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Background Quinoline-3-carboxamides, such as laquinimod, ameliorate CNS autoimmunity in patients and reduce tumor cell metastasis experimentally. Previous studies have focused on the immunomodulatory effect of laquinimod on myeloid cells. The data contained herein suggest that quinoline-3-carboxamides improve the immunomodulatory and anti-tumor effects of NK cells by upregulating the adhesion molecule DNAX accessory molecule-1 (DNAM-1). Methods We explored how NK cell activation by laquinimod inhibits CNS autoimmunity in experimental autoimmune encephalomyelitis (EAE), the most utilized model of MS, and improves immunosurveillance of experimental lung melanoma metastasis. Functional manipulations included in vivo NK and DC depletion experiments and in vitro assays of NK cell function. Clinical, histological, and flow cytometric read-outs were assessed. Results We demonstrate that laquinimod activates natural killer (NK) cells via the aryl hydrocarbon receptor and increases their DNAM-1 cell surface expression. This activation improves the cytotoxicity of NK cells against B16F10 melanoma cells and augments their immunoregulatory functions in EAE by interacting with CD155+ dendritic cells (DC). Noteworthy, the immunosuppressive effect of laquinimod-activated NK cells was due to decreasing MHC class II antigen presentation by DC and not by increasing DC killing. Conclusions This study clarifies how DNAM-1 modifies the bidirectional crosstalk of NK cells with CD155+ DC, which can be exploited to suppress CNS autoimmunity and strengthen tumor surveillance. Open-Access-Publikationsfonds 2019

Cortical demyelination is a widely recognized hallmark of multiple sclerosis (MS) and correlate of disease progression and cognitive decline. The pathomechanisms initiating and driving gray matter damage are only incompletely understood. Here, we determined the infiltrating leukocyte subpopulations in 26 cortical demyelinated lesions of biopsied MS patients and assessed their contribution to cortical lesion formation in a newly developed mouse model. We find that conformation-specific anti-myelin antibodies contribute to cortical demyelination even in the absence of the classical complement pathway. T cells and natural killer cells are relevant for intracortical type 2 but dispensable for subpial type 3 lesions, whereas CCR2+ monocytes are required for both. Depleting CCR2+ monocytes in marmoset monkeys with experimental autoimmune encephalomyelitis using a novel humanized CCR2 targeting antibody translates into significantly less cortical demyelination and disease severity. We conclude that biologics depleting CCR2+ monocytes might be attractive candidates for preventing cortical lesion formation and ameliorating disease progression in MS. Electronic supplementary material The online version of this article (doi:10.1007/s00401-017-1706-x) contains supplementary material, which is available to authorized users.

In this multicenter study, we used dynamic causal modeling to characterize the abnormalities of effective connectivity of the sensorimotor network in 61 patients with multiple sclerosis (MS) compared with 74 age‐matched healthy subjects. We also investigated the correlation of such abnormalities with findings derived from structural MRI. In a subgroup of subjects, diffusion tensor (DT) MRI metrics of the corpus callosum and the left corticospinal tract (CST) were also assessed. MS patients showed increased effective connectivity relative to controls between: (a) the left primary SMC and the left dorsal premotor cortex (PMd), (b) the left PMd and the supplementary motor areas (SMA), (c) the left secondary sensorimotor cortex (SII) and the SMA, (d) the right SII and the SMA, (e) the left SII and the right SII, and (f) the right SMC and the SMA. MS patients had relatively reduced effective connectivity between the left SMC and the right cerebellum. No interaction was found between disease group and center. Coefficients of altered connectivity were weakly correlated with brain T2 LV, but moderately correlated with DT MRI‐measured damage of the left CST. In conclusion, large multicenter fMRI studies of effective connectivity changes in diseased people are feasible and can facilitate studies with sample size large enough for robust outcomes. Increased effective connectivity in the patients for the simple motor task suggests local network modulation contributing to enhanced long‐distance effective connectivity in MS patients. This extends and generalizes previous evidence that enhancement of effective connectivity may provide an important compensatory mechanism in MS. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.

Laquinimod (LAQ) is a new oral immunomodulatory compound that reduces relapse rate, brain atrophy and disability progression in multiple sclerosis (MS). LAQ has well-documented effects on inflammation in the periphery, but little is known about its direct activity within the central nervous system (CNS). To elucidate the impact of LAQ on CNS-intrinsic inflammation, we investigated the effects of LAQ on cuprizone-induced demyelination in mice in vivo and on primary CNS cells in vitro. Demyelination, inflammation, axonal damage and glial pathology were evaluated in LAQ-treated wild type and Rag-1-deficient mice after cuprizone challenge. Using primary cells we tested for effects of LAQ on oligodendroglial survival as well as on cytokine secretion and NF-κB activation in astrocytes and microglia. LAQ prevented cuprizone-induced demyelination, microglial activation, axonal transections, reactive gliosis and oligodendroglial apoptoses in wild type and Rag-1-deficient mice. LAQ significantly decreased pro-inflammatory factors in stimulated astrocytes, but not in microglia. Oligodendroglial survival was not affected by LAQ in vitro. Astrocytic, but not microglial, NF-κB activation was markedly reduced by LAQ as evidenced by NF-κB reporter assay. LAQ also significantly decreased astrocytic NF-κB activation in cuprizone-treated mice. Our data indicate that LAQ prevents cuprizone-induced demyelination by attenuating astrocytic NF-κB activation. These effects are CNS-intrinsic and not mediated by peripheral immune cells. Therefore, LAQ downregulation of the astrocytic pro-inflammatory response may be an important mechanism underlying its protective effects on myelin, oligodendrocytes and axons. Modulation of astrocyte activation may be an attractive therapeutic target to prevent tissue damage in MS. Electronic supplementary material The online version of this article (doi:10.1007/s00401-012-1009-1) contains supplementary material, which is available to authorized users.

Dear Sirs, We report the rare case of a primary angiitis of the CNS (PACNS) with isolated spinal cord manifestation. This 44-year-old female presented diffuse dysesthesia with moderate progressive weakness of the lower limbs. There were no cerebral symptoms; cMRI was normal. The diagnosis of PACNS was made by a spinal cord biopsy demonstrating granulomatous vasculitis. The patient was successfully treated with steroids and methotrexate. During a 2 year follow-up our patient did not show any brain or other organ involvement. The 44-year-old female presented with moderate progressive weakness of both legs and burning sensory symptoms of all limbs and the trunk. In addition to moderate paraparesis, the physical examination revealed a moderate pallhypesthesia of the legs with reduced vibratory sense and a diffuse hyp- and dysesthesia below the level of CD5. The family history was unremarkable for neurological diseases. The MRI of the cervical spine showed a gadolinium-enhancing lesion in the posterior part of the myelon with intramedullary edema. This lesion extended from cervical vertebral bodies 2–7 (Fig. 1a). Fig. 1 a MR study of the untreated patient. Sagittal FSE T1-weighted image shows a big, homogeneously enhancing lesion located in the cervical cord. b Follow-up MR study 24 months later. Sagittal FSE T1-weighted image shows no evidence of contrast enhancement ... The cerebral MRI and visual evoked potentials were entirely normal, the examination of the CSF revealed a slight pleocytosis (12 cells/mm3), cytological examination showed regular cells. Oligoclonal bands were absent which makes multiple sclerosis highly improbable. Laboratory examinations did not reveal any evidence for either metabolic (vitamin-B12, folate), autoimmune or infectious disorder. We found no aquaporin-4-antibodies. With normal VEP, we had no evidence for neuromyelitis optica. We started with intravenous high dose methylprednisolone therapy (1 g for 5 days), but symptoms relapsed after 3 months of disease freedom. Before introduction of another immunosuppressive therapy, and to exclude a spinal lymphoma, a biopsy of the spinal lesion was taken. The neuropathological examination revealed a granulomatous vasculitis with transmural inflammation consisting of lymphocytes, epitheloid cells and giant cells (Fig. 2a–h). There was no evidence for systemic organ involvement assessed by thoracic and abdominal computer tomography. Fig. 2 The histological features of primary spinal vasculitis. The neuropathological examination revealed vascular thrombosis (a 100× magnification, H&E staining) and vessel walls with transmural infiltration mainly consisting of several lymphocytes ... Treatment was started with methotrexate (20 mg/week) combined with prednisolone (tapered from 80 to 10 mg/d within 6 weeks). Neurological examination at 3 month intervals revealed normal findings except a slight dysesthesia in the legs. A follow-up MRI after 24 months of treatment demonstrated an obvious regression of the signal intensities within the cervical cord (Fig. 1b), whereas the cMRI remained normal. Spinal symptoms are a rare presentation of primary CNS vasculitis [1]. The previously reported cases with spinal cord involvement also showed progressive paraparesis and dysesthesia as the most common clinical symptoms [2]. However, usually these symptoms occur in the course of the disease and not at disease onset as in our case. A review of the literature showed only eight cases with initially pure spinal cord involvement [3]; half of these cases developed brain lesions later on [1, 4]. The stereotactic biopsy remains the gold standard to assure the diagnosis of a CNS vasculitis [5], but the diagnosis in daily clinical routine is often only based on clinical and imaging findings as well as the response to treatment. This might be a potential reason for overdiagnosing PACNS in clinical routine. As illustrated by our case, histological verification is crucial for the diagnosis. The standard therapy for PACNS consists of corticosteroids (1 mg/kg prednisolone) and pulsed cyclophosphamide (0.5 mg/kg). The treatment with cyclophosphamide can have severe side effects [6]. Monotherapy with steroids leads to higher recurrence rates [7]. Since methotrexate has been successfully used in systemic vasculitis [8], we started treatment with a combination of steroids and methotrexate. Our patient reached remission within 3 months and remains stable now more than 2 years later. In biopsy-proven PACNS of the spinal cord, methotrexate seems to be an effective and less toxic alternative to cyclophosphamide.

The olfactory bulb is an important information coding system in the informational pathway of the olfactory sense, but we still lack a good understanding of the coding mechanism in the bulb and how the odor information from the bulb is translated to the higher cerebral areas. In the past years new knowledge was achieved on the field of the olfactory sensorial transmission from the olfactory receptors to the olfactory bulb: The mammalian nasal epithelium is separated in four regions and each receptor cell type exists just in one of the four areas [1]. Furthermore, olfactory receptors identify odorants based on the chemical features of the odor molecule [2] and receptor neurons of the same type converge to the same spot in the bulb, called glomerulus [3]. This knowledge leads to the assumption that the olfactory bulb might be also separated into four regions and that information coding in the bulb is organized by a chemotopic representation. By using the 2-DG-uptaketechnique, odorant-specific activity patterns across the glomeruli in rat olfactory bulbs can be illustrated [4]. We used the non-negative matrix factorization (NMF) on 143 distinct uptake-images of the rat olfactory bulb in order to get insight in the chemotopic coding map. NMF is designed for revealing inherent structures and similarities in the data and creates a decomposition in parts which display common features of the data. Our analysis on the NMF parts result in four very stable regions of the bulb, which are hierarchically splitted in smaller regions when the number of parts increase. We found a good representation of our data with nine bulb regions, called modules. These modules show some analogy to previously reported regional structures in the bulb [5][6]. Furthermore, we demonstrate a linkage between typical odorant characteristics and our modules, so this speaks in favour of a chemotopic coding map in the bulb. We suggest to understand the modules as a coding character in a coding alphabet. After determining the codeword for each odorant, we designed an odor experiment to investigate whether our coding model can explain the human odor perception. We think our coding model can give new ideas and directions for further research on this topic and want to present our research with a poster.

One object of olfactory research is to understand the coding map of an olfactory bulb. Even after decades of olfactory research, it is still not possible to predict if two odorants smell similar or not without asking human subjects and/or using prior knowledge on exactly these substances. There is only a single source of data, which includes the activity of the whole bulb under exposure of a single compound: The uptake data from Leon & Johnson [1]. Given that the activity is a chemotopic ordered multifactorial code, there are several possible ways these codes might be implemented by nature. So far, specific bulb regions were declared as modules by using the Nonnegative Matrix Factorization. To examine the codes we imagine the modules as letters of an alphabet. Analog to the orthography and grammar of a language, we want to find rules that explain the meaning of the composition of individual words. We consider an alphabet consisting of nine letters, one for each module. Odorants are characterized by module activities and thus form words of the alphabet. The number of activated modules classifies the odorants into groups with different word lengths. To understand complex words, an intuitive approach is to first concentrate on the relations between the letters to each other. We present three different models that describe how odor quality on this modular abstraction could be measured. First of all there is a chemotopic approach, which assumes that odorants with similar chemical epitopes address the same types of receptors. But the corresponding glomeruli are not necessarily close to each other. In order to implement this model we define regions of interest using above-threshold uptake induced by incoming receptor neuron activity. The second model combines the chemotopic approach with the spatial arrangement of the