Detrimental effects of exuberant and restrained immune responses against the central nervous system in the context of multiple sclerosis and glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common and most aggressive astrocytic tumor of the central nervous system (CNS) in adults. The standard treatment consisting of surgery, followed by a combinatorial radio- and chemotherapy, is only palliative and prolongs patient median survival to 12 to 15 months. The tumor subpopulation of stem cell-like glioma-initiating cells (GICs) shows resistance against radiation as well as chemotherapy, and has been suggested to be responsible for relapses of more aggressive tumors after therapy. The efficacy of immunotherapies, which exploit the immune system to specifically recognize and eliminate malignant cells, is limited due to strong immunosuppressive activities of the GICs and the generation of a specialized protective microenvironment. The molecular mechanisms underlying the therapy resistance of GICs are largely unknown. rnThe first aim of this study was to identify immune evasion mechanisms in GICs triggered by radiation. A model was used in which patient-derived GICs were treated in vitro with fractionated ionizing radiation (2.5 Gy in 7 consecutive passages) to select for a more radio-resistant phenotype. In the model cell line 1080, this selection process resulted in increased proliferative but diminished migratory capacities in comparison to untreated control GICs. Furthermore, radio-selected GICs downregulated various proteins involved in antigen processing and presentation, resulting in decreased expression of MHC class I molecules on the cellular surface and diminished recognition potential by cytotoxic CD8+ T cells. Thus, sub-lethal fractionated radiation can promote immune evasion and hamper the success of adjuvant immunotherapy. Among several immune-associated proteins, interferon-induced transmembrane protein 3 (IFITM3) was found to be upregulated in radio-selected GICs. While high expression of IFITM3 was associated with a worse overall survival of GBM patients (TCGA database) and increased proliferation and migration of differentiated glioma cell lines, a strong contribution of IFITM3 to proliferation in vitro as well as tumor growth and invasiveness in a xenograft model could not be observed. rnMultiple sclerosis (MS) is the most common autoimmune disease of the CNS in young adults of the Western World, which leads to progressive disability in genetically susceptible individuals, possibly triggered by environmental factors. It is assumed that self-reactive, myelin-specific T helper cell 1 (Th1) and Th17 cells, which have escaped the control mechanisms of the immune system, are critical in the pathogenesis of the human disease and its animal model experimental autoimmune encephalomyelitis (EAE). It was observed that in vitro differentiated interleukin 17 (IL-17) producing Th17 cells co-expressed the Th1-phenotypic cytokine Interferon-gamma (IFN-γ) in combination with the two respective lineage-associated transcription factors RORγt and T-bet after re-isolation from the CNS of diseased mice. Pathogenic molecular mechanisms that render a CD4+ T cell encephalitogenic have scarcely been investigated up to date. rnIn the second part of the thesis, whole transcriptional changes occurring in in vitro differentiated Th17 cells in the course of EAE were analyzed. Evaluation of signaling networks revealed an overrepresentation of genes involved in communication between the innate and adaptive immune system and metabolic alterations including cholesterol biosynthesis. The transcription factors Cebpa, Fos, Klf4, Nfatc1 and Spi1, associated with thymocyte development and naïve T cells were upregulated in encephalitogenic CNS-isolated CD4+ T cells, proposing a contribution to T cell plasticity. Correlation of the murine T-cell gene expression dataset to putative MS risk genes, which were selected based on their proximity (± 500 kb; ensembl database, release 75) to the MS risk single nucleotide polymorphisms (SNPs) proposed by the most recent multiple sclerosis GWAS in 2011, revealed that 67.3% of the MS risk genes were differentially expressed in EAE. Expression patterns of Bach2, Il2ra, Irf8, Mertk, Odf3b, Plek, Rgs1, Slc30a7, and Thada were confirmed in independent experiments, suggesting a contribution to T cell pathogenicity. Functional analysis of Nfatc1 revealed that Nfatc1-deficient CD4+ T cells were restrained in their ability to induce clinical signs of EAE. Nfatc1-deficiency allowed proper T cell activation, but diminished their potential to fully differentiate into Th17 cells and to express high amounts of lineage cytokines. As the inducible Nfatc1/αA transcript is distinct from the other family members, it could represent an interesting target for therapeutic intervention in MS.rn

Inherited cavernous malformations of the central nervous system: clinical and genetic features in 19 Swiss families

Cavernous malformations (CCMs) are benign, well-circumscribed, and mulberry-like vascular malformations that may be found in the central nervous system in up to 0.5% of the population. Cavernous malformations can be sporadic or inherited. The common symptoms are epilepsy, hemorrhages, focal neurological deficits, and headaches. However, CCMs are often asymptomatic. The familiar form is associated with three gene loci, namely 7q21-q22 (CCM1), 7p13-p15 (CCM2), and 3q25.2-q27 (CCM3) and is inherited as an autosomal dominant trait with incomplete penetrance. The CCM genes are identified as Krit 1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3). Here, we present the clinical and genetic features of CCMs in 19 Swiss families. Furthermore, surgical aspects in such families are also discussed.

Rapid assessment of internodal myelin integrity in central nervous system tissue

Monitoring pathology/regeneration in experimental models of de-/remyelination requires an accurate measure not only of functional changes but also of the amount of myelin. We tested whether X-ray diffraction (XRD), which measures periodicity in unfixed myelin, can assess the structural integrity of myelin in fixed tissue. From laboratories involved in spinal cord injury research and in studying the aging primate brain, we solicited "blind" samples and used an electronic detector to record rapidly the diffraction patterns (30 min each pattern) from them. We assessed myelin integrity by measuring its periodicity and relative amount. Fixation of tissue itself introduced +/-10% variation in periodicity and +/-40% variation in relative amount of myelin. For samples having the most native-like periods, the relative amounts of myelin detected allowed distinctions to be made between normal and demyelinating segments, between motor and sensory tracts within the spinal cord, and between aged and young primate CNS. Different periodicities also allowed distinctions to be made between samples from spinal cord and nerve roots and between well-fixed and poorly fixed samples. Our findings suggest that, in addition to evaluating the effectiveness of different fixatives, XRD could also be used as a robust and rapid technique for quantitating the relative amount of myelin among spinal cords and other CNS tissue samples from experimental models of de- and remyelination.

Cavernous malformations of the central nervous system in children: presentation, treatment and outcome of 20 cases

Cavernous malformations (CM) of the central nervous system are vascular malformations responsible for symptoms such as seizures, headache, and neurological deficits: 25% of cases already present in childhood.

Atypical presentation of Behçet's disease with central nervous system involvement successfully treated with infliximab

Central nervous system involvement is a rare and serious complication of Behçet's disease (BD). Herein, we describe a patient with an atypical central lesion, who experienced progressive hypesthesia of the right arm and sensory loss of the trigeminal nerve together with intense headache. A repeated biopsy was necessary to conclusively establish the diagnosis of BD. Therapy with infusions of infliximab led to a remarkable full remission. TNFα-blocking therapy was successfully replaced by azathioprine. The present well-illustrated case demonstrates the difficulty of establishing the diagnosis of BD with central nervous system involvement, the dramatic benefit of short given TNF-α-blocking agent, and the long-term remission with azathioprin.

Ultrabithorax Confers Spatial Identity in a Context-Specific Manner in the Drosophila Postembryonic Ventral Nervous System

In holometabolous insects such as Drosophila melanogaster, neuroblasts produce an initial population of diverse neurons during embryogenesis and a much larger set of adult-specific neurons during larval life. In the ventral CNS, many of these secondary neuronal lineages differ significantly from one body segment to another, suggesting a role for anteroposterior patterning genes. Here we systematically characterize the expression pattern and function of the Hox gene Ultrabithorax (Ubx) in all 25 postembryonic lineages. We find that Ubx is expressed in a segment-, lineage-, and hemilineage-specific manner in the thoracic and anterior abdominal segments. When Ubx is removed from neuroblasts via mitotic recombination, neurons in these segments exhibit the morphologies and survival patterns of their anterior thoracic counterparts. Conversely, when Ubx is ectopically expressed in anterior thoracic segments, neurons exhibit complementary posterior transformation phenotypes. Our findings demonstrate that Ubx plays a critical role in conferring segment-appropriate morphology and survival on individual neurons in the adult-specific ventral CNS. Moreover, while always conferring spatial identity in some sense, Ubx has been co-opted during evolution for distinct and even opposite functions in different neuronal hemilineages.

Tight junctions in brain barriers during central nervous system inflammation

Homeostasis within the central nervous system (CNS) is a prerequisite to elicit proper neuronal function. The CNS is tightly sealed from the changeable milieu of the blood stream by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB). Whereas the BBB is established by specialized endothelial cells of CNS microvessels, the BCSFB is formed by the epithelial cells of the choroid plexus. Both constitute physical barriers by a complex network of tight junctions (TJs) between adjacent cells. During many CNS inflammatory disorders, such as multiple sclerosis, human immunodeficiency virus infection, or Alzheimer's disease, production of pro-inflammatory cytokines, matrix metalloproteases, and reactive oxygen species are responsible for alterations of CNS barriers. Barrier dysfunction can contribute to neurological disorders in a passive way by vascular leakage of blood-borne molecules into the CNS and in an active way by guiding the migration of inflammatory cells into the CNS. Both ways may directly be linked to alterations in molecular composition, function, and dynamics of the TJ proteins. This review summarizes current knowledge on the cellular and molecular aspects of the functional and dysfunctional TJ complexes at the BBB and the BCSFB, with a particular emphasis on CNS inflammation and the role of reactive oxygen species.

[Drug-independent blood pressure control through the autonomous nervous system]

Arterial hypertension is a chronic disease with a therapeutical challenge for the patient and the physician involved. Patient-independent techniques with good efficacy and tolerability are wanted. The autonomous nervous system insufficiently therapeutically exploited to date, is now approachable by two types of intervention: renal nerve ablation, an endovascular approach without remaining foreign body, and BAT, baroreflex activating therapy using an implantable device stimulating the carotid sinus. The blood pressure lowering potency of BAT appears more than with renal nerve ablation and also clinical study data are more prevalent. With both treatment options the patients having the most profit are insufficiently defined. Given this knowledge, any form of secondary hypertension needs to be excluded beforehand.

Training-related modulations of the autonomic nervous system in endurance athletes: is female gender cardioprotective?

The risk of sudden death is increased in athletes with a male predominance. Regular physical activity increases vagal tone, and may protect against exercise-induced ventricular arrhythmias. We investigated training-related modulations of the autonomic nervous system in female and male endurance athletes. Runners of a 10-mile race were invited. Of 873 applicants, 68 female and 70 male athletes were randomly selected and stratified according to their average weekly training hours in a low (≤4 h) and high (>4 h) volume training group. Analysis of heart rate variability was performed over 24 h. Spectral components (high frequency [HF] and low frequency [LF] power in normalized units) were analyzed for hourly 5 min segments and averaged for day- and nighttime. One hundred and fourteen athletes (50 % female, mean age 42 ± 7 years) were included. No significant gender difference was observed for training volume and 10-mile race time. Over the 24-h period, female athletes exhibited a higher HF and lower LF power for each hourly time-point. Female gender and endurance training hours were independent predictors of a higher HF and lower LF power. In female athletes, higher training hours were associated with a higher HF and lower LF power during nighttime. In male athletes, the same was true during daytime. In conclusion, female and male athletes showed a different circadian pattern of the training-related increase in markers of vagal tone. For a comparable amount of training volume, female athletes maintained their higher markers of vagal tone, possibly indicating a superior protection against exercise-induced ventricular arrhythmias.

The overexpression of homeotic complex gene Ultrabithorax in the post-embryonic neuronal lineages of the ventral nervous system in Drosophila melanogaster

This study uses a molecular technique called MARCM (Mosaic Analysis with a Repressible Cell Marker) to label neuronal lineages that overexpress the Hox gene Ultrabithorax (Ubx) in an unlabeled, wild type background. The results indicate that the overexpression of Ubx is sufficient to transform more anterior neuronal lineages to themorphology of their more posterior counterparts. The data presented here begin to elucidate the role that the Hox genes have in shaping segment-specific neural connections in the post-embryonic ventral nervous system.

Dosing algorithm to target a predefined AUC in patients with primary central nervous system lymphoma receiving high dose methotrexate

There is no consensus regarding optimal dosing of high dose methotrexate (HDMTX) in patients with primary CNS lymphoma. Our aim was to develop a convenient dosing algorithm to target AUC(MTX) in the range between 1000 and 1100 µmol l(-1) h.

The Role of Antennapedia in Anteroposterior Patterning of the Drosophila Melanogaster Ventral Nervous System

A major unresolved question in developmental neurobiology is how the nervous system is adapted to the specific needs of the organism at different life stages. In the holometabolous insect Drosophila melanogaster, the larval ventral nervous system (VNS) is comprised of similar repeating segments, as opposed to the adult VNS, which varies greatly from segment to segment both in number and types of neurons. The adult-specific neurons of each segment are generated by 25 distinct types of neuronal progenitor cells called neuroblasts (NBs) that appear in a stereotyped array (Truman et al., 2004). Each NB divides repeatedly to produce a distinct set of daughter cells termed a lineage, which is bilaterally symmetric but present to varying degrees in each segment. These daughter cells can be distinguished by their position within the nervous system as well as by their axonal projections. Each of the 25 NBs produces neurons; if both daughter cells are present in a lineage then both sibling populations survived, whereas if only one projection is seen cell death occurred, leaving a hemilineage (half lineage). In some lineages, the same sibling type survives in all segments in which the lineage appears, but in others, the surviving sibling type varies across segments, resulting in a different morphology for the same lineage in different segments. How are these differences in survival and morphology controlled? The Hox genes provide positional information for developing structures along the anterior-posterior (AP) axis of animals. They encode transcription factors, thereby controlling the activity of genes down stream. In the postembryonic VNS, each NB lineage features its own characteristic expression pattern of Hox genes Antp and Ubx, which can vary from segment-to-segment, and can thereby cause variation in the number of neural cells and axonal projections that survive. This study defines the wild-type expression pattern of Antp and elucidates the role of Antp in gain of function studies. These studies are possible due to the MARCM (Mosaic Analysis with a Repressible Cell Marker) method, which allows the genetically manipulated cells to be specifically labeled in an otherwise normal, unlabeled organism. The results indicate that Antp is expressed in a segment-, lineage-, and hemilineage-specific manner. Antp is sufficient for both anterior and posterior transformations of particular lineages, including promotion of cell death and/or survival as well as axon guidance.

The anatomical and cellular basis of immune surveillance in the central nervous system

The central nervous system (CNS) comprises the brain, spinal cord, optic nerves and retina, and contains post-mitotic, delicate cells. As the rigid coverings of the CNS render swelling dangerous and destructive, inflammatory reactions must be carefully controlled in CNS tissues. Nevertheless, effector immune responses that protect the host during CNS infection still occur in the CNS. Here, we describe the anatomical and cellular basis of immune surveillance in the CNS, and explain how this shapes the unique immunology of these tissues. The Review focuses principally on insights gained from the study of autoimmune responses in the CNS and to a lesser extent on models of infectious disease. Furthermore, we propose a new model to explain how antigen-specific T cell responses occur in the CNS.

T-cell trafficking in the central nervous system

To perform their distinct effector functions, pathogen-specific T cells have to migrate to target tissue where they recognize antigens and produce cytokines that elicit appropriate types of protective responses. Similarly, migration of pathogenic self-reactive T cells to target organs is an essential step required for tissue-specific autoimmunity. In this article, we review data from our laboratory as well as other laboratories that have established that effector function and migratory capacity are coordinately regulated in different T-cell subsets. We then describe how pathogenic T cells can enter into intact or inflamed central nervous system (CNS) to cause experimental autoimmune encephalomyelitis or multiple sclerosis. In particular, we elaborate on the role of CCR6/CCL20 axis in migration through the choroid plexus and the involvement of this pathway in immune surveillance of and autoimmunity in the CNS.