Fine-tuning of regulatory T cell function: the role of calcium signals and naive regulatory T cells for regulatory T cell deficiency in multiple sclerosis.

The suppressor function of regulatory T cells (Tregs) is impaired in multiple sclerosis (MS), but the mechanisms underlying this deficiency are not fully understood. As Tregs counteract the sustained elevation of intracellular calcium, which is indispensable for full activation of conventional T cells (Tcons), we hypothesized that interference with this pathway might prompt MS-related Treg dysfunction. Using single-cell live imaging, we observed that Tregs rapidly reduce Ca(2+) influx and downstream signals in Tcons upon cell contact, yet differ in their potency to efficiently suppress several target cells at the same time.

Monoclonal antibodies in neuroinflammatory diseases.

Introduction: Monoclonal antibodies (mAbs) represent an emerging and rapidly growing field of therapy in neuroinflammatory diseases. Adhesion molecule blockade by natalizumab represents the first approved mAb therapy in neurology, approved for therapy of highly active multiple sclerosis (MS). Removal of immune cells by anti-CD52 mAb alemtuzumab or anti-CD20 mAb rituximab are other prime examples with existing positive Phase II and Phase III trials.

Neurons as targets for T cells in the nervous system.

Accumulating evidence shows that T cells penetrate the central nervous system (CNS) parenchyma in several autoimmune, infectious, and degenerative neurological diseases. The structural and functional consequences for CNS neurons of their encounter with activated T cells have been investigated in several experimental systems, including ex vivo co-cultures, electrophysiology, and in vivo imaging. Here, we review the modalities of neuron/T cell interactions.

Anti-JC virus antibody prevalence in a multinational multiple sclerosis cohort.

JC virus (JCV) is an opportunistic virus known to cause progressive multifocal leukoencephalopathy. Anti-JC virus (Anti-JCV) antibody prevalence in a large, geographically diverse, multi-national multiple sclerosis (MS) cohort was compared in a cross-sectional study. Overall, anti-JCV antibody prevalence was 57.

Thalamic involvement in patients with neurologic impairment due to Shiga toxin 2.

Objective: The outbreak of hemolytic-uremic syndrome and diarrhea caused by Shiga toxin-producing Escherichia coli O104:H4 in Germany during May to July 2011 involved severe and characteristic neurologic manifestations with a strong female preponderance. Owing to these observations, we designed a series of experimental studies to evaluate the underlying mechanism of action of this clinical picture.

Methods: A magnetic resonance imaging and electroencephalographic study of patients was performed to evaluate the clinical picture in detail.

An assay to quantify species-specific anti-JC virus antibody levels in MS patients.

Background: The StratifyJCV® test is a qualitative assay to classify MS patients as anti-JC virus (JCV) antibody positive or negative. Quantification of anti-JCV antibody levels in serum and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients might add to the progressive multifocal leukoencephalopathy (PML) risk assessment.

Objective: The objective of this study is to test sera of patients in a quantitative anti-JCV antibody assay, and to compare the results with preexisting data from the StratifyJCV® test.

Dendritic cell vaccination in autoimmune disease.

Purpose Of Review: Autoimmune diseases are the result of an imbalanced immune regulatory network. Tolerogenic dendritic cells (tolDCs) are key players of this network by inducing and maintaining both central and peripheral tolerance. Therefore, ex vivo generated tolDCs are considered as therapeutic vaccines to re-establish (antigen-specific) tolerance in autoimmune disorders.

Multiple sclerosis: reprogramming the immune repertoire with alemtuzumab in MS.

Results from two phase III trials show the potency of alemtuzumab—a T-cell and B-cell depleting antibody—in reducing clinical and paraclinical measures of disease activity in relapsing–remitting multiple sclerosis. The effects of this immunotherapeutic agent highlight the relevance of T lymphocytes in the early pathogenesis of disease.

HLA-G 2012 conference: the 15-year milestone update.

The non-classical human leukocyte antigen (HLA) Class I molecule HLA-G is best known for its tolerogenic function at the maternal-fetal interface, where it protects the fetus from destruction by the immune system of its mother. Yet, HLA-G has been the topic of intense investigations and its functions reach much further than originally believed. International conferences on HLA-G have taken place every 3 years since 1998, and the Sixth International Conference on HLA-G, that took place in Paris in July 2012.

Clinical effects of natalizumab on multiple sclerosis appear early in treatment course.

In clinical practice natalizumab is typically used in patients who have experienced breakthrough disease during treatment with interferon beta (IFNβ) or glatiramer acetate. In these patients it is important to reduce disease activity as quickly as possible. In a phase II study, differences between natalizumab and placebo in MRI outcomes reflecting inflammatory activity were evident after the first infusion and maintained through a 6-month period, suggesting a rapid onset of natalizumab treatment effects.

Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature.

We have recently identified T cells as important mediators of ischemic brain damage, but the contribution of the different T-cell subsets is unclear. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) are generally regarded as prototypic anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. In the present study, we examined the role of Tregs after experimental brain ischemia/reperfusion injury.

Cerebrospinal fluid parameters of B cell-related activity in patients with active disease during natalizumab therapy.

Recently, the disappearance of oligoclonal bands (OCBs) from the cerebrospinal fluid (CSF) of a few natalizumab-treated patients with multiple sclerosis (MS) has been reported. This is interesting since CSF-restricted OCB are believed to persist in MS. We pooled CSF data from 14 MS centers to obtain an adequate sample size for investigating the suspected changes in central nervous system (CNS)-restricted humoral immune activities in the context of natalizumab therapy.

TRPM2 cation channels modulate T cell effector functions and contribute to autoimmune CNS inflammation.

TRPM2, a highly Ca(2+)-permeable member of the transient receptor potential melastatin-related (TRPM) family of cation channels, is expressed in cells of the immune system. We demonstrate firstly that TRPM2 cation channels on T cells critically influence T cell proliferation and proinflammatory cytokine secretion following polyclonal T cell receptor stimulation. Consistently, trpm2-deficient mice exhibited an attenuated clincal phenotype of experimental autoimmune encephalomyelitis (EAE) with reduced inflammatory and demyelinating spinal cord lesions.

Identification of two-pore domain potassium channels as potent modulators of osmotic volume regulation in human T lymphocytes.

Many functions of T lymphocytes are closely related to cell volume homeostasis and regulation, which utilize a complex network of membrane channels for anions and cations. Among the various potassium channels, the voltage-gated K(V)1.3 is well known to contribute greatly to the osmoregulation and particularly to the potassium release during the regulatory volume decrease (RVD) of T cells faced with hypotonic environment.

Paraneoplastic and non-paraneoplastic autoimmunity to neurons in the central nervous system.

Autoimmune central nervous system (CNS) inflammation occurs both in a paraneoplastic and non-paraneoplastic context. In a widening spectrum of clinical disorders, the underlying adaptive (auto) immune response targets neurons with a divergent role for cellular and humoral disease mechanisms: (1) in encephalitis associated with antibodies to intracellular neuronal antigens, neuronal antigen-specific CD8(+) T cells seemingly account for irreversible progressive neuronal cell death and neurological decline with poor response to immunotherapy. However, a pathogenic effect of humoral immune mechanisms is also debated.

The TASK1 channel inhibitor A293 shows efficacy in a mouse model of multiple sclerosis.

The two-pore domain potassium channel TASK1 (KCNK3) has recently emerged as an important modulator in autoimmune CNS inflammation. Previously, it was shown that T lymphocytes obtained from TASK1(-/-) mice display impaired T cell effector functions and that TASK1(-/-) mice show a significantly reduced disease severity in myelin oligodendrocyte glycoprotein (MOG(35-55)) peptide induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We here evaluate a potent and specific TASK1 channel inhibitor, A293, which caused a dose-dependent reduction of T cell effector functions (cytokine production and proliferation).

Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor(+) regulatory T cells.

Mature dendritic cells (DCs) are established as unrivaled antigen-presenting cells (APCs) in the initiation of immune responses, whereas steady-state DCs induce peripheral T cell tolerance. Using various genetic approaches, we depleted CD11c(+) DCs in mice and induced autoimmune CNS inflammation. Unexpectedly, mice lacking DCs developed aggravated disease compared to control mice.

Cytotoxic CD8+ T cells and CD138+ plasma cells prevail in cerebrospinal fluid in non-paraneoplastic cerebellar ataxia with contactin-associated protein-2 antibodies.

Objective: The purpose of this paper is to report a patient with otherwise unexplained cerebellar ataxia with serum antibodies against contactin-associated protein-2 (CASPR-2) and provide a detailed description of the composition of cellular infiltrates in the cerebrospinal fluid (CSF) compared to the peripheral blood (PB). CASPR-2 antibodies strongly labeling axons of cerebellar granule neurons have recently been identified in sera from nine patients with otherwise unexplained progressive cerebellar ataxia with mild to severe cerebellar atrophy.

Design: This is a report of a single case.

Immune therapy of multiple sclerosis--future strategies.

Baseline disease-modifying therapies (DMTs) for multiple sclerosis (MS) include three different preparations of interferon-beta (IFN-β) and glatiramer acetate (GA). These substances reduce relapse rates, side-effects are tolerated by most patients and - after more than 15 years of experience - the long-term safety profile for these drugs can be appraised as very good. In 2006, the therapeutic tool kit was augmented by the first monoclonal antibody, natalizumab, approved as monotherapy for treatment-refractory highly active MS.

Anti-JC virus antibodies in a large German natalizumab-treated multiple sclerosis cohort.

Objective: To investigate the rate of seropositivity of anti-JC virus (JCV) antibodies in a German multiple sclerosis (MS) cohort treated with natalizumab in the postmarketing setting and to assess anti-JCV serostatus in samples obtained before diagnosis of progressive multifocal leukoencephalopathy (PML).

Methods: This was a blinded, retrospective cross-sectional and longitudinal analysis for anti-JCV antibodies using a confirmatory 2-step ELISA on 2,782 blood samples obtained from 2,253 patients nationwide for routine testing for anti-natalizumab antibodies during open-label treatment between 2007 and 2010.

Results: Of the natalizumab-treated patients with MS, 58.

Immune mechanisms of stroke.

Purpose Of Review: Only recently has it been realized that immune mechanisms contribute to the pathophysiology of ischemic stroke, which for many years was regarded mainly as a vascular disease. These immunologic processes are present during all stages of stroke and involve both the innate and adaptive immune systems. This review highlights the latest findings related to the 'immunology of stroke'.