Repetitive Pertussis Toxin Promotes Development of Regulatory T Cells and Prevents Central Nervous System Autoimmune Disease

Bacterial and viral infections have long been implicated in pathogenesis and progression of multiple sclerosis (MS). Incidence and severity of its animal model experimental autoimmune encephalomyelitis (EAE) can be enhanced by concomitant administration of pertussis toxin (PTx), the major virulence factor of Bordetella pertussis. Its adjuvant effect at the time of immunization with myelin antigen is attributed to an unspecific activation and facilitated migration of immune cells across the blood brain barrier into the central nervous system (CNS). In order to evaluate whether recurring exposure to bacterial antigen may have a differential effect on development of CNS autoimmunity, we repetitively administered PTx prior to immunization. Mice weekly injected with PTx were largely protected from subsequent EAE induction which was reflected by a decreased proliferation and pro-inflammatory differentiation of myelin-reactive T cells. Splenocytes isolated from EAE-resistant mice predominantly produced IL-10 upon re-stimulation with PTx, while non-specific immune responses were unchanged. Longitudinal analyses revealed that repetitive exposure of mice to PTx gradually elevated serum levels for TGF-β and IL-10 which was associated with an expansion of peripheral CD4+CD25+FoxP3+ regulatory T cells (Treg). Increased frequency of Treg persisted upon immunization and thereafter. Collectively, these data suggest a scenario in which repetitive PTx treatment protects mice from development of CNS autoimmune disease through upregulation of regulatory cytokines and expansion of CD4+CD25+FoxP3+ Treg. Besides its therapeutic implication, this finding suggests that encounter of the immune system with microbial products may not only be part of CNS autoimmune disease pathogenesis but also of its regulation

J. Jakob Hemmer's ... Verhaltungsregeln, wenn man sich zur Gewitterzeit in keinem bewafneten Gebäude befindet ...

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Anleitung, Wetterleiter an allen Gattungen von Gebäuden auf die sicherste Art anzulegen ...

Verfasser J. Jakob Hemmer ..

Kurzer begriff und nuzen der Wetterleiter bei gelegenheit derjenigen, di auf dem schlosse, und den übrigen kurfürstlichen gebäüden zu Düsseldorf errichtet worden sind

abgefasset von J. Jakob Hemmer'n, kurpfälzischem geistlichen rate und stiftshern zu Heinsberg ...Vorlageform des Erscheinungsvermerks: Düsseldorf mit stahlischen Schriften, 1782.In Fraktu

The Combination of Interferon-Beta and HMG-CoA Reductase Inhibition in Multiple Sclerosis: Enthusiasm Lost too Soon?

Recent studies support the notion that statins, widely prescribed cholesterol-lowering agents, may target key elements in the immunological cascade leading to inflammation and tissue damage in the pathogenesis of multiple sclerosis (MS). Compelling experimental and observational clinical studies highlighted the possibility that statins may also exert immunomodulatory synergy with approved MS drugs, resulting in several randomized clinical trials testing statins in combination with interferon-beta (IFN-?). Some data, however, suggest that this particular combination may not be clinically beneficial, and might actually have a negative effect on the disease course in some patients with MS. In this regard, a small North American trial indicated that atorvastatin administered in combination with IFN-? may increase disease activity in relapsing-remitting MS. Although other trials did not confirm this finding, the enthusiasm for studies with statins dwindled. This review aims to provide a comprehensive overview of the completed clinical trials and reports of the interim analyses evaluating the combination of IFN-? and statins in MS. Moreover, we try to address the evident question whether usage of this combination routinely requires caution, since the number of IFN-?-treated MS patients receiving statins for lowering of cholesterol is expected to grow

Thermal Conductivity in Aged Li-Ion Cells under Various Compression Conditions and State-of-Charge

Thermal conductivity (TC) is a parameter, which significantly influences the spatial temperature gradients of lithium ion batteries in operative or abuse conditions. It affects the dissipation of the generated heat by the cell during normal operation or during thermal runaway propagation from one cell to the next after an external short circuit. Hence, the thermal conductivity is a parameter of great importance, which concurs to assess the safety of a Li-ion battery. In this work, an already validated, non-destructive measurement procedure was adopted for the determination of the evolution of the through-plane thermal conductivity of 41 Ah commercially available Li-ion pouch cells (LiNiMnCoO2-LiMn2O4/Graphite) as function of battery lifetime and state of charge (SOC). Results show a negative parabolic behaviour of the thermal conductivity over the battery SOC-range. In addition, an average decrease of TC in thickness direction of around 4% and 23% was measured for cells cycled at 60 °C with and without compression, respectively. It was shown that pretension force during cycling reduces battery degradation and thus minimises the effect of ageing on the thermal parameter deterioration. Nevertheless, this study highlights the need of adjustment of the battery pack cooling system due to the deterioration of thermal conductivity after certain battery lifetime with the aim of reducing the risk of battery overheating after certain product life

Systemic thrombolysis in ischemic stroke after recent oral surgery and management of oral cavity bleeding

Thrombolysis with recombinant tissue plasminogen activator in the treatment of acute ischemic stroke carries a long list of contraindications. One of these is recent surgery, but the extent of complications after minor surgeries such as dental extraction or oral surgical procedures is unclear. Here, we report the management of 2 cases with accidental bleeding from the oral cavity during systemic thrombolysis in ischemic stroke because of recent unreported oral surgery. Bleeding at the operation site occurred early and was stopped by prompt discontinuation of the recombinant tissue plasminogen activator infusion and local compressive therapy. Patients and relatives may not be aware that surgical procedures within the oral cavity are regarded as minor surgery and should be explicitly asked during the evaluation of ischemic stroke within the period for thrombolysis

CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation

<p>Abstract</p> <p>Background</p> <p>The chemokines and cytokines CXCL13, CXCL12, CCL19, CCL21, BAFF and APRIL are believed to play a role in the recruitment of B cells to the central nervous system (CNS) compartment during neuroinflammation. To determine which chemokines/cytokines show the strongest association with a humoral immune response in the cerebrospinal fluid (CSF), we measured their concentrations in the CSF and correlated them with immune cell subsets and antibody levels.</p> <p>Methods</p> <p>Cytokine/chemokine concentrations were measured in CSF and serum by ELISA in patients with non-inflammatory neurological diseases (NIND, n = 20), clinically isolated syndrome (CIS, n = 30), multiple sclerosis (MS, n = 20), Lyme neuroborreliosis (LNB, n = 8) and patients with other inflammatory neurological diseases (OIND, n = 30). Albumin, IgG, IgA and IgM were measured by nephelometry. CSF immune cell subsets were determined by seven-color flow cytometry.</p> <p>Results</p> <p>CXCL13 was significantly elevated in the CSF of all patient groups with inflammatory diseases. BAFF levels were significantly increased in patients with LNB and OIND. CXCL12 was significantly elevated in patients with LNB. B cells and plasmablasts were significantly elevated in the CSF of all patients with inflammatory diseases. CXCL13 showed the most consistent correlation with CSF B cells, plasmablasts and intrathecal Ig synthesis.</p> <p>Conclusions</p> <p>CXCL13 seems to be the major determinant for B cell recruitment to the CNS compartment in different neuroinflammatory diseases. Thus, elevated CSF CXCL13 levels rather reflect a strong humoral immune response in the CNS compartment than being specific for a particular disease entity.</p