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Background: Serum neurofilament light chain (sNfL) is a promising biomarker to complement the decision-making process in multiple sclerosis (MS) patients. However, although sNfL levels are able to detect disease activity and to predict future disability, the growing evidence has not yet been translated into practicable recommendations for an implementation into clinical routine. Methods: The observation of a patient with extensive inflammatory activity in magnetic resonance imaging (MRI) along with an extremely high sNfL level in the absence of any clinical symptoms prompted us to investigate common characteristics of our MS patients with the highest sNfL levels in a retrospective cohort study. The 97.5th percentile was chosen as a cut-off value because the mean sNfL level of the resulting extreme neurofilament light chain (NfL) cohort corresponded well to the sNfL level of the presented case. Patient characterization included clinical and MRI assessment with a focus on disease activity markers. sNfL levels were determined by single molecule array. Results: The 97.5th percentile of our MS cohort (958 sNfL measurements in 455 patients) corresponded to a threshold value of 46.1 pg/ml. The mean sNfL level of the extreme sNfL cohort ( n = 24) was 95.6 pg/ml (standard deviation 68.4). Interestingly, only 15 patients suffered from a relapse at the time point of sample collection, whereas nine patients showed no signs of clinical disease activity. sNfL levels of patients with and without relapse did not differ [median 81.3 pg/ml (interquartile range [IQR] 48.0–128) versus 80.2 pg/ml (IQR 46.4–97.6), p = 0.815]. The proportion of patients with contrast-enhancing lesions was high and also did not differ between patients with and without relapse (92.9% versus 87.5%, p = 0.538); 78.9% of the patients not receiving a high-efficacious therapy had ongoing disease activity during a 2-year follow-up. Conclusion: Extremely high sNfL levels are indicative of subclinical disease activity and might complement treatment decisions in ambiguous cases.

Background Patients with multiple sclerosis (MS) receiving immunomodulatory drugs were excluded from clinical trials on COVID-19 vaccines. Therefore, data regarding the efficacy of COVID-19 vaccines to induce humoral immunity in MS patients treated with B- and T-cell depleting agents is urgently warranted. Cladribine tablets are a high-efficacy disease-modifying treatment that exerts its therapeutic effect via sustained but transient lymphocyte depletion. Aim We report humoral responses in a German cohort of MS patients treated with cladribine tablets. Methods This retrospective analysis included patients ≥18 years who were treated with cladribine tablets for relapsing MS in the first or second year and were fully vaccinated against COVID-19. Two weeks after the second vaccination at the earliest, blood samples were obtained for the assessment of anti-SARS-CoV-2 IgG antibodies, lymphocyte counts, B-cells, CD4+ T-cells, and CD8+ T-cells. Anti-SARS-CoV-2 IgG antibodies were quantified with the LIAISON® SARS-CoV-2 TrimericS IgG assay. Positivity was defined at a cutoff value of 33.8 BAU/mL. Results In total, 38 patients (73.7% female, aged 23–66 years) were included in the analysis. Ten patients (26.3%) were treatment-naïve before initiating treatment with cladribine tablets. Most patients (84.2%) received mRNA vaccines. The time between the last dose of cladribine tablets and vaccination ranged between 2 and 96 weeks. Six patients (15.8%) were vaccinated within 4 weeks of their last cladribine dose. All patients achieved positive anti-SARS-CoV-2 IgG antibody levels. Humoral immune response was independent of age, time of vaccination in relation to the last cladribine dose, lymphocyte counts as well as B- and T-cell counts. Conclusions Treatment with cladribine tablets did not impair humoral response to COVID-19 vaccination. Time since last cladribine dose, age, prior therapy, lymphocyte count as well as B- and T-cell counts had no effect on seropositivity of anti-SARS-CoV-2 IgG antibodies.

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, and Switzerland). in press, CA extern

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that is caused by an autoimmune response against central nervous system (CNS) structures. Traditionally considered a T-cell-mediated disorder, the contribution of B cells to the pathogenesis of MS has long been debated. Based on recent promising clinical results from CD20-depleting strategies by three therapeutic monoclonal antibodies in clinical phase II and III trials (rituximab, ocrelizumab and ofatumumab), targeting B cells in MS is currently attracting growing interest among basic researchers and clinicians. Many questions about the role of B and plasma cells in MS remain still unanswered, ranging from the role of specific B-cell subsets and functions to the optimal treatment regimen of B-cell depletion and monitoring thereafter. Here, we will assess our current knowledge of the mechanisms implicating B cells in multiple steps of disease pathology and examine current and future therapeutic approaches for the treatment of MS.

Although various types of ion channels are known to have an impact on human T cell effector functions, their exact mechanisms of influence are still poorly understood. The patch clamp technique is a well-established method for the investigation of ion channels in neurons and T cells. However, small cell sizes and limited selectivity of pharmacological blockers restrict the value of this experimental approach. Building a realistic T cell computer model therefore can help to overcome these kinds of limitations as well as reduce the overall experimental effort. The computer model introduced here was fed off ion channel parameters from literature and new experimental data. It is capable of simulating the electrophysiological behaviour of resting and activated human CD4(+) T cells under basal conditions and during extracellular acidification. The latter allows for the very first time to assess the electrophysiological consequences of tissue acidosis accompanying most forms of inflammation.

Background The treatment of patients with multiple sclerosis (MS) is associated with constantly rising costs for the healthcare system and pharmaceuticals constitute 60 % of the direct medical costs. The Pharmaceutical Market Restructuring Act (Arzneimittelmarkt-Neuordnungsgesetz, AMNOG) came into force on 1 January 2011 with the aim of limiting the costs of pharmaceuticals by obligating newly approved products to be subjected to an early evaluation of the additional benefits by the Federal Joint Committee (FJC, Gemeinsamer Bundesausschuss, G‑BA). The majority of products evaluated up to October 2015 in neurology (5 out of 8) were approved for treatment of MS. Objective Has the AMNOG been able to fulfill the original aims? Material and methods Analysis of available information on MS therapies evaluated by the FJC between December 2010 and October 2015. Results For various reasons an additional benefit could be shown in only 2 out of 5 assessment procedures for MS drugs. It is obvious that some methodological shortcomings of the process have to be improved. Additionally requirements for pivotal clinical trials have to be harmonized with AMNOG requirements taking the best available evidence and real-life data into consideration (e.g. non-interventional studies) and a closer collaboration between the FJC, healthcare providers and the neurological societies is necessary. Conclusion The AMNOG procedure currently only partially fulfills the original aims, which could be the reason why guidelines play a more important role for therapy decision-making than FJC decisions. As the early evaluation procedure is an adaptive process methodological shortcomings might be overcome in the future; however, this requires a much closer collaboration between the FJC and neurological societies.

Breakdown of the blood-brain barrier (BBB) is an early hallmark of multiple sclerosis (MS), a progressive inflammatory disease of the central nervous system. Cell adhesion in the BBB is modulated by sphingosine-1-phosphate (S1P), a signaling protein, via S1P receptors (S1P\(_1\)). Fingolimod phosphate (FTY720-P) a functional S1P\(_1\) antagonist has been shown to improve the relapse rate in relapsing-remitting MS by preventing the egress of lymphocytes from lymph nodes. However, its role in modulating BBB permeabilityin particular, on the tight junction proteins occludin, claudin 5 and ZO-1has not been well elucidated to date. In the present study, FTY720-P did not change the transendothelial electrical resistance in a rat brain microvascular endothelial cell (RBMEC) culture exposed to inflammatory conditions and thus did not decrease endothelial barrier permeability. In contrast, occludin was reduced in RBMEC culture after adding FTY720-P. Additionally, FTY720-P did not alter the amount of endothelial matrix metalloproteinase (MMP)-9 and MMP-2 in RBMEC cultures. Taken together, our observations support the assumption that S1P\(_1\) plays a dual role in vascular permeability, depending on its ligand. Thus, S1P\(_1\) provides a mechanistic basis for FTY720-P-associated disruption of endothelial barrierssuch as the blood-retinal barrierwhich might result in macular edema.

// Tobias Ruck 1 , Stefan Bittner 2 , Ali Maisam Afzali 1 , Kerstin Gobel 1 , Sarah Glumm 1 , Peter Kraft 3 , Claudia Sommer 3 , Christoph Kleinschnitz 3 , Corinna Preuse 4 , Werner Stenzel 4 , Heinz Wiendl 1,* and Sven G. Meuth 1,* 1 Department of Neurology, University of Muenster, Muenster, Germany 2 Department of Neurology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany 3 Department of Neurology, University Hospital of Wuerzburg, Wuerzburg, Germany 4 Department of Neuropathology, Charite-Universitatsmedizin, Berlin, Germany * These authors have contributed equally to this work Correspondence to: Tobias Ruck, email: // Keywords : NKG2D, IL-15, polymyositis, idiopathic inflammatory myopathies, T cell activation, Pathology Section Received : June 08, 2015 Accepted : November 14, 2015 Published : December 04, 2015 Abstract NKG2D is an activating receptor on T cells, which has been implicated in the pathogenesis of autoimmune diseases. T cells are critically involved in idiopathic inflammatory myopathies (IIM) and have been proposed as specific therapeutic targets. However, the mechanisms underlying T cell-mediated progressive muscle destruction in IIM remain to be elucidated. We here determined the involvement of the NKG2D – IL-15 signaling pathway. Primary human myoblasts expressed NKG2D ligands, which were further upregulated upon inflammatory stimuli. In parallel, shedding of the soluble NKG2D ligand MICA (sMICA) decreased upon inflammation potentially diminishing inhibition of NKG2D signaling. Membrane-related expression of IL-15 by myoblasts induced differentiation of naive CD8 + T cells into highly activated, cytotoxic CD8 + NKG2D high T cells demonstrating NKG2D-dependent lysis of myoblasts in vitro . CD8 + NKG2D high T cell frequencies were increased in the peripheral blood of polymyositis (PM) patients and correlated with serum creatinine kinase concentrations, while serum sMICA levels were not significantly changed. In muscle biopsy specimens from PM patients expression of the NKG2D ligand MICA/B was upregulated, IL-15 was expressed by muscle cells, CD68 + macrophages as well as CD4 + T cells, and CD8 + NKG2D + cells were frequently detected within inflammatory infiltrates arguing for a local signaling circuit in the inflammatory muscle milieu. In conclusion, the NKG2D – IL-15 signaling pathway contributes to progressive muscle destruction in IIM potentially opening new therapeutic avenues.

Background As vitamins and dietary supplements are obtainable without prescription, treating physicians often ignore their intake by patients with multiple sclerosis (MS) and may therefore miss potential adverse effects and interactions. Objective We aimed to assess the spectrum and intake frequency of supplementary medication in a cohort of MS patients and to analyse the effect of biotin intake on measurement of serum neurofilament light chain (sNfL), an emerging marker of disease activity. Methods MS patients visiting our neurology outpatient clinic completed a questionnaire on their past or present use of vitamins or dietary supplements. In addition, the impact of two different doses of biotin (10 and 300 mg/day) on sNfL was studied in healthy volunteers. Results Of 186 patients, 72.6% reported taking over-the-counter vitamins or dietary supplements currently or previously. Most frequently used was vitamin D (60.0%), followed by biotin. Female patients and patients with primary progressive MS tended to use supplements more frequently. Biotin intake did not interfere with sNfL measurement by single molecule array (Simoa). Conclusions The use of vitamins and dietary supplements is frequent among patients with MS. Thus, treating physicians should be aware of the pitfalls of supplementary treatment and educate their patients accordingly.

ObjectiveTo provide first real-world experience on patients with MS treated with the B cell–depleting antibody ocrelizumab.MethodsWe retrospectively collected data of patients who had received at least 1 treatment cycle (2 infusions) of ocrelizumab at 3 large neurology centers. Patients' characteristics including premedication, clinical disease course, and documented side effects were analyzed.ResultsWe could identify 210 patients (125 women, mean age ± SD, 42.1 ± 11.4 years) who had received ocrelizumab with a mean disease duration of 7.3 years and a median Expanded Disability Status Scale score of 3.75 (interquartile range 2.5–5.5; range 0–8). Twenty-six percent of these patients had a primary progressive MS (PPMS), whereas 74% had a relapsing-remitting (RRMS) or active secondary progressive (aSPMS) disease course. Twenty-four percent of all patients were treatment naive, whereas 76% had received immune therapies before. After ocrelizumab initiation (median follow-up was 200 days, range 30–1,674 days), 13% of patients with RRMS/aSPMS experienced a relapse (accounting for an annualized relapse rate of 0.17, 95% CI 0.10–0.24), and 5% of all patients with MS experienced a 12-week confirmed disability progression. Treatment was generally well tolerated, albeit only short-term side effects were recorded, including direct infusion-related reactions and mild infections.ConclusionsWe provide class IV evidence that treatment with ocrelizumab can stabilize naive and pretreated patients, indicating that ocrelizumab is an option following potent MS drugs such as natalizumab and fingolimod. Further studies are warranted to confirm these findings and to reveal safety concerns in the longer-term follow-up.Classification of evidenceThis study provides Class IV evidence that for patients with MS, ocrelizumab can stabilize both treatment-naive and previously treated patients.

We present an experimental study of the effects of temporal modulation of the pump intensity on a random laser. The nanosecond pump pulses exhibit rapid intensity fluctuations which differ from pulse to pulse. Specific temporal profiles of the pump pulses produce extraordinarily strong emission from the random laser. This process is deterministic and insensitive to the spatial configuration of the scatterers and spontaneous emission noise.

Lasers have enabled scientific and technological progress, owing to their high brightness and high coherence. However, the high spatial coherence of laser illumination is not always desirable, because it can cause adverse artefacts such as speckle noise. To reduce spatial coherence, new laser cavity geometries and alternative feedback mechanisms have been developed. By tailoring the spatial and spectral properties of cavity resonances, the number of lasing modes, the emission profiles and the coherence properties can be controlled. In this Technical Review, we present an overview of such unconventional, complex lasers, with a focus on their spatial coherence properties. Laser coherence control not only provides an efficient means for eliminating coherent artefacts but also enables new applications in imaging and wavefront shaping. High spatial coherence of laser illumination is not always desirable, because it can cause adverse artefacts such as speckle noise. This Technical Review describes unconventional lasers that have inherently low and/or tunable spatial coherence.

A major objective in photonics is to tailor the emission properties of microcavities which is usually achieved with specific cavity shapes. Yet the dynamical change of the emission properties during operation would often be advantageous. The implementation of such a method is still a challenging issue. We present an effective procedure for the dynamical control of the emission lobes which relies on the selection of a specific coherent superposition of degenerate modes belonging to different symmetry classes. It is generally applicable to systems exhibiting pairs of degenerate modes. We explored it experimentally and analytically with organic square microlasers, which emit narrow lobes parallel to their sidewalls. By means of the pump polarization, emission lobes are switched on and off selectively with an extinction ratio better than $1/50$.

Background: Monitoring neuronal injury remains one key challenge in early relapsing-remitting multiple sclerosis (RRMS) patients. Upon axonal damage, neurofilament – a major component of the neuro-axonal cytoskeleton – is released into the cerebrospinal fluid (CSF) and subsequently peripheral blood. Objective: To investigate the relevance of serum neurofilament light chain (sNfL) for acute and chronic axonal damage in early RRMS. Methods: sNfL levels were determined in 74 patients (63 therapy-naive) with recently diagnosed clinically isolated syndrome (CIS) or RRMS using Single Molecule Array technology. Standardized 3 T magnetic resonance imaging (MRI) was performed at baseline and 1–3 consecutive follow-ups (42 patients; range: 6–37 months). Results: Baseline sNfL correlated significantly with T2 lesion volume ( r = 0.555, p Conclusion: sNfL indicates acute inflammation as demonstrated by correlation with Gd+ lesions. It is a promising biomarker for neuro-axonal damage in early multiple sclerosis (MS) patients, since higher baseline sNfL levels predicted future brain atrophy within 2 years.

We investigate in detail the resonant properties of a two-dimensional dielectric cavity with an equilateral triangle shape, using a numerical integral equations approach and a semiclassical approach. The homogeneous Muller boundary equations are used to calculate the resonant modes of a dielectric triangle in a wide range of frequencies. It is shown that the modes of dielectric triangles localized on families of periodic orbits can be well described in terms of a semiclassical superscar model. Special attention is given to the families of resonances based on the inscribed triangle periodic orbit.

Taming laser instabilities Broad-area and high-power lasers often suffer from instabilities owing to the chaotic interference of multiple modes within the cavity. Such instabilities can ultimately limit the operation of the laser or damage the cavity. The usual approach to minimizing such instabilities is to limit the number of modes in the cavity. Bittner et al. designed a chaotic cavity that disrupts the formation of self-organized structures that lead to instabilities (see the Perspective by Yang). This approach of fighting chaos with chaos by using the boundary condition of the cavity shape may provide a robust route to stabilizing lasers at high operating powers. Science , this issue p. 1225 ; see also p. 1201

The suppression of spatio-temporal instabilities of broad-area semiconductor lasers is demonstrated for microcavities with chaotic ray dynamics. We attribute the stabilization to the disruption of coherent instabilities by complex wave interference.

ObjectiveTo determine the factors that influence B-cell repopulation after B-cell depletion therapy in neurologic patients and derive recommendations for monitoring and dosing of patients.MethodsIn this study, we determined the association of body surface area (BSA; calculated by body weight and height with the Dubois formula), sex, pretreatment therapy, age, CSF data, and white blood cell counts with the risk and timing of B-cell repopulation, defined as 1% CD19+ cells (of total lymphocytes), following 87 B cell–depleting anti-CD20 treatment cycles of 45 neurologic patients (28 women; mean age ± SD, 44.5 ± 15.0 years).ResultsPatients with a larger BSA had a higher probability to reach 1% CD19+ cells than those with a smaller BSA (p < 0.05) following B-cell depletion therapy, although those patients had received BSA-adapted doses of rituximab (375 mg/m2). Sex, pretreatment, age, CSF data, or absolute lymphocyte and leukocyte counts during treatment did not significantly influence CD19+ B-cell recovery in the fully adjusted models. Intraindividual B-cell recovery in patients with several treatment cycles did not consistently change over time.ConclusionsB-cell repopulation after depletion therapy displays both high inter- and intra-individual variance. Our data indicate that a larger BSA is associated with faster repopulation of B cells, even when treatment is adapted to the BSA. A reason is the routinely used Dubois formula, underestimating a large BSA. In these patients, there is a need for a higher therapy dose. Because B-cell count–dependent therapy regimes are considered to reduce adverse events, B-cell monitoring will stay highly relevant. Patients' BSA should thus be determined using the Mosteller formula, and close monitoring should be done to avoid resurgent B cells and disease activity.

Background: Currently, no unequivocal predictors of disease evolution exist in patients with multiple sclerosis (MS). Cortical atrophy measurements are, however, closely associated with cumulative disability. Objective: Here, we aim to forecast longitudinal magnetic resonance imaging (MRI)-driven cortical atrophy and clinical disability from cerebrospinal fluid (CSF) markers. Methods: We analyzed CSF fractions of albumin and immunoglobulins (Ig) A, G, and M and their CSF to serum quotients. Results: Widespread atrophy was highly associated with increased baseline CSF concentrations and quotients of albumin and IgA. Patients with increased CSFIgA and CSFIgM showed higher functional disability at follow-up. Conclusion: CSF markers of blood–brain barrier integrity and specific immune response forecast emerging gray matter pathology and disease progression in MS.

In this work, we analyse the resonant frequencies and fields of dielectric equilateral triangular resonators using the Muller boundary integral equations. The results are presented for both TE- and TM-modes and interpreted in terms of semiclassical physics.

Despite intense research, few treatments are available for most neurological disorders. Demyelinating diseases are no exception. This is perhaps not surprising considering the multifactorial nature of these diseases, which involve complex interactions between immune system cells, glia and neurons. In the case of multiple sclerosis, for example, there is no unanimity among researchers about the cause or even which system or cell type could be ground zero. This situation precludes the development and strategic application of mechanism-based therapies. We will discuss how computational modeling applied to questions at different biological levels can help link together disparate observations and decipher complex mechanisms whose solutions are not amenable to simple reductionism. By making testable predictions and revealing critical gaps in existing knowledge, such models can help direct research and will provide a rigorous framework in which to integrate new data as they are collected. Nowadays, there is no shortage of data; the challenge is to make sense of it all. In that respect, computational modeling is an invaluable tool that could, ultimately, transform how we understand, diagnose, and treat demyelinating diseases.

Natural killer (NK) cells are a subset of cytotoxic lymphocytes that recognize and kill tumor- and virus-infected cells without prior stimulation. Killing of target cells is a multistep process including adhesion to target cells, formation of an immunological synapse, and polarization and release of cytolytic granules. The role of distinct potassium channels in this orchestrated process is still poorly understood. The current study reveals that in addition to the voltage-gated KV 1.3 and the calcium-activated KCa 3.1 channels, human NK cells also express the two-pore domain K2 P channel TASK2 (TWIK-related acid-sensitive potassium channel). Expression of Task2 varies among NK-cell subsets and depends on their differentiation and activation state. Despite its different expression in TASK2(high) CD56(bright) CD16(-) and TASK2(low) CD56(dim) CD16(+) NK cells, TASK2 is involved in cytokine-induced proliferation and cytolytic function of both subsets. TASK2 is crucial for leukocyte functional antigen (LFA-1) mediated adhesion of both resting and cytokine-activated NK cells to target cells, an early step in killing of target cells. With regard to the following mechanism, TASK2 plays a role in release of cytotoxic granules by resting, but not IL-15-induced NK cells. Taken together, our data exhibit two-pore potassium channels as important players in NK-cell activation and effector function.

Lymphocytes express potassium channels that regulate physiological cell functions, such as activation, proliferation and migration. Expression levels of K2P5.1 (TASK2, KCNK5) channels belonging to the family of two-pore domain potassium channels have previously been correlated to the activity of autoreactive T lymphocytes in patients with multiple sclerosis and rheumatoid arthritis. In humans, K2P5.1 channels are upregulated upon T cell stimulation and influence T cell effector functions. However, a further clinical translation of targeting K2P5.1 is currently hampered by a lack of highly selective inhibitors, making it necessary to evaluate the impact of KCNK5 in established preclinical animal disease models. We here demonstrate that K2P5.1 knockout (K2P5.1−/−) mice display no significant alterations concerning T cell cytokine production, proliferation rates, surface marker molecules or signaling pathways. In an experimental model of autoimmune neuroinflammation, K2P5.1−/− mice show a comparable disease course to wild-type animals and no major changes in the peripheral immune system or CNS compartment. A compensatory upregulation of the potassium channels K2P3.1 and KV1.3 seems to counterbalance the deletion of K2P5.1. As an alternative model mimicking autoimmune neuroinflammation, experimental autoimmune encephalomyelitis in the common marmoset has been proposed, especially for testing the efficacy of new potential drugs. Initial experiments show that K2P5.1 is functionally expressed on marmoset T lymphocytes, opening up the possibility for assessing future K2P5.1-targeting drugs.

Discovered during the 1990s and in the beginning regarded as passive membrane pores, the family of two-pore domain potassium (K2P)-channels initially received only little attention. Today the view on this channel family comprising 15 ubiquitously expressed members in mammals has greatly changed. K2P-channels carry potassium outward current that counterbalances membrane depolarization and stabilizes the resting membrane potential. Thereby they are important regulators for the excitability and the firing behaviour especially in neurons. The long list of modulating mechanisms underlines the channels’ relevance. K2P-channels in the thalamus contribute to the regulation of the sleep-wake cycle. They also mediate the effect of volatile anaesthetics by supporting the thalamic activity mode that is also typical for sleep. This review summarizes our knowledge about K2P-channel physiology in the brain, provides an idea of the role of these channels in neurological diseases and lists open questions as well as technical challenges in K2P-channel research.

Background: Common symptoms of multiple sclerosis (MS) such as gait ataxia, poor coordination of the hands, and intention tremor are usually the result of dysfunctionality in the cerebellum. Magnetic resonance imaging (MRI) has frequently failed to detect cerebellar damage in the form of inflammatory lesions in patients presenting with symptoms of cerebellar dysfunction. Objective: To detect microstructural cerebellar tissue alterations in early MS patients with a “normal appearing” cerebellum using diffusion tensor imaging (DTI). Methods: A total of 68 patients with relapsing–remitting MS (RRMS) and without cerebellar lesions and 26 age-matched healthy controls were admitted to high-resolution MRI and DTI to assess microstructure and volume of the cerebellar white matter (CBWM). Results: We found cerebellar fractional anisotropy (FA) and CBWM volume reductions in the group of 68 patients. Interestingly, a subgroup of these patients that was derived by including only patients with early and mild MS ( N=23, median age 30 years, median Expanded Disability Status Scale =1.5, median duration 28 months) showed already cerebellar FA but no CBWM volume reductions. FA reductions were correlated with disability, atrophy, and disease duration. Conclusion: “Normal appearing” cerebellar white matter can be damaged in a very early stage of RRMS. DTI seems to be a sensitive tool for detecting this hidden cerebellar damage.

Members of the two-pore domain K+ channel (K2P) family are increasingly recognized as being potential targets for therapeutic drugs and could play a role in the diagnosis and treatment of neurologic disorders. Their broad and diverse expression pattern in pleiotropic cell types, importance in cellular function, unique biophysical properties, and sensitivity toward pathophysiologic parameters represent the basis for their involvement in disorders of the central nervous system (CNS). This review will focus on multiple sclerosis (MS) and stroke, as there is growing evidence for the involvement of K2P channels in these two major CNS disorders. In MS, TASK1–3 channels are expressed on T lymphocytes and are part of a signaling network regulating Ca2+- dependent pathways that are mandatory for T cell activation, differentiation, and effector functions. In addition, TASK1 channels are involved in neurodegeneration, resulting in autoimmune attack of CNS cells. On the blood–brain barrier, TREK1 channels regulate immune cell trafficking under autoinflammatory conditions. Cerebral ischemia shares some pathophysiologic similarities with MS, including hypoxia and extracellular acidosis. On a cellular level, K2P channels can have both proapoptotic and antiapoptotic effects, either promoting neurodegeneration or protecting neurons from ischemic cell death. TASK1 and TREK1 channels have a neuroprotective effect on stroke development, whereas TASK2 channels have a detrimental effect on neuronal survival under ischemic conditions. Future research in preclinical models is needed to provide a more detailed understanding of the contribution of K2P channel family members to neurologic disorders, before translation to the clinic is an option.

Extracellular signal-regulated kinase (ERK) signaling plays a crucial role in regulating immune cell function and has been implicated in autoimmune disorders. To date, all commercially available inhibitors of ERK target upstream components, such as mitogen-activated protein (MAP) kinase/ERK kinase (MEKs), but not ERK itself. Here, we directly inhibit nuclear ERK translocation by a novel pharmacological approach (Glu-Pro-Glu (EPE) peptide), leading to an increase in cytosolic ERK phosphorylation during T helper (Th)17 cell differentiation. This was accompanied by diminished secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine influencing the encephalitogenicity of Th17 cells. Neither the production of the cytokine interleukin (IL)-17 nor the proliferation rate of T cells was affected by the EPE peptide. The in vivo effects of ERK inhibition were challenged in two independent variants of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Overall, ERK inhibition had only a very minor impact on the clinical disease course of EAE. This indicates that while ERK translocation might promote encephalitogenicity in T cells in vitro by facilitating GM-CSF production, this effect is overcome in more complex in vivo animal models of central nervous system (CNS) autoimmunity.

Ongoing axonal degeneration is thought to underlie disability in chronic neuroinflammation, such as multiple sclerosis (MS), especially during its progressive phase. Upon inflammatory attack, axons undergo pathological swelling, which can be reversible. Because we had evidence for beneficial effects of T helper 2 lymphocytes in experimental neurotrauma and discovered interleukin-4 receptor (IL-4R) expressed on axons in MS lesions, we aimed at unraveling the effects of IL-4 on neuroinflammatory axon injury. We demonstrate that intrathecal IL-4 treatment during the chronic phase of several experimental autoimmune encephalomyelitis models reversed disease progression without affecting inflammation. Amelioration of disability was abrogated upon neuronal deletion of IL-4R. We discovered direct neuronal signaling via the IRS1-PI3K-PKC pathway underlying cytoskeletal remodeling and axonal repair. Nasal IL-4 application, suitable for clinical translation, was equally effective in improving clinical outcome. Targeting neuronal IL-4 signaling may offer new therapeutic strategies to halt disability progression in MS and possibly also neurodegenerative conditions.

On-chip photonic devices are often considered in the framework of a two-dimensional (2D) approximation, with light propagating within a defined horizontal plane. Nethertheless, the finite cavity thickness plays an important role in understanding relevant three-dimensional (3D) effects. For instance, the light propagating in the device is diffracted and emitted out of plane if the thickness is comparable to or smaller than the wavelength [1]. Actual 3D microcavities (i.e., cavities where each dimension is comparable in size) were seldom investigated [2]. Here, we evidence that resonances in 3D Fabry-Perot microlasers propagate out of the substrate plane. We also report preliminary results on non-cylindrical microcavity shapes such as cone and pyramid shaped structures which are fabricated by nanoimprinting lithography.

For two decades, microcavities have been widely studied due to their numerous applications, from microlasers on chip [1] to biological or chemical sensing [2]. One of the main concerns is the control of the light propagation inside the resonator and its emission in one or several selected directions. Here, we focus on the square microlaser because it emits very narrow emission lobes [3], and we report a new mechanism to dynamically suppress or enhance some of these lobes by means of the polarization of the pump beam. This method is based on the control of the coherent superposition of degenerate modes belonging to different symmetry classes. This generic concept can be further extended to other cavity shapes.

Epigenetic regulators are increasingly recognized as relevant modulators in the immune and nervous system. The class of sirtuins consists of NAD+-dependent histone deacetylases that regulate transcription. Sirtuin family member Sirt1 has already been shown to influence the disease course in an animal model of autoimmune neuroinflammation (experimental autoimmune encephalomyelitis (EAE). A role of Sirt7, a related epigenetic regulator, on immune system regulation has been proposed before, as these mice are more susceptible to develop inflammatory cardiomyopathy. Sirt7-/- animals showed no differences in clinical score compared to wild-type littermates after EAE induction with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55, although we found subtle immune alterations at different phases of EAE and decreased survival of newly generated neurons in the hippocampus. Our data indicate that Sirt7 has a slight protective impact on both the adaptive immune system and neurogenesis. However, overall this epigenetic factor is not capable of impacting the acute or chronic phase of neuroinflammation.

T-cell migration across the blood-brain barrier (BBB) is a crucial step in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple scle rosis (MS). Two-photon intravital microscopy (2P-IVM) has been established as a powerful tool to study cell-cell interactions in inflammatory EAE lesions in living animals. In EAE, central nervous system inflammation is strongly pronounced in the spinal cord, an organ in which 2P-IVM imaging is technically very challenging and has been limited to the lumbar spinal cord. Here, we describe a novel spinal cord window preparation allowing to use 2P-IVM to image immune cell interactions with the cervical spinal cord microvascular endothelium during EAE. We describe differences in the angioarchitecture of the cervical spinal cord versus the lumbar spinal cord, which will entail different hemodynamic parameters in these different vascular beds. Using T cells as an example, we demonstrate the suitability of this novel methodology in imaging the post-arrest multistep T-cell extravasation across the cervical spinal cord microvessels. The novel methodology includes an outlook to the analysis of the cellular pathway of T-cell diapedesis across the BBB by establishing visualization of endothelial junctions in this vascular bed.

Multiple sclerosis (MS) patients exhibit neuropsychological symptoms in early disease despite the immune attack occurring predominantly in white matter and spinal cord. It is unclear why neurodegeneration may start early in the disease and is prominent in later stages. We assessed cortical microcircuit activity by employing spiking-specific two-photon Ca2+ imaging in proteolipid protein-immunized relapsing-remitting SJL/J mice in vivo. We identified the emergence of hyperactive cortical neurons in remission only, independent of direct immune-mediated damage and paralleled by elevated anxiety. High levels of neuronal activity were accompanied by increased caspase-3 expression. Cortical TNFα expression was mainly increased by excitatory neurons in remission; blockade with intraventricular infliximab restored AMPA spontaneous excitatory postsynaptic current frequencies, completely recovered normal neuronal network activity patterns and alleviated elevated anxiety. This suggests a dysregulation of cortical networks attempting to achieve functional compensation by synaptic plasticity mechanisms, indicating a link between immune attack and early start of neurodegeneration.

Myelin loss is a severe pathological hallmark common to a number of neurodegenerative diseases, including multiple sclerosis (MS). Demyelination in the central nervous system appears in the form of lesions affecting both white and gray matter structures. The functional consequences of demyelination on neuronal network and brain function are not well understood. Current therapeutic strategies for ameliorating the course of such diseases usually focus on promoting remyelination, but the effectiveness of these approaches strongly depends on the timing in relation to the disease state. In this study, we sought to characterize the time course of sensory and behavioral alterations induced by de- and remyelination to establish a rational for the use of remyelination strategies. By taking advantage of animal models of general and focal demyelination, we tested the consequences of myelin loss on the functionality of the auditory thalamocortical system: a well-studied neuronal network consisting of both white and gray matter regions. We found that general demyelination was associated with a permanent loss of the tonotopic cortical organization in vivo, and the inability to induce tone-frequency-dependent conditioned behaviors, a status persisting after remyelination. Targeted, focal lysolecithin-induced lesions in the white matter fiber tract, but not in the gray matter regions of cortex, were fully reversible at the morphological, functional and behavioral level. These findings indicate that remyelination of white and gray matter lesions have a different functional regeneration potential, with the white matter being able to regain full functionality while cortical gray matter lesions suffer from permanently altered network function. Therefore therapeutic interventions aiming for remyelination have to consider both region- and time-dependent strategies.

This second paper on the Fabry-Perot cavity presents a semi-classical approach, which means that we consider the transition from wave optics to geometrical optics. The basic concepts are the periodic orbits and their stability. For the plano-concave Fabry-Perot cavity in the paraxial approximation, the derivation of the trace formula demonstrates that the spectrum is based only on the axial periodic orbit and its repetitions. Experiments with micro-lasers illustrate the relation to periodic orbits. The methods presented in this paper are not limited to laser cavities and can be applied to a large range of wave systems., Comment: Submitted to European Journal of Physics for the focus issue on advanced optics

Lymphocyte adhesion and subsequent trafficking across endothelial barriers are essential steps in various immune-mediated disorders of the CNS, including MS. The molecular mechanisms underlying these processes, however, are still unknown. Phospholipase D1 (PLD1), an enzyme that generates phosphatidic acid through hydrolysis of phosphatidylcholine and additionally yields choline as a product, has been described as regulator of the cell mobility. By using PLD1-deficient mice, we investigated the functional significance of PLD1 for lymphocyte adhesion and migration in vitro and after myelin oligodendrocyte glycoprotein (MOG)35-55 -induced EAE, a model of human MS. The lack of PLD1 reduced chemokine-mediated static adhesion of lymphocytes to the endothelial adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) in vitro, and was accompanied by a decreased migratory capacity in both blood brain barrier and cell migration models. Importantly, PLD1 is also relevant for the recruitment of immune cells into the CNS in vivo since disease severity after EAE was significantly attenuated in PLD1-deficient mice. Furthermore, PLD1 expression could be detected on lymphocytes in MS patients. Our findings suggest a critical function of PLD1-dependent intracellular signaling cascades in regulating lymphocyte trafficking during autoimmune CNS inflammation.

Background and Purpose— T lymphocytes have recently been identified as key mediators of tissue damage in ischemic stroke. The interaction between very late antigen-4 (VLA-4) and vascular adhesion molecule-1 is crucial for the transvascular egress of T lymphocytes, and inhibition of this interaction by specific antibodies is a powerful strategy to combat autoimmune neuroinflammation. However, whether pharmacological blocking of T-lymphocyte trafficking is also protective during brain ischemia is still unclear. We investigated the efficacy of a monoclonal antibody directed against VLA-4 in mouse models of ischemic stroke. Methods— Transient and permanent middle cerebral artery occlusion was induced in male C57Bl/6 mice. Animals treated with a monoclonal anti-CD49d antibody (300 μg) 24 hours before or 3 hours after the onset of cerebral ischemia and stroke outcome, including infarct size, functional status, and mortality, were assessed between day 1 and day 7. The numbers of immune cells invading the ischemic brain were determined by immunocytochemistry and flow cytometry. Results— Blocking of VLA-4 significantly reduced the invasion of T lymphocytes and neutrophils on day 5 after middle cerebral artery occlusion and inhibited the upregulation of vascular adhesion molecule-1. However, the anti-CD49d antibody failed to influence stroke outcome positively irrespective of the model or the time point investigated. Conclusions— Pharmacological inhibition of the VLA-4/vascular adhesion molecule-1 axis in experimental stroke was ineffective in our hands. Our results cast doubt on the effectiveness of anti-CD49d as a stroke treatment. Further translational studies should be performed before testing anti–VLA-4 antibodies in patients with stroke.

CD4(+) T cells expressing the immunotolerizing molecule HLA-G have been described as a unique human thymus-derived regulatory T (tTreg) cell subset involved in immunoregulation and parenchymal homeostasis during infectious and autoimmune inflammation. We compared properties and molecular characteristics of human CD4(+)HLA-G(+) with those of CD4(+)CD25(+)FoxP3-expressing tTreg cells using in vitro studies of T-cell receptor (TCR) signaling, single-cell electrophysiology, and functional in vivo studies. Both tTreg populations are characterized by alterations in proximal-signaling pathways on TCR stimulation and a hyperpolarization of the plasma membrane when compared to conventional CD4(+) T cells. However, both clearly differ in phenotype and pattern of secreted cytokines, which results in distinct mechanisms of suppression: While CD4(+)HLA-G(+) cells secrete high levels of inhibitory molecules (IL-10, soluble HLA-G, IL-35), CD4(+)CD25(+)FoxP3(+) cells express these molecules at significantly lower levels and seem to exert their function mainly in a contact-dependent manner via cyclic adenosine-monophosphate. Finally we demonstrate that human CD4(+)HLA-G(+) tTreg cells significantly ameliorated graft-versus-host disease in a humanized mouse model as a first proof of their in vivo relevance. Our data further characterize and establish CD4(+)HLA-G(+) cells as a potent human tTreg population that can modulate polyclonal adaptive immune responses in vivo and thus being a promising candidate for potential clinical applications in the future.

TWIK-related potassium channel-1 (TREK1, KCNK2) is the most extensively studied member of the two-pore domain potassium (K2P) channel family. Recent studies have already demonstrated a key role in the pathophysiology of depression, pain and neurodegenerative damage pointing towards an important role in a broad spectrum of CNS disorders. The mammalian blood–brain barrier (BBB) is a highly specialized structure and an integral part of the neurovascular unit, which controls the transition of cells and molecules into the CNS. While BBB dysregulation is common in neurologic diseases, the molecular mechanisms involved in this process remain largely unknown. Recently, we were able to describe a role of TREK1 in this context. TREK1 was downregulated in murine and human BBB upon inflammation. Blocking of TREK1 increased lymphocyte migration, while activation had the opposite effect. In TREK1-deficient (Trek1 −/− ) mice, brain endothelial cells displayed an inflammatory phenotype and leukocyte trafficking was facilitated, as demonstrated in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Here we summarize these findings and discuss the implications in diseases related to BBB dysfunction.

Background/objective Dalfampridine is the extended-release formulation of 4-aminopyridine and is approved for the symptomatic treatment of impaired mobility in patients with multiple sclerosis. Our aim was to examine the short- and long-term effects of treatment with dalfampridine on motoric and cognitive assessment parameters of multiple sclerosis (MS) patients over 9–12 months. Methods Fifty-two patients with MS with an EDSS between 4.0 and 7.0 and impaired mobility were evaluated for parameters of walking ability, MSFC, cognitive and motor fatigue and evoked potentials at treatment initiation with dalfampridine as well as 2 weeks and after 9–12 months later. Results Thirty out of fifty-two patients (~ 60%) were still on treatment after 9–12 months. Two weeks after treatment initiation, significant ameliorations could be found for T25FW, maximum walking distance as well as motoric and cognitive fatigue which still persisted after 9–12 months. In contrast significant effects for velocity were observed only after 2 weeks, for improvement in PASAT only after 9–12 months. A tendency for improvement of somatosensory evoked potentials was found in a subset of patients. Conclusion Dalfampridine shows positive short- and long-term effects on motoric and cognitive assessment parameters in an open-label observational study in a cohort of patients with MS.

Introduction Dysphagia is one of the most important and prognostically relevant complications of acute stroke. Pharyngeal Electrical Stimulation (PES) is a treatment device that enhances cortical reorganization for the restoration of swallowing function after cerebral injury. Furthermore, it was shown that PES leads to a temporary increase of Substance P (SP) level in saliva but not serum in healthy adults. The neuropeptide SP likely acts as a neurotransmitter in the pharyngeal mucosa and enhances the swallow and cough reflex. Post-stroke dysphagia may be related to reduced SP-levels. Here, we investigated the association of PES treatment in neurointensive care patients suffering from severe post-stroke dysphagia and salivary SP level, as well as a possible link between SP level and decannulation success after PES. Material and methods In this prospective single-center study, 23 tracheotomized stroke patients from our neurological intensive care unit were included. Due to severe and persisting dysphagia and according to the protocol for standardized endoscopic evaluation of tracheotomy decannulation in critically ill neurologic patients, participants could not be decannulated. Comorbidities that are known to likely cause dysphagia were not an exclusion criterion in contrast to other studies investigating on PES. 10 min of PES were applied on three consecutive days (= one treatment cycle). Three patients received multiple stimulation cycles. Saliva samples were collected prior to and directly after each treatment. To determine SP concentration, Enzyme-linked immunosorbent assay (ELISA) was performed. Results After the first treatment cycle 60% (n = 14) of all participants, respectively 73% (n = 7) of patients without comorbidities that likely cause dysphagia were decannulated. There was a close relation between increase of SP directly after the treatment and stimulation success (= decannulation). In 89% (n = 9) of patients without clinical improvement of dysphagia, SP levels remained stable or even decreased; 79% (n = 11) of successfully treated patients showed a post-stimulation increase of SP. Applying logistic regression analysis, increased SP level showed to be independently predictive of improved swallowing function after PES (p Conclusion The increase of salivary SP level following PES may indicate treatment success and SP therefore possibly acts as a biomarker of an improved swallowing function following PES.

In the version of this article initially published, Inigo Ruiz de Azua’s name was miscategorized. His given name is Inigo and his surname is Ruiz de Azua. This has been corrected in the HTML coding.

Sir, We present a PM patient refractory to standard therapy, who showed effective clinical remission after a single treatment cycle with alemtuzumab for >3 years of follow-up. This is, to our knowledge, the first report of long-term efficacy of alemtuzumab in the treatment of PM. This Caucasian male patient was born in 1957. PM manifested at the age of 52 with progressive symmetrical muscle weakness and myalgia of proximal limb musculature starting in 2009. At first consultation the patient showed a positive Gower’s sign and maximum walking distance was reduced to 500 m. The diagnosis of PM was established in May 2009 and was based on typical clinical presentation, elevated creatine kinase (CK) levels (3237 U/l), myopathic changes in the electromyogram and muscle biopsy showing endomysial CD8+ T cell infiltration (Fig. 1A). Ro-52 autoantibodies were positive; other myositis-specific autoantibodies (anti-Jo-1, ant-Mi-2 or anti-SRP) could not be detected. Therapy with oral prednisolone (80 mg/day) in combination with azathioprine (start dose 50 mg/day, end dose 225 mg/day) was initiated, significantly ameliorating muscle weakness and myalgia. Azathioprine therapy had to be withdrawn in August 2009 due to extremely elevated liver enzymes. Under subsequent therapy with ciclosporin (200 mg/day), it was not possible to further taper the prednisolone dose ( 200 cells/µl. Approximately 12 weeks later the patient noticed an improvement in muscle strength, which was confirmed on physical examination and was slightly preceded by a continuous decrease in CK level. In addition, constant improvement of walking distance and prednisolone tapering to 7.5 mg/day was achieved. Until the beginning of July 2014 the disease course remained stable, when the patient reported progressive myalgia and deterioration of walking distance. No severe adverse events have been observed so far. We decided to administer another cycle of alemtuzumab. Fig. 1 Histology, clinical disease course and creatine kinase levels in a patient with PM Current therapeutic options of PM consist of corticosteroids, IVIG and immunosuppressants such as AZA or MTX [1]. These therapies are mainly non-specific, have various adverse effects and often show limited efficacy. Monoclonal antibodies are emerging as new therapeutic strategies for autoimmune myopathies, however, to date only limited evidence exists for their use [2]. Alemtuzumab is a monoclonal anti-CD52 antibody leading to rapid, long-lasting depletion of immune cells, but not of haematopoietic stem cells. After depletion, the reconstitution of immune cells follows a certain pattern, with T cells being the last to recover after years [3]. Here, anti-CD52 treatment was initiated under the rationale that CD8+ T cells are critically involved in the progressive destruction of muscle cells in PM and are found clonally expanded in the muscle of PM patients [4]. In our standard therapy–refractory patient, we observed a stable disease course with constant improvement of muscle strength lasting for ∼3 years, adding to previous reports providing short-term observations of alemtuzumab efficacy in PM [5, 6]. It should be kept in mind, however, that interpretation of our data is limited by previous immunosuppressive medication. The high incidence of secondary autoimmunity (∼30%) in alemtuzumab-treated patients should always be considered in therapeutic decisions [7]. Thorough surveillance is needed to prevent serious adverse events after alemtuzumab infusion. In conclusion, we present the first long-term follow-up case of adult PM effectively treated with alemtuzumab. Therefore alemtuzumab might be a new, promising alternative in long-term PM therapy. However, randomized and controlled trials are required to draw definite conclusions.

Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein–kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders., Factor XII initiates the intrinsic blood coagulation cascade and the kinin system. Here the authors show that Factor XII is elevated in the blood of multiple sclerosis patients, activates dendritic cells via CD87 and cAMP, and its blockade inhibits immunopathology in a mouse model of the disease.

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Relapsing-remitting multiple sclerosis (MS)(2) is characterized by phases of acute neuroinflammation followed by spontaneous remission. Termination of inflammation is accompanied by an influx of regulatory T cells (Tregs).(3) The molecular mechanisms responsible for directing Tregs into the inflamed CNS tissue, however, are incompletely understood. In an MS mouse model we show that the stress kinase general control non-derepressible 2 (GCN2),(4) expressed in T cells, contributes to the resolution of autoimmune neuroinflammation. Failure to recover from acute inflammation was associated with reduced frequencies of CNS-infiltrating Tregs. GCN2 deficient Tregs displayed impaired migration to a CCL2 gradient. These data suggest an important contribution of the T cell stress response to the resolution of autoimmune neuroinflammation.

In multiple sclerosis (MS), the immune cell attack leads to axonal injury as a major cause for neurological disability. Here, we report a novel role of the cell adhesion molecule L1 in the crosstalk between the immune and nervous systems. L1 was found to be expressed by CNS axons of MS patients and human T cells. In MOG35–55-induced murine experimental neuroinflammation, CD4+ T cells were associated with degenerating axons in the spinal cord, both expressing L1. However, neuronal L1 expression in the spinal cord was reduced, while levels of the transcriptional repressor REST (RE1-Silencing Transcription Factor) were up-regulated. In PLP139–151-induced relapsing–remitting neuroinflammation, L1 expression was low at the peak stage of disease, reached almost normal levels in the remission stage, but decreased again during disease relapse indicating adaptive expression regulation of L1. In vitro, activated CD4+ T cells caused contact-dependent down-regulation of L1, up-regulation of its repressor REST and axonal injury in co-cultured neurons. T cell adhesion to neurons and axonal injury were prevented by an antibody blocking L1 suggesting that down-regulation of L1 ameliorates neuroinflammation. In support of this hypothesis, antibody-mediated blocking of L1 in C57BL/6 mice as well as neuron-specific depletion of L1 in synapsinCre × L1fl/fl mice reduces disease severity and axonal pathology despite unchanged immune cell infiltration of the CNS. Our data suggest that down-regulation of neuronal L1 expression is an adaptive process of neuronal self-defense in response to pro-inflammatory T cells, thereby alleviating immune-mediated axonal injury.

We study experimentally the spatio-temporal dynamics of broad-area semiconductor lasers. Fast random and periodic oscillations of the laser emission are observed. Their dependence on the pump strength and cavity size are investigated.