers of MOG Ab were observed in more severe phenotypes and during active disease, supporting the pathogenic role of MOG Ab. Loss of MOG Ab seropositivity was observed upon conformational changes to MOG, and this greatly impacted the sensitivity of the detection of relapsing disorders, largely considered as more severe. Careful consideration of the binding characteristics of autoantigens should be taken into account when detecting disease-relevant autoantibodies

TRAIL limits excessive host immune responses in bacterial meningitis

Apart from potential roles in anti-tumor surveillance, the TNF-related apoptosis-inducing ligand (TRAIL) has important regulatory functions in the host immune response. We studied antiinflammatory effects of endogenous and recombinant TRAIL (rTRAIL) in experimental meningitis. Following intrathecal application of pneumococcal cell wall, a TLR2 ligand, we found prolonged inflammation, augmented clinical impairment, and increased apoptosis in the hippocampus of TRAIL–/– mice. Administration of rTRAIL into the subarachnoid space of TRAIL–/– mice or reconstitution of hematopoiesis with wild-type bone marrow cells reversed these effects, suggesting an autoregulatory role of TRAIL within the infiltrating leukocyte population. Importantly, intrathecal application of rTRAIL in wild-type mice with meningitis also decreased inflammation and apoptosis. Moreover, patients suffering from bacterial meningitis showed increased intrathecal synthesis of TRAIL. Our findings provide what we believe is the first evidence that TRAIL may act as a negative regulator of acute CNS inflammation. The ability of TRAIL to modify inflammatory responses and to reduce neuronal cell death in meningitis suggests that it may be used as a novel antiinflammatory agent in invasive infections

Environmental triggers of multiple sclerosis

Multiple sclerosis is a chronic immune-mediated disease of the central nervous system that develops in young adults with a complex genetic predisposition. Similar to other autoimmune disease, HLA-DR and -DQ alleles within the HLA class II region on chromosome 6p21 are by far the strongest risk-conferring genes. Less robust susceptibility effects have been reported for non-MHC related genetic variants. Improvements in the design of epidemiological studies helped to identify consistent environmental risk-associations such as the increased susceptibility for MS in individuals with a history of infectious mononucleosis, a symptomatic primary infection with the human γ-herpesvirus Epstein-Barr virus (EBV). Sun exposure and serum vitamin D levels are emerging non-infectious environmental risk factors that may have independent roles. The analysis of environmental effects will likely expand in the next few years and will allow for the generation of testable hypotheses as to how environmental insults interact with genetic factors to jointly determine the susceptibility to MS. Insights gained from these studies might facilitate the development of prevention strategies and more effective treatments for MS

Five Years of Searches for Point Sources of Astrophysical Neutrinos with the AMANDA-II Neutrino Telescope.

We report the results of a five-year survey of the northern sky to search for point sources of high energy neutrinos. The search was performed on the data collected with the AMANDA-II neutrino telescope in the years 2000 to 2004, with a live-time of 1001 days. The sample of selected events consists of 4282 upward going muon tracks with high reconstruction quality and an energy larger than about 100 GeV. We found no indication of point sources of neutrinos and set 90% confidence level flux upper limits for an all-sky search and also for a catalog of 32 selected sources. For the all-sky search, our average (over declination and right ascension) experimentally observed upper limit \Phi^{0}=(E/TeV)^\gamma d\Phi/dE to a point source flux of muon and tau neutrino (detected as muons arising from taus) is \Phi_{\nu_\mu}^{0} + \Phi_{\nu_\tau}^{0} = 11.1 x 10^{-11} TeV^-1 cm^-2 s^-1, in the energy range between 1.6 TeV and 2.5 PeV for a flavor ratio \Phi_{\nu_\mu}^{0} / \Phi_{\nu_\tau}^{0}= 1 and assuming a spectral index \gamma=2. It should be noticed that this is the first time we set upper limits to the flux of muon and tau neutrinos. In previous papers we provided muon neutrino upper limits only neglecting the sensitivity to a signal from tau neutrinos, which improves the limits by 10% to 16%. The value of the average upper limit presented in this work corresponds to twice the limit on the muon neutrino flux \Phi_{\nu_\mu}^{0} = 5.5 \cdot 10^{-11} TeV^-1 cm^-2 s^-1. A stacking analysis for preselected active galactic nuclei and a search based on the angular separation of the events were also performed. We report the most stringent flux upper limits to date, including the results of a detailed assessment of systematic uncertainties.Comment: 32 pages, 9 figures, submitted to Phys. Rev.

Finite volume method to solve electromagnetic diffraction problem

Communication to : ICOLSE'99 international conference on lightning and static electricity, Toulouse (France), June 22-24, 1999Available from INIST (FR), Document Supply Service, under shelf-number : 22419, issue : a.1999 n.65 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueSIGLEFRFranc

Improved limits on dark matter annihilation in the Sun with the 79-string IceCube detector and implications for supersymmetry

Point, linear and areal elements, which are two-dimensional and of a graphic nature, are the morphological elements employed when designing tactile maps and symbols for visually impaired users. However, beyond the two-dimensional domain, there is a fourth group of elements – volumetric elements – which mapmakers do not take sufficiently into account when it comes to designing tactile maps and symbols. This study analyses the effect of including volumetric, or 3D, symbols within a tactile map. In order to do so, the researchers compared two tactile maps. One of them uses only two-dimensional elements and is produced using thermoforming, one of the most popular systems in this field, while the other includes volumetric symbols, thus highlighting the possibilities opened up by 3D printing, a new area of production. The results of the study show that including 3D symbols improves the efficiency and autonomous use of these products.he work reported here is part of the research project entitled ‘Estudio y diseño de elementos de orientación, soportes de comunicación y otros accesorios para la mejora de la accesibilidad en distintos ámbitos de interpretación del patrimonio natural y/o construidos’ supported by the Spanish Ministry of Science and Innovation (project DPI2008-03981/DPI). The authors wish to thank the Centre de Recursos Educatius (Organización Nacional de Ciegos Españoles-ONCE) and the Associació Discapacitat Visual Cataluña B1+B2+B3 in Barcelona, as well as the ONCE offices in Castellón, Tarragona and Valencia for supporting this research. Finally, this work has also been supported by the Programa de Mobilitat del Personal Investigador de la Universitat Jaume I (E-2010-32) and the Fundació Caixa Castelló-Bancaixa