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Abstract Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by motor neuron loss in the brain and spinal cord. Mutations in Cu-Zn superoxide dismutase (SOD1) are the first identified genetic mutations that are causative for familial ALS. Soluble SOD1 oligomers are considered the most toxic species and play a key role in the pathologic process of ALS. Here we present a therapeutic strategy for ALS with an oligomer-specific antibody (W20) targeting toxic SOD1 oligomers. Our study showed that W20 significantly improved motor neuron survival and motor performance in SOD1-G93A mouse model of ALS when administrated even at low dose within short time. Further investigation demonstrated that the beneficial effects of W20 resulted from the reduction of SOD1 oligomer levels and the inhibition of gliosis and neuroinflammation in the spinal cords and brain stems of ALS model mice. These findings for the first time suggest that an oligomer-specific antibody has promising therapeutic potential for ALS and open a new way for ALS treatment. Highlights • Antibody W20 improved motor neuron survival and motor performance in SOD1-G93A mice. • Antibody W20 reduced SOD1 aggregates and oligomer levels in SOD1-G93A mice. • Antibody W20 inhibited gliosis and neuroinflammation in SOD1-G93A mice. [ABSTRACT FROM AUTHOR]

Monocytes are amongst the first cells recruited into the brain after traumatic brain injury (TBI). We have shown monocyte depletion 24 hours prior to TBI reduces brain edema, decreases neutrophil infiltration and improves behavioral outcomes. Additionally, both lesion and ventricle size correlate with poor neurologic outcome after TBI. Therefore, we aimed to determine the association between monocyte infiltration, lesion size, and ventricle volume. We hypothesized that monocyte depletion would attenuate lesion size, decrease ventricle enlargement, and preserve white matter in mice after TBI. C57BL/6 mice underwent pan monocyte depletion via intravenous injection of liposome-encapsulated clodronate. Control mice were injected with liposome-encapsulated PBS. TBI was induced via an open-head, controlled cortical impact. Mice were imaged using magnetic resonance imaging (MRI) at 1, 7, and 14 days post-injury to evaluate progression of lesion and to detect morphological changes associated with injury (3D T1-weighted MRI) including regional alterations in white matter patterns (multi-direction diffusion MRI). Lesion size and ventricle volume were measured using semi-automatic segmentation and active contour methods with the software program ITK-SNAP. Data was analyzed with the statistical software program PRISM. No significant effect of monocyte depletion on lesion size was detected using MRI following TBI (p = 0.4). However, progressive ventricle enlargement following TBI was observed to be attenuated in the monocyte-depleted cohort (5.3 ± 0.9mm3) as compared to the sham-depleted cohort (13.2 ± 3.1mm3; p = 0.02). Global white matter integrity and regional patterns were evaluated and quantified for each mouse after extracting fractional anisotropy maps from the multi-direction diffusion-MRI data using Siemens Syngo DTI analysis package. Fractional anisotropy (FA) values were preserved in the monocyte-depleted cohort (123.0 ± 4.4mm3) as compared to sham-depleted mice (94.9 ± 4.6mm3; p = 0.025) by 14 days post-TBI. All TBI mice exhibited FA values lower than those from a representative naïve control group with intact white matter tracts and FA~200 mm3). The MRI derived assessment of injury progression suggests that monocyte depletion at the time of injury may be a novel therapeutic strategy in the treatment of TBI. Furthermore, non-invasive longitudinal imaging allows for the evaluation of both TBI progression as well as therapeutic response over the course of injury. [ABSTRACT FROM AUTHOR]

Background Cytomegalovirus (CMV) has been linked to higher risk of cardiovascular disease and mortality. We aimed to determine if CMV is associated with neurocognitive performance in adults infected with human immunodeficiency virus (HIV). Methods In this cross-sectional analysis, anti-CMV immunoglobulin G (IgG) concentrations in blood and CMV DNA copies in blood and cerebrospinal fluid (CSF) were measured in stored specimens of 80 HIV-infected adults who were previously assessed with a comprehensive neurocognitive test battery. Thirty-eight were taking suppressive antiretroviral therapy (ART) and 42 were not taking ART. A panel of 7 soluble biomarkers was measured by immunoassay in CSF. Results Anti-CMV IgG concentrations ranged from 5.2 to 46.1 IU/mL. CMV DNA was detected in 7 (8.8%) plasma specimens but in no CSF specimens. Higher anti-CMV IgG levels were associated with older age (P =.0017), lower nadir CD4+ T-cell count (P <.001), AIDS (P <.001), and higher soluble CD163 (P =.009). Higher anti-CMV IgG levels trended toward an association with worse neurocognitive performance overall (P =.059). This correlation was only present in those taking suppressive ART (P =.0049). Worse neurocognitive performance remained associated with higher anti-CMV IgG levels after accounting for other covariates in multivariate models (model P =.0038). Detectable plasma CMV DNA was associated with AIDS (P =.05) but not with neurocognitive performance. Conclusions CMV may influence neurocognitive performance in HIV-infected adults taking suppressive ART. Future clinical trials of anti-CMV therapy should help to determine whether the observed relationships are causal. [ABSTRACT FROM AUTHOR]

Interleukin-33 (IL-33) is an IL-1 family member, which exhibits both pro- and anti-inflammatory properties solely based on the type of the disease itself. Generally, IL-33 is expressed by both endothelial and epithelial cells and mediates its function based on the interaction with various receptors, mainly with ST2 variants. IL-33 is a potent inducer for the Th2 immune response which includes defence mechanism in brain diseases. Thus, in this paper, we review the biological features of IL-33 and the critical roles of IL-33/ST2 pathway in selected neurological disorders including Alzheimer’s disease, multiple sclerosis, and malaria infection to discuss the involvement of IL-33/ST2 pathway during these brain diseases and its potential as future immunotherapeutic agents or for intervention purposes. [ABSTRACT FROM AUTHOR]

Abstract: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an intractable inflammatory disease affecting peripheral nerves. The etiology of CIDP remains to be established, but it is regarded as a mixture of heterogeneous conditions presenting a variety of clinical and electrophysiological manifestations. In recent years, autoantibodies against paranodal cell adhesion molecules, such as neurofascin 155 (NF155), contactin 1 and contactin‐associated protein 1, have been detected in subsets of CIDP patients. The clinical characteristics of anti‐NF155 antibody‐positive CIDP have been delineated, and include a younger onset age, higher frequency of distal muscle weakness, sensory ataxia and tremor, higher cerebrospinal fluid protein levels, more conspicuous demyelination on nerve conduction studies, and nerve root hypertrophy on magnetic resonance neurography, when compared with anti‐NF155 antibody‐negative CIDP patients. Predominant elevation of immunoglobulin G4 subclass is also a characteristic of this disease. Sural nerve biopsy specimens of anti‐NF155 antibody‐positive CIDP patients show axo‐glial detachment in paranodes without inflammatory cell infiltrates or onion bulb formation. While intravenous immunoglobulin is not as effective as expected against anti‐NF155 antibody‐positive CIDP patients, other immunotherapies, such as corticosteroids, plasmapheresis and B‐cell depletion therapy, seem to be effective. Early diagnosis and treatment is important for preventing secondary axonal degeneration. The present review summarizes the emerging details of anti‐NF155 antibody‐related neuropathy. [ABSTRACT FROM AUTHOR]

Abstract: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a form of chronic neuropathy characterized by demyelination due to immune‐mediated processes. In addition to the typical form of CIDP, several atypical forms, such as multifocal acquired demyelinating sensory and motor, distal acquired demyelinating symmetric (DADS), pure sensory, pure motor, and focal types, have also been included as subtypes of CIDP, indicating the heterogeneity of pathogenesis. The degradation of the myelin sheath by macrophages has been reported in CIDP and is considered to play an important role in the pathogenesis of this disease. By contrast, recent studies have suggested the association of autoantibodies directed against paranodal junction proteins, such as anti‐neurofascin 155 and anti‐contactin 1 antibodies, with subpopulations of CIDP patients. Although patients with these antibodies tend to manifest typical CIDP or DADS symptoms, such patients show unique clinical characteristics, such as a younger age at onset, sensory ataxia, tremor and poor response to intravenous immunoglobulin treatment. Classical macrophage‐induced demyelination is not observed in patients with these antibodies, whereas paranodal dissection resulting from attachment of immunoglobulin G4 antibodies to paranodal junctions plays a pivotal role in the mechanisms of neuropathy. Therefore, two distinct mechanisms exist that lead to nerve conduction abnormalities from a pathological viewpoint in CIDP. Advances in the search for autoantibodies in CIDP might make it necessary to reconsider the classification of this disease from the viewpoint of antibody recognition sites. [ABSTRACT FROM AUTHOR]

Introduction: Immune-mediated peripheral neuropathy is the term applied to a spectrum of peripheral nerve disorders where immune dysregulation plays a role. Therefore, they are treatable. We analyzed the cases seen in the past 3 years by us and evaluated the clinical, laboratory, and outcome parameters in these patients. Patients and Methods: Consecutive patients seen by the authors and diagnosed as immune-mediated neuropathy were analyzed for etiology, pathology, and outcome assessed. Results: A total of sixty patients, 31 acute and 29 chronic neuropathies, were identified. Their subtypes treatment and outcome assessed. Males were significantly more in both acute and chronic cases. Miller Fisher 4, AMAN 1, paraplegic type 1, motor dominant type 19, Sensory-motor 1, MADSAM 3, Bifacial 2. Nonsystemic vasculitis was seen in 16 out of 29 chronic neuropathy and HIV, POEMS, and diabetes mellitus one each. Discussion: There is a spectrum of immune-mediated neuropathy which varies in clinical course, response to treatment, etc., Small percentage of uncommon cases are seen. In this group, mortality was nil and morbidity was minimal. Conclusion: Immune-mediated neuropathies are treatable and hence should be diagnosed early for good quality outcome. [ABSTRACT FROM AUTHOR]

Background: Analysis of cerebrospinal fluid (CSF) is a frequently used diagnostic tool in a variety of neurological diseases. Recent studies suggested that investigating membrane particles enriched with the stem cell marker CD133 may offer new avenues for studying neurological disease. In this study, we evaluated the amount of membrane particle-associated CD133 in human CSF in neuroinflammatory and degenerative diseases. Methods: We compared the amount of membrane particle-associated CD133 in CSF samples collected from 45 patients with normal pressure hydrocephalus, parkinsonism, dementia, and cognitive impairment, chronic inflammatory diseases and 10 healthy adult individuals as controls. After ultracentrifugation of CSF, gel electrophoresis and immunoblotting using anti-CD133 monoclonal antibody 80B258 were performed. Antigen-antibody complexes were detected using chemiluminescence. Results: The amount of membrane particle-associated CD133 was significantly increased in patients with normal pressure hydrocephalus (p < 0.001), parkinsonism (p = 0.011) as well as in patients with chronic inflammatory disease (p = 0.008). Analysis of CSF of patients with dementia and cognitive impairment revealed no significant change compared with healthy individuals. Furthermore, subgroup analysis of patients with chronic inflammatory diseases demonstrated significantly elevated levels in individuals with relapsing-remitting multiple sclerosis (p = 0.023) and secondary progressive multiple sclerosis (SPMS; p = 0.010). Conclusion: Collectively, our study revealed elevated levels of membrane particle-associated CD133 in patients with normal pressure hydrocephalus, parkinsonism as well as relapsing-remitting and SPMS. Membrane glycoprotein CD133 may be of clinical value for several neurological diseases. [ABSTRACT FROM AUTHOR]

Bullous pemphigoid ( BP) is the most common autoimmune blistering disease and is linked to IgG recognition of 2 hemidesmosomal antigens, that is, BP230 ( BP antigen 1) and BP180 ( BP antigen 2, collagen XVII). The association of BP with other systemic diseases, particularly neurocognitive diseases, provides a potential clue in the underlying pathogenesis of BP. The role of HLA-DQB1*03:01 binding to the immunogenic portion of BP180 provides a potential mechanism by which exposure to neuronal collagen BP180 may lead to cutaneous disease. In our proposed multi-hit hypothesis, patients with underlying neuronal disease are exposed to previously sequestered self-antigen, most importantly BP180. Patients with the HLA-DQB1*03:01 allele show an increased T-cell avidity to several epitopes of BP180, particularly the BP180-NC16a domain. Thus, they have a genetic susceptibility to developing BP upon exposure to the target antigen. In a patient with dysregulation of Th1/Th2 balance, anergy is lost and T-cells are subsequently primed resulting in the development of functional autoimmunity against the BP180-NC16a domain leading to clinically overt disease. [ABSTRACT FROM AUTHOR]

We have focused on the epidemiology and immunobiology of Zika virus (ZIKV) infection and factors associated with the development of Guillain-Barré syndrome (GBS) and other neurological syndromes in Cúcuta, the capital of North Santander department, Colombia. Data of patients with ZIKV disease reported to the national population-based surveillance system were used to calculate the basic reproduction number (R 0 ) and the attack rates (ARs) as well as to develop epidemiological maps. Patients with neurological syndromes were contacted and their diagnoses were confirmed. A case-control study in which 29 patients with GBS associated with ZIKV compared with 74-matched control patients with ZIKV infection alone was undertaken. Antibodies against arboviruses and other infections that may trigger GBS were evaluated. The estimated value of R 0 ranged between 2.68 (95% CI 2.54–2.67) to 4.57 (95% CI 4.18–5.01). The sex-specific ARs were 1306 per 100,000 females, and 552 per 100,000 males. A non-linear interaction between age and gender on the ARs was observed. The incidence of GBS in Cúcuta increased 4.41 times secondary to ZIKV infection. The lag time between ZIKV infection and neurological symptoms was 7 days (interquartile range 2–14.5). Patients with GBS appeared to represent a lower socioeconomic status and were living near to environmentally contaminated areas. All GBS patients were positive for IgG antibodies against both ZIKV and Dengue virus, and 69% were positive for Chikungunya virus. Noteworthy, GBS was associated with a previous infection with M. pneumoniae (OR: 3.95; 95% CI 1.44–13.01; p = 0.006). No differences in antibody levels against C. jejuni, Epstein-Barr virus and cytomegalovirus were observed. High rates of cranial nerves involvement and dysautonomia were present in 82% and 75.9%, respectively. Intensive care unit (ICU) admission was necessary in 69% of the GBS patients. Most of the patients disclosed a high disability condition (Hughes grade 4). Dysautonomia was the main risk factor of poor GBS prognosis (i.e., ICU admission and disability). Thirteen patients were diagnosed with other neurological syndromes different to GBS (6 with transverse myelitis, 3 with encephalitis, 3 with peripheral facial palsy and one with thoraco-lumbosacral myelopathy). Our data confirm an increased transmission of ZIKV in Cúcuta, and provide support to the view that severe neurological syndromes are related to ZIKV disease. The complex ways by which previous infections and socioeconomic status interact to increase the risk of GBS in people infected by ZIKV should be further investigated. [ABSTRACT FROM AUTHOR]

Immune cells display a high degree of phenotypic plasticity, which may facilitate their participation in both the progression and resolution of injury-induced inflammation. The purpose of this study was to investigate the temporal expression of genes associated with classical and alternative polarization phenotypes described for macrophages and to identify related cell populations in the brain following neonatal hypoxia-ischemia (HI). HI was induced in 9-day old mice and brain tissue was collected up to 7 days post-insult to investigate expression of genes associated with macrophage activation. Using cell-markers, CD86 (classic activation) and CD206 (alternative activation), we assessed temporal changes of CD11b+ cell populations in the brain and studied the protein expression of the immunomodulatory factor galectin-3 in these cells. HI induced a rapid regulation (6 h) of genes associated with both classical and alternative polarization phenotypes in the injured hemisphere. FACS analysis showed a marked increase in the number of CD11b+CD86+ cells at 24 h after HI (+3667%), which was coupled with a relative suppression of CD11b+CD206+ cells and cells that did not express neither CD86 nor CD206. The CD11b+CD206+ population was mixed with some cells also expressing CD86. Confocal microscopy confirmed that a subset of cells expressed both CD86 and CD206, particularly in injured gray and white matter. Protein concentration of galectin-3 was markedly increased mainly in the cell population lacking CD86 or CD206 in the injured hemisphere. These cells were predominantly resident microglia as very few galectin-3 positive cells co-localized with infiltrating myeloid cells in Lys-EGFP-ki mice after HI. In summary, HI was characterized by an early mixed gene response, but with a large expansion of mainly the CD86 positive population during the first day. However, the injured hemisphere also contained a subset of cells expressing both CD86 and CD206 and a large population that expressed neither activation marker CD86 nor CD206. Interestingly, these cells expressed the highest levels of galectin-3 and were found to be predominantly resident microglia. Galectin-3 is a protein involved in chemotaxis and macrophage polarization suggesting a novel role in cell infiltration and immunomodulation for this cell population after neonatal injury. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is a chronic humoral immunity–mediated autoimmune disorder of the neuromuscular junction characterized by muscle weakness. Follicular helper T (Tfh) cells may be the key Th cell subset that promotes MG development, as their major function is helping B cell activation and Ab production. Aberrance of thymus-derived Tfh cells might be implicated in autoimmune diseases including MG; just how circulating Tfh cells, especially those from patients with a normal thymus, contribute to MG pathogenesis remains to be uncovered. In this article, we characterize a population of circulating CD4+CXCR5+PD-1+ Tfh cells in ocular and generalized MG patients without thymic abnormalities and demonstrate that the circulating Tfh cells are significantly enriched in generalized MG patients but not in ocular MG patients compared with healthy subjects, whereas a proportion of follicular regulatory T cells decreased in MG patients. In addition, the frequency of plasma cells and B cells was higher and the serum levels of IL-6/IL-21 were also elevated in these MG patients. The activated Tfh1 and Tfh17 in Tfh cells are the major source for IL-21 production in MG patients. A strong correlation between Tfh cells and the plasma cell frequency and anti–acetylcholine receptor Ab titers was evident in generalized MG patients. In particular, we found that Tfh cells derived from MG patients promoted B cells to produce Abs in an IL-21 signaling–dependent manner. Collectively, our results suggest that circulating Tfh cells may act on autoreactive B cells and thus contribute to the development of MG in patients without thymic abnormalities. [ABSTRACT FROM AUTHOR]

Copyright of Neurosciences is the property of Neurosciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Evolution has yielded multiple complex and complementary mechanisms to detect environmental danger and protect tissues from damage. The nervous system rapidly processes information and coordinates complex defense behaviors, and the immune system eliminates diverse threats by virtue of mobile, specialized cell populations. The two systems are tightly integrated, cooperating in local and systemic reflexes that restore homeostasis in response to tissue injury and infection. They further share a broad common language of cytokines, growth factors, and neuropeptides that enables bidirectional communication. However, this reciprocal cross talk permits amplification of maladaptive feedforward inflammatory loops that contribute to the development of allergy, autoimmunity, itch, and pain. Appreciating the immune and nervous systems as a holistic, coordinated defense system provides both new insights into inflammation and exciting opportunities for managing acute and chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

Several neurological disorders have been described in patients with autoimmunity associated with GAD antibodies. Among these disorders, nystagmus and oculomotor dysfunction are increasingly recognized, although they have been rarely reported isolated or as the main manifestation of anti-GAD autoimmunity. Moreover, therapeutic approaches for such patients are unclear. Here we present a 44-year-old man with disabling oscillopsia secondary to downbeat nystagmus, abnormal saccades, ocular pursuit and optokinetic nystagmus, as well as mild gait ataxia and cerebellar atrophy associated with high serum GAD antibodies with intrathecal secretion of such antibodies. The patient did not have clinical benefit with plasma exchange, but had a robust symptomatic improvement with cyclophosphamide. We discuss the possible pathogenic role of GAD antibodies in nystagmus and the role of immunotherapy in these patients. [ABSTRACT FROM AUTHOR]

Bilateral thalamic infarction involving the artery of Percheron (AOP) can cause diagnostic difficulties due to the varying clinical presentations. AOP infarcts presented with isolated memory impairment are not common and the factors affecting the persistence of memory disorders are still unknown. A 41-year-old male patient was hospitalized with acute unconsciousness. MRI disclosed bilateral paramedian thalamic infarction The patient had isolated memory deficit and his anterograde amnesia continued without any change in the past decade. More cases might answer the questions concerning the intra- and extra-thalamic structures responsible for the amnesic syndrome and the factors affecting the persistence of the symptoms. [ABSTRACT FROM AUTHOR]

Background: Fetal alcohol exposure is a leading cause of preventable birth defects, yet drinking during pregnancy remains prevalent worldwide. Studies suggest that activation of the neuroimmune system plays a role in the effects of alcohol exposure during the rodent equivalent to the third trimester of human pregnancy (i.e., first week of neonatal life), particularly by contributing to neuronal loss. Here, we performed a comprehensive study investigating differences in the neuroimmune response in the cerebellum and hippocampus, which are important targets of third trimester-equivalent alcohol exposure. Methods: To model heavy, binge-like alcohol exposure during this period, we exposed rats to alcohol vapor inhalation during postnatal days (P)3-5 (blood alcohol concentration = 0.5 g/dL). The cerebellar vermis and hippocampus of rat pups were analyzed for signs of glial cell activation and neuronal loss by immunohistochemistry at different developmental stages. Cytokine production was measured by reverse transcriptase polymerase chain reaction during peak blood alcohol concentration and withdrawal periods. Additionally, adolescent offspring were assessed for alterations in gait and spatial memory. Results: We found that this paradigm causes Purkinje cell degeneration in the cerebellar vermis at P6 and P45; however, no signs of neuronal loss were found in the hippocampus. Significant increases in pro-inflammatory cytokines were observed in both brain regions during alcohol withdrawal periods. Although astrocyte activation occurred in both the hippocampus and cerebellar vermis, microglial activation was observed primarily in the latter. Conclusions: These findings suggest that heavy, binge-like third trimester-equivalent alcohol exposure has time- and brain region-dependent effects on cytokine levels, morphological activation of microglia and astrocytes, and neuronal survival. [ABSTRACT FROM AUTHOR]

Intelligent behavior demands not only multiple forms of spatial representation, but also coordination among the brain regions mediating those representations. Retrosplenial cortex is densely interconnected with the majority of cortical and subcortical brain structures that register an animal's position in multiple internal and external spatial frames of reference. This unique anatomy suggests that it functions to integrate distinct forms of spatial information and provides an interface for transformations between them. Evidence for this was found in rats traversing two different routes placed at different environmental locations. Retrosplenial ensembles robustly encoded conjunctions of progress through the current route, position in the larger environment and the left versus right turning behavior of the animal. Thus, the retrosplenial cortex has the requisite dynamics to serve as an intermediary between brain regions generating different forms of spatial mapping, a result that is consistent with navigational and episodic memory impairments following damage to this region in humans. [ABSTRACT FROM AUTHOR]

We present a 10-year-old boy with a predominantly motor multifocal neuropathy with demyelinating and axonal changes with sensory involvement, affecting only one upper extremity. Laboratory studies revealed an elevated titer of immunoglobulin M (IgM) antibodies against the NS6S antigen. He responded to treatment with high dose intravenous immunoglobulins. Focal or multifocal immune-mediated neuropathies are not common in children and may be underdiagnosed. [ABSTRACT FROM PUBLISHER]

Summary The discovery of hypocretins (orexins) and their causal implication in narcolepsy is the most important advance in sleep research and sleep medicine since the discovery of rapid eye movement sleep. Narcolepsy with cataplexy is caused by hypocretin deficiency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. Ablation of hypocretin or hypocretin receptors also leads to narcolepsy phenotypes in animal models. Although the exact mechanism of hypocretin deficiency is unknown, evidence from the past 20 years strongly favours an immune-mediated or autoimmune attack, targeting specifically hypocretin neurons in genetically predisposed individuals. These neurons form an extensive network of projections throughout the brain and show activity linked to motivational behaviours. The hypothesis that a targeted immune-mediated or autoimmune attack causes the specific degeneration of hypocretin neurons arose mainly through the discovery of genetic associations, first with the HLA-DQB1*06:02 allele and then with the T-cell receptor α locus. Guided by these genetic findings and now awaiting experimental testing are models of the possible immune mechanisms by which a specific and localised brain cell population could become targeted by T-cell subsets. Great hopes for the identification of new targets for therapeutic intervention in narcolepsy also reside in the development of patient-derived induced pluripotent stem cell systems. [ABSTRACT FROM AUTHOR]

Abstract: Neurodegenerative diseases affect a considerable percentage of the elderly population. New therapeutic approaches are warranted, aiming to at least delay and possibly reverse disease progression. Strategies to elaborate such approaches require knowledge of specific immune system involvement in disease pathogenesis. In this review, innate and adaptive immunological aspects of neurodegenerative disorders, in particular Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS), are discussed. Initiating disease factors, as well as common mechanistic pathways, are detailed and potential immunological therapeutic targets are identified. [Copyright &y& Elsevier]

Bacterial colonisation of the gut plays a major role in postnatal development and maturation of key systems that have the capacity to influence central nervous system (CNS) programming and signaling, including the immune and endocrine systems. Individually, these systems have been implicated in the neuropathology of many CNS disorders and collectively they form an important bidirectional pathway of communication between the microbiota and the brain in health and disease. Regulation of the microbiome-brain-gut axis is essential for maintaining homeostasis, including that of the CNS. Moreover, there is now expanding evidence for the view that commensal organisms within the gut play a role in early programming and later responsivity of the stress system. Research has focused on how the microbiota communicates with the CNS and thereby influences brain function. The routes of this communication are not fully elucidated but include neural, humoral, immune and metabolic pathways. This view is underpinned by studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic agents or antibiotics which indicate a role for the gut microbiota in the regulation of mood, cognition, pain and obesity. Thus, the concept of a microbiome-brain-gut axis is emerging which suggests that modulation of the gut microflora may be a tractable strategy for developing novel therapeutics for complex stress-related CNS disorders where there is a huge unmet medical need. [ABSTRACT FROM AUTHOR]

Highlights: [•] Glycolipids form heteromeric complexes through lateral interaction in lipid membranes. [•] A class of antibodies exist that only bind glycolipids when in heteromeric complex. [•] Other antibody epitopes may become cryptic when complexed in heteromers. [•] Antibodies to glycolipid complexes are associated with peripheral neuropathies. [•] Combinatorial glycoarrays can be used to detect anti-complex antibodies. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene, impairs information processing in the striatum, which, as part of the basal ganglia, modulates motor output. Growing evidence suggests that huntingtin interacting protein 14 (HIP14) contributes to HD neuropathology. Here, we recorded local field potentials (LFPs) in the striatum as HIP14 knockout mice and wild-type controls freely navigated a plus-shaped maze. Upon entering the choice point of the maze, HIP14 knockouts tend to continue in a straight line, turning left or right significantly less often than wild-types, a sign of motor inflexibility that also occurs in HD mice. Striatal LFP activity anticipates this difference. In wild-types, the power spectral density pattern associated with entry into the choice point differs significantly from the pattern immediately before entry, especially at low frequencies (=13 Hz), whereas HIP14 knockouts show no change in LFP activity as they enter the choice point. The lack of change in striatal activity may explain the turning deficit in the plus maze. Our results suggest that HIP14 plays a critical role in the aberrant behavioral modulation of striatal neuronal activity underlying motor inflexibility, including the motor signs of HD. [ABSTRACT FROM AUTHOR]

Abstract: Background: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological inflammatory disease associated with a predominant infiltration of CD4+ T lymphocytes, which are the main subset of HTLV-1-infected cells. It has been demonstrated that in cell line the viral Tax protein transcriptionnally regulate expression of osteopontin, an inflammatory cytokine associated with Th17-related pathologies. Objectives: The aim of the study was to explore osteopontin expression in HTLV-1 asymptomatic carriers and in HAM/TSP patients and consequences on IL17 expression. Study design: We quantified Tax, osteopontin, RORγ, IL17 and IL22 mRNA expressions in cells from 10 HAM/TSP patients, 6 asymptomatic HTLV-1 carriers (ASY) and 4 HTLV-1-negative healthy donors during ex vivo culture. Results: We observed that the expression of osteopontin was higher in HAM/TSP patients and correlated with Tax expression levels. Positive regulation of RORγ, IL17 and IL22 were also observed during cell culture. Conclusions: Our results propose a new mechanism which could contribute to HAM/TSP pathogenesis. [Copyright &y& Elsevier]

Copyright of Neurophysiologie-Labor is the property of Elsevier GmbH, Urban & Fischer Verlag and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: Epilepsy is a common neurological disorder characterized by an initial injury due to stroke, traumatic brain injury, brain infection, or febrile seizures causing status epilepticus (SE). This phenomenon precedes recurrent (secondary) seizures, the latent period (period without seizures) and downstream appearance of spontaneous recurrent seizures (SRS). Epilepsy inducers include the organophosphorous (OP) compounds modified as chemical warfare nerve agents, such as soman. SE induced by soman is a result of cholinergic system hyperactivity caused by the irreversible inhibition of acetylcholinesterase, and the subsequent increase in the amount of the neurotransmitter acetylcholine at central and peripheral sites. SE leads to profound, permanent, complex and widespread brain damage and associated cognitive and behavioral deficits, accompanied by impaired neurogenesis. Several anticonvulsant and neuroprotective strategies have been studied in order to avoid the epileptogenesis which occurs after SE caused by soman exposure. In recent studies, we showed that SRS occur post-soman exposure and neuropathology can be reduced with diazepam (DZP) and valproic acid (VPA) when administered in combination treatment. These effects are accompanied by neurogenesis seen 15 days post-exposure in the hippocampal dentate gyrus (DG). This review discusses several findings about epilepsy induced by soman exposure such as behavioral changes, EEG anomalies, neuropathology, neuroinflammation, neurogenesis, possible circuitry changes and current strategies for treatment. The soman seizure model is an important model of temporal lobe epilepsy (TLE) and comparable in certain respects with well studied models in the literature such as pilocarpine and kainic acid. All these models together allow for a greater understanding of the different mechanisms of seizure induction, propagation and options for treatment. These studies are very necessary for current military and civilian treatment regimens, against OP nerve agent exposure, which fail to prevent SE resulting in severe neuropathology and epilepsy. [Copyright &y& Elsevier]

Neural-specific autoantibodies have been documented and their diagnostic utility validated in diseases affecting the neuraxis from cerebral cortex to the somatic, autonomic, and enteric nervous system and skeletal muscle. These neurological disorders occur both idiopathically and in a paraneoplastic context. Molecular identification of the antigens has expedited development of confirmatory and high-throughput tests for serum and cerebrospinal fluid, which permit early diagnosis and reveal the underlying molecular pathogenic mechanisms. The autoantibodies are classifiable on the basis of antigen location: intracellular (nuclear or cytoplasmic) or plasma membrane. Immunohistopathological studies of patients' biopsied and autopsied tissues suggest that effector T cells mediate the autoimmune neurological disorders for which defining autoantibodies recognize intracellular antigens. Antigens within intact cells are inaccessible to circulating antibody, and the associated neurological deficits rarely improve with antibody-depleting therapies. Tumoricidal therapies may arrest neurological progression, but symptom reversal is rare. In contrast, autoantibodies specific for plasma membrane antigens have pathogenic potential, and the associated neurological deficits are often amenable to antibody-depleting immunotherapy, such as plasma exchange and anti-B-cell monoclonal antibody therapy. These reversible neurological disorders are frequently misdiagnosed as neurodegenerative. The focus of this review is the immunobiology, pathophysiology, and clinical spectrum of autoimmune neurological disorders accompanied by neural-specific IgGs. [ABSTRACT FROM AUTHOR]

An increasing number of neurologic diseases is associated with autoimmunity. The immune effectors contributing to the pathogenesis of such diseases are often unclear. To explore whether self-reactive CD8 T cells could attack CNS neurons in vivo, we generated a mouse model in which the influenza virus hemagglutinin (HA) is expressed specifically in CNS neurons. Transfer of cytotoxic anti-HA CD8 T cells induced an acute but reversible encephalomyelitis in HA-expressing recipient mice. Unexpectedly, diabetes insipidus developed in surviving animals. This robust phenotype was associated with preferential accumulation of cytotoxic CD8 T cells in the hypothalamus, up-regulation of MHC class I molecules, and destruction of vasopressin-expressing neurons. I FN-γ production by the pathogenic CD8 T cells was necessary for MHC class I upregulation by hypothalamic neurons and their destruction. This novel mouse model, in combination with related human data, supports the concept that autoreactive CD8 T cells can trigger central diabetes insipidus. [ABSTRACT FROM AUTHOR]

Neurotrophins regulate neuronal survival and differentiation, and facilitate synaptic plasticity in the central nervous system (CNS). Although neurons are the major source of neurotrophic factors, they are also expressed within the peripheral blood mononuclear cell (PBMC) fraction of the immunological system. Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), causing cognitive impairment in approximately half of the patients. In MS additional neurotrophic support from PBMCs might compensate the relative neurotrophin deficiency in the damaged CNS tissue that needs to be repaired. Neurotrophins, namely nerve growth factor (NGF), brainderived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5), may exert a po tentially neuroprotective role in MS-damaged CNS, in - fluencing the structural brain atrophy rate and functional connectivity, with both these aspects contributing to cognitive performance in MS patients. So far a lot of evidence has been gathered based on animal model studies, and evidence from studying human disease is gradually emerging. The association between neurotrophins and the CNS cholinergic system has been underlined; however, the exact mechanism of neurotrophin-mediated neuroprotection is not yet fully understood. Neurotrophins have been considered as potential novel therapies for neurodegenerative diseases, especially those with cognitive involvement. The aim of this review is to present the role of neurotrophins in the context of MS-related cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: To explore the relationship between enteroviruses and hospitalized children with hand, foot and mouth disease (HFMD) complicated with nervous system disease. 234 hospitalized HFMD patients treated in Shengjing Hospital, Liaoning Province were analyzed retrospectively. Based on the presence and severity of nervous system disease, the patients were grouped as follows: general patients, severely ill patients, critically ill patients and fatal patients. Based on the detected pathogen, the patients were grouped as follows: Enterovirus 71 (EV71) infection, coxsackie A16 (CA16) infection and other enterovirus (OE) infection. Results: Of the 423 hospitalized patients, most were admitted in July 2010(129/423, 30.5%). Enteroviruses were detected in 177(41.8%). 272/423 patients were male (64.3%), and fatal patients had the greatest proportion of male patients (p < 0.05). EV71 infection was found in 89/423 patients (21%). CA16 infection was detected in 8/423 patients (16.1%). Compared to group CA16, patients in group EV71 were hospitalized earlier, and the duration of hospitalization was longer (p < 0.05). Of the 92 patients with nervous system damage, 65 were infected with EV71 and 19 were infected with CA16. Among these CA16 infected patients, 2 had brainstem encephalitis and 1 had AFP. There were more patients with nervous system dysfunction in group EV71 than in groups CA16 or OE (p < 0.05). The 5 fatalities all occurred in group EV71 patients (p < 0.05). Infection with EV71 was most likely to cause neurogenic pulmonary edema (p < 0.05). Patients in group EV71 had a higher rate of suffering from coma and limb movement disorder than patients in groups CA16 or OE (p < 0.05). Conclusion: The disease progresses faster in EV71-infected HFMD patients. These patients are more likely to suffer nervous system damage, neurogenic pulmonary edema, severe sequelae or death. CA16 and other enteroviruses can also cause HFMD with severe nervous system complications. [ABSTRACT FROM AUTHOR]

Astrocytes are activated in experimental autoimmune encephalomyelitis (EAE) and have been suggested to either aggravate or ameliorate EAE. However, the mechanisms leading to an adverse or protective effect of astrocytes on the course of EAE are incompletely understood. To gain insight into the astrocyte-specific function of gp130 in EAE, we immunized mice lacking cell surface expression of gp130, the signal-transducing receptor for cytokines of the IL-6 family, with myelin oligodendrocyte glycoprotein35-55 peptide. These glial fibrillary acid protein (GFAP)-Cre gp130fl/fl mice developed clinically a significantly more severe EAE than control mice and succumbed to chronic EAE. Loss of astrocytic gp130 expression resulted in apoptosis of astrocytes in inflammatory lesions of GFAP-Cre gp130fl/fl mice, whereas gp130fl/fl control mice developed astrogliosis. Astrocyte loss of GFAP-Cre gp130fl/fl mice was paralleled by significantly larger areas of demyelination and significantly increased numbers of CD4 T cells in the CNS. Additionally, loss of astrocytes in GFAP-Cre gp130fl/fl mice resulted in a reduction of CNS regulatory Foxp3+ CD4 T cells and an increase of IL-17-, IFN-γ-, and TNF-producing CD4 as well as IFN-γ- and TNF-producing CD8 T cells, illustrating that astrocytes regulate the phenotypic composition of T cells. An analysis of mice deficient in either astrocytic gp130- Src homology region 2 domain-containing phosphatase 2/Ras/ERK or gp130-STAT1/3 signaling revealed that prevention of astrocyte apoptosis, restriction of demyelination, and T cell infiltration were dependent on the astrocytic gp130-Src homology region 2 domain-containing phosphatase 2/Ras/ERK, but not on the gp130-STAT1/3 pathway, further demonstrating that gp130-dependent astrocyte activation is crucial to ameliorate EAE. [ABSTRACT FROM AUTHOR]

The author makes a detailed presentation of molecular and clinical neuroimmunology aspects, concerning the peripheral and central nervous system vasculitis in child. Certain clinical features are exemplified, this article being focused on preclinical characteristics. [ABSTRACT FROM AUTHOR]

Background: In the neurodevelopmental disorder autism, several neuroimmune abnormalities have been reported. However, it is unknown whether microglial somal volume or density are altered in the cortex and whether any alteration is associated with age or other potential covariates. Methods: Microglia in sections from the dorsolateral prefrontal cortex of nonmacrencephalic male cases with autism (n = 13) and control cases (n = 9) were visualized via ionized calcium binding adapter molecule 1 immunohistochemistry. In addition to a neuropathological assessment, microglial cell density was stereologically estimated via optical fractionator and average somal volume was quantified via isotropic nucleator. Results: Microglia appeared markedly activated in 5 of 13 cases with autism, including 2 of 3 under age 6, and marginally activated in an additional 4 of 13 cases. Morphological alterations included somal enlargement, process retraction and thickening, and extension of filopodia from processes. Average microglial somal volume was significantly increased in white matter (p = .013), with a trend in gray matter (p = .098). Microglial cell density was increased in gray matter (p = .002). Seizure history did not influence any activation measure. Conclusions: The activation profile described represents a neuropathological alteration in a sizeable fraction of cases with autism. Given its early presence, microglial activation may play a central role in the pathogenesis of autism in a substantial proportion of patients. Alternatively, activation may represent a response of the innate neuroimmune system to synaptic, neuronal, or neuronal network disturbances, or reflect genetic and/or environmental abnormalities impacting multiple cellular populations. [ABSTRACT FROM AUTHOR]

RNA sequencing is a next-generation sequencing-based approach for comprehensive gene expression analysis. The 'big data'' of RNA sequencing have been deposited in public databases. Two recent studies attempted to use such data to answer clinically relevant questions pertaining to neuroimmunology. [ABSTRACT FROM AUTHOR]

Several lines of evidence suggest that neuroimmune mechanisms may be involved in the neurodegenerative process of Parkinson’s disease (PD). Interleukin-6 (IL-6) is increased in the nigrostriatal region and in the cerebrospinal fluid of patients with PD. IL-6 serum level was evaluated in PD patients. The effects of levodopa treatment and disease severity on IL-6 were also studied. The IL-6 levels were similar between PD patients (treated and not treated) and controls. However, there was a negative correlation of IL-6 levels and the activities of daily living scale ( P < 0.05), indicating that patients with more severe disease have higher levels of this cytokine. No correlation involving levodopa treatment and IL-6 serum level was found. The results suggest that only marginal effects of IL-6 occur on the peripheral immune system, and that the role of IL-6 and others neuroimmune factors needs to be well elucidated on PD. [ABSTRACT FROM AUTHOR]

Abstract: In the present study, we investigated the influence of HLA class I and class II genes in the response to interferon-beta (IFNβ) in multiple sclerosis (MS) patients. HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 DNA typing was performed by polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) in a cohort of 149 relapsing–remitting MS patients classified into IFNβ responders (n =74) and non-responders (n =75) based on stringent clinical criteria. Distribution of HLA class I and class II alleles individually and the HLA-DR2 haplotype was similar between responders and non-responders to treatment. These findings do not support a role of the HLA class I and class II genes as modifiers of the response to IFNβ. [Copyright &y& Elsevier]

Abstract: This study compares the effects of daytime versus nighttime intravenous glucocorticoid treatment of multiple sclerosis (MS) relapses for several immune indicators. The levels of serum CRP, TNFα, ESR, MMP-2, MMP-9, TIMP-1, and TIMP-2 were determined at trial entry and at day 7 post therapy initiation in 35 MS patients. Serum MMP-9 protein levels were differentially affected by treatment regimen, and were significantly lower after nighttime treatment. Both treatment protocols led to a similar reduction of ESR, CRP and TNFα. These findings provide preliminary characterization of biomarkers in the application of chronobiology-based glucocorticoid therapeutics in MS and other immune disorders. [Copyright &y& Elsevier]

Abstract: The type I interferons, interferon-beta and alpha (IFN-β, IFN-α), are widely used for the treatment of autoimmune demyelination in the central nervous system (CNS). Their effects on de- and remyelination through the broadly expressed type I IFN receptor (IFNAR), however, are highly speculative. In order to elucidate the role of endogenous type I interferons for myelin damage and recovery we induced toxic demyelination in the absence of IFNAR1. We demonstrate that IFNAR signalling was induced during acute demyelination since the cytokine IFN-β as well as the IFN-dependent genes IRF7, ISG15 and UBP43 were strongly upregulated. Myelin damage, astrocytic and microglia response, however, were not significantly reduced in the absence of IFNAR1. Furthermore, motor skills of IFNAR1-deficient animals during non-immune demyelination were unaltered. Finally, myelin recovery was found to be independent from endogenous IFNAR signalling, indicating a redundant role of this receptor for non-inflammatory myelin damage and repair. [Copyright &y& Elsevier]

Zusammenfassung  Der chimärisierte monoklonale Anti-CD20-Antikörper Rituximab wurde bereits erfolgreich in der Behandlung hämatologischer und auch rheumatologischer Erkrankungen eingesetzt. Der Wirkmechanismus von Rituximab beruht auf der Depletion CD20-positiver B-Zellen, die unter anderem über komplement- und antikörperabhängige Zytotoxizität und Apoptose vermittelt wird. Neuere histopathologische und auch immunologische Studien weisen auf eine zentrale Funktion von B-Zellen in der Pathogenese vieler neuroimmunologischer Erkrankungen hin, dies gilt insbesondere auch für die Multiple Sklerose. Einzelfallbeschreibungen und Fallserien zum Einsatz von Rituximab bei der Neuromyelitis optica (NMO), der Myasthenia gravis und Immunneuropathien sowie randomisierte Studien bei der schubförmigen Multiplen Sklerose zeigen vielversprechende Ergebnisse, die im Rahmen dieser Übersicht diskutiert werden. [ABSTRACT FROM AUTHOR]

Abstract: Chronic fatigue syndrome (CFS) is a specific clinical condition that characterises unexplained disabling fatigue and a combination of non-specific accompanying symptoms for at least 6 months, in the absence of a medical diagnosis that would otherwise explain the clinical presentation. Other common symptoms include headaches, myalgia, arthralgia, and post-exertional malaise; cognitive difficulties, with impaired memory and concentration; unrefreshing sleep; and mood changes. Similar disorders have been described for at least two centuries and have been differently named neurasthenia, post-viral fatigue, myalgic encephalomyelitis and chronic mononucleosis. Recent longitudinal studies suggest that some people affected by chronic fatigue syndrome improve with time but that most remain functionally impaired for several years. The estimated worldwide prevalence of CFS is 0.4–1% and it affects over 800,000 people in the United States and approximately 240,000 patients in the UK. No physical examination signs are specific to CFS and no diagnostic tests identify this syndrome. The pathophysiological mechanism of CFS is unclear. The main hypotheses include altered central nervous system functioning resulting from an abnormal immune response against a common antigen; a neuroendocrine disturbance; cognitive impairment caused by response to infection or other stimuli in sentient people. The current concept is that CFS pathogenesis is a multifactorial condition. Various studies have sought evidence for a disturbance in immunity in people with CFS. An alteration in cytokine profile, a decreased function of natural killer (NK) cells, a presence of autoantibodies and a reduced responses of T cells to mitogens and other specific antigens have been reported. The observed high level of pro-inflammatory cytokines may explain some of the manifestations such as fatigue and flu-like symptoms and influence NK activity. Abnormal activation of the T lymphocyte subsets and a decrease in antibody-dependent cell-mediated cytotoxicity have been described. An increased number of CD8+ cytotoxic T lymphocytes and CD38 and HLA-DR activation markers have been reported, and a decrease in CD11b expression associated with an increased expression of CD28+ T subsets has been observed. This review discusses the immunological aspects of CFS and offers an immunological hypothesis for the disease processes. [Copyright &y& Elsevier]

Inflammation is a normal response caused by physical stress like infection, injury and trauma; and progressive or psychological stress like in psychiatric diseases such as major depression, schizophrenia and posttraumatic stress. The host responds with a complex series of immune, endocrine and nervous reactions to face the stressful stimuli named neuroendocrine immune interaction. These interactions help us to maintain the homeostasis under stressful stimuli. Stress is a physicochemical or emotional process that induces tension. This process promotes the release of proinflammatory cytokines, hormones such as the corticotrophin release hormone (CRH) and cortisol, and a wide number of neurotransmitters that are together responsible for some behavioral alterations. Both systemic and psychological stress elicits an equivalent response in an organism. Particularly, the onset of inflammation is characterized by release of pro-inflammatory mediators including tumor necrosis factor (TNF)-α, interleukin (IL)-1, adhesion molecules, vasoactive mediators, and reactive oxygen species. The early release of proinflammatory cytokines by a widely variety of immune and nonimmune cells has a pivotal role in triggering the local inflammatory response. Apart from their involvement in local inflammation, TNF-α and IL-1β are signal molecules for activation of brain derived neuroendocrine and immunomodulatory responses. Excessive production of cytokines, such as TNF-α and IL-1β however can be more injurious than the inciting event, initiating diffuse coagulation, tissue injury, hypotension, and death. The inflammatory response is balanced by anti-inflammatory molecules like the cytokines IL-10 and IL-4, soluble TNF receptors, IL-1 receptor antagonists, and transforming growth factor (TGF)-β. Neuroendocrine pathways, such as the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic division of the Autonomic Nervous System (SNS) control the inflammation process by triggering anti-inflammatory balancing mechanisms. The brain can monitor immune status and sense peripheral inflammation through two main pathways: neural and humoral. The neural mechanism relies upon activation of vagus nerve afferent sensory fibers that signal the brain that inflammation is occurring. Stressful stimuli activate vagal afferents either directly by cytokines released from dendritic cells, macrophages, and other vagal-associated immune cells, or indirectly through the chemoreceptive cells located in vagal paraganglia. The transmission of cytokine signals to the brain through the vagal sensory neurons depends upon the magnitude of the stressful challenge. Subdiaphragmatic vagotomy inhibits the stimulation of the HPA axis and noradrenaline (NA) release in hypothalamic nuclei in response to intraperitoneal administration of endotoxin or IL-1β. Intravenous endotoxin administration induces expression of the neural activation marker c-Fos in the brainstem medulla, regardless of the integrity of the vagus nerve. Vagotomy fails to suppress high dose endotoxininduced. IL-1β immunoreactivity in the brain and increases blood corticosterone levels. It is likely that the vagal afferent neural pathway plays a dominant role in mild to moderate peripheral inflammatory responses, whereas acute, robust inflammatory responses signal the brain primarily via humoral mechanisms. By other hand, humoral pathway are supported by a large body of evidence, especially in cases of systemic immune challenge; circulatory cytokines like IL-1β and TNF-α can cross the blood-brain barrier and enter cerebrospinal fluid and the interstitial fluid spaces of the brain and spinal cord by a saturable carrier mediated mechanism that may function only at very high plasma cytokine concentrations.… [ABSTRACT FROM AUTHOR]

Los patrones de síntesis intratecal de inmunoglobulinas forman parte de la respuesta inmune en el sistema nervioso central (SNC). Demostrar que la edad del paciente, las características del agente biológico y las condiciones epidemiológicas modulan los patrones de síntesis intratecal de inmunoglobulinas (IgG). Como objetivo general, en estes estudio se describen los patrones de síntesis intratecal de inmunoglobulinas en meningoencefalitis provocadas por bacterias, virus y parásitos en niños. El objetivo específico es describir el patrón de síntesis intratecal de inmunoglobulinas y subclases de IgG en niños con meningoencefalitis eosinofílicas por Angiostrongylus cantonensis, el patrón de respuesta inmune intratecal y el funcionamiento de la barrera sangre-líquido cefalorraquídeo en niños con meningoencefalitis por Neisseria meningitidis, Echovirus 4, 6, 9, 16 y Coxsackie A9 y B5, así como proponer nuevas aplicaciones y modificaciones al reibergrama. Se demuestra que los patrones de síntesis intratecal de inmunoglobulinas son típicos para cada afección estudiada. Estos patrones aparecen en los niños antes que en los adultos con iguales enfermedades. Se observan variaciones en algunas infecciones virales en periodos epidémicos que las diferencian de los periodos interepidémicos. El reibergrama permite caracterizar las epidemias, porque su patrón de síntesis intratecal es particular y la diferencia de otras. El reibergrama se adecua para las subclases, especialmente novedoso para la IgG3 . Por primera vez se reportan los patrones de síntesis intratecal para estas enfermedades infecciosas en niños. El nuevo uso del reibergrama y la evaluación las subclases de IgG, abren nuevas perspectivas para la neuroinmunología en general y para la neuroinmunología pediátrica y tropical en particular. [ABSTRACT FROM AUTHOR]

Autoreactive T cells are a regular component of the healthy immune system. It has been proposed that some of these autoreactive T cells even might have a protective function. Recent studies support this notion by demonstrating that: a) myelin-autoreactive T cells show neuroprotective effects in vivo, and b) activated antigen-specific human T cells and other immune cells produce bioactive brain-derived neurotrophic factor (BDNF) and other neurotrophic factors in vitro. Furthermore, BDNF is expressed in different types of inflammatory cells in brain lesions of patients with acute disseminated leukoencephalopathy or multiple sclerosis. It seems plausible that the immune cell-mediated import of BDNF and other neurotrophic factors into the central nervous system has functional consequences and implications for the therapy of multiple sclerosis and other neuroimmunological diseases. [ABSTRACT FROM AUTHOR]

Abstract: Chemokine receptors represent promising targets to attenuate inflammatory responses and subsequent secondary damage after brain injury. We studied the response of the chemokines CXCL1/CINC-1 and CXCL2/MIP-2 and their receptors CXCR1 and CXCR2 after controlled cortical impact injury in adult rats. Rapid upregulation of CXCL1/CINC-1 and CXCL2/MIP-2, followed by CXCR2 (but not CXCR1), was observed after injury. Constitutive neuronal CXCR2 immunoreactivity was detected in several brain areas, which rapidly but transiently downregulated upon trauma. A second CXCR2-positive compartment, mainly colocalized with the activated microglia/macrophage marker ED1, was detected rapidly after injury in the ipsilateral cortex, progressively emerging into deeper areas of the brain later in time. It is proposed that CXCR2 has a dual role after brain injury: (i) homologous neuronal CXCR2 downregulation would render neurons more vulnerable to injury, whereas (ii) chemotaxis and subsequent differentiation of blood-borne cells into a microglial-like phenotype would be promoted by the same receptor. [Copyright &y& Elsevier]

When human microglia are co-cultured with activated human T lymphocytes, several cytokines become up-regulated in significant quantities. This condition can also occur at sites of inflammation in autoimmune inflammatory diseases of the central nervous system (CNS), including multiple sclerosis (MS), where T cells infiltrate the brain tissue and come in proximity to microglia. Therefore, T cell-microglia interaction is a potential avenue of drug therapy to decrease neuroinflammation. An immunomodulator used in autoimmune disorders is intravenous immunoglobulins (IVIg). The mechanisms of IVIg activity in diseases such as MS remain unclear. Here, we report that the application of IVIg to activated T cells leads to their decreased ability to engage microglia. As a result of IVIg treatment of T cells, there were reduced levels of tumor necrosis factor-α a and interleukin-10 in T cell-microglia co-culture. Our results add to the understanding of how IVIg may affect inflammation of the CNS. [ABSTRACT FROM AUTHOR]

Summary: Guillain-Barre syndrome consists of at least four subtypes of acute peripheral neuropathy. Major advances have been made in understanding the mechanisms of some of the subtypes. The histological appearance of the acute inflammatory demyelinating polyradiculoneuropathy (AIDP) subtype resembles experimental autoimmune neuritis, which is predominantly caused by T cells directed against peptides from the myelin proteins P0, P2, and PMP22. The role of T-cell-mediated immunity in AIDP remains unclear and there is evidence for the involvement of antibodies and complement. Strong evidence now exists that axonal subtypes of Guillain-Barre syndrome, acute motor axonal neuropathy (AMAN), and acute motor and sensory axonal neuropathy (AMSAN), are caused by antibodies to gangliosides on the axolemma that target macrophages to invade the axon at the node of Ranvier. About a quarter of patients with Guillain-Barre syndrome have had a recent Campylobacter jejuni infection, and axonal forms of the disease are especially common in these people. The lipo-oligosaccharide from the C jejuni bacterial wall contains ganglioside-like structures and its injection into rabbits induces a neuropathy that resembles acute motor axonal neuropathy. Antibodies to GM1, GM1b, GD1a, and GalNac-GD1a are in particular implicated in acute motor axonal neuropathy and, with the exception of GalNacGD1a, in acute motor and sensory axonal neuropathy. The Fisher's syndrome subtype is especially associated with antibodies to GQ1b, and similar cross-reactivity with ganglioside structures in the wall of C jejuni has been discovered. Anti-GQ1b antibodies have been shown to damage the motor nerve terminal in vitro by a complement-mediated mechanism. Results of international randomised trials have shown equivalent efficacy of both plasma exchange and intravenous immunoglobulin, but not corticosteroids, in hastening recovery from Guillain-Barre syndrome. Further research is needed to discover treatments to prevent 20% of patients from being left with persistent and significant disability. [ABSTRACT FROM AUTHOR]

Intravenous immunoglobulin (IVIg) has been used in the treatment of primary and secondary antibody deficiencies for over 25 years. It is a safe preparation with no long-term side effects. IVIg was first demonstrated to be effective in autoimmune disorders, two decades ago, in the treatment of acute immune thrombocytopenia. Since then, the therapeutic efficacy of IVIg has been established in Guillain Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP),myasthenia gravis (MG), dermatomyositis (DM), Kawasaki syndrome and the prevention of graft-versus-host disease in recipients of allogeneic bone marrow transplants and reported in a large number of other autoimmune and systemic inflammatory conditions. [ABSTRACT FROM AUTHOR]

Presents several abstracts for articles on clinical neuropharmacology. "A New Approach to Cognitive Disorders and Stroke: Opportunities for Neuropharmacology," by V. Hachinski; "Ethics in Clinical Neuropharmacology," by F. Gerstenbrand, H. Baumgartner, and W. Struhal; "Role of Sympathetic Nervous System in Neuroimmune Diseases," by E. S. Vizi and A. Lajtha.