Neurofilament Light Chain Levels Interact with Neurodegenerative Patterns and Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving rapid motor neuron degeneration leading to brain, primarily precentral, atrophy. Neurofilament light chains are a robust prognostic biomarker highly specific to ALS, yet associations between neurofilament light chains and MR imaging outcomes are not well-understood. We investigated the role of neurofilament light chains as mediators among neuroradiologic assessments, precentral neurodegeneration, and disability in ALS. MATERIALS AND METHODS: We retrospectively analyzed a prospective cohort of 29 patients with ALS (mean age, 56 [SD, 12] years; 18 men) and 36 controls (mean age, 49 [SD, 11] years; 18 men). Patients underwent 3T (n = 19) or 7T (n = 10) MR imaging, serum (n = 23) and CSF (n = 15) neurofilament light chains, and clinical (n = 29) and electrophysiologic (n = 27) assessments. The control group had equivalent 3T (n = 25) or 7T (n = 11) MR imaging. Two trained neuroradiologists performed blinded qualitative assessments of MR imaging anomalies (n = 29 patients, n = 36 controls). Associations between precentral cortical thickness and neurofilament light chains and clinical and electrophysiologic data were analyzed. RESULTS: We observed extensive cortical thinning in patients compared with controls. MR imaging analyses showed significant associations between precentral cortical thickness and bulbar or arm impairment following distributions corresponding to the motor homunculus. Finally, uncorrected results showed positive interactions among precentral cortical thickness, serum neurofilament light chains, and electrophysiologic outcomes. Qualitative MR imaging anomalies including global atrophy (P = .003) and FLAIR corticospinal tract hypersignal anomalies (P = .033), correlated positively with serum neurofilament light chains. CONCLUSIONS: Serum neurofilament light chains may be an important mediator between clinical symptoms and neuronal loss according to cortical thickness. Furthermore, MR imaging anomalies might have underestimated prognostic value because they seem to indicate higher serum neurofilament light chain levels.

Clinical, biological, electrophysiological and therapeutic profile of patients with anti-MAG neuropathy according to MYD88L265P and CXCR4 mutations and underlying haemopathy.

INTRODUCTION: Anti-MAG neuropathies are associated with an IgM monoclonal gammopathy of undetermined significance (MGUS) or with a malignant haemopathy. Our objective was to determine whether the presence of a haemopathy or somatic mutations of MYD88 and CXCR4 genes influences disease presentation and response to rituximab (RTX). METHODS: We included 79 patients (mean age 74 years, disease duration 9.68 years) who had a bone marrow aspiration with morphologic and immunophenotypic analysis. MYD88L265P and CXCR4 mutations were analysed in peripheral B cells. Information collected included: inflammatory neuropathy cause and treatment sensory sum score (ISS), MRC testing, overall neuropathy limitation scale (ONLS), Rash-built Overall Disability Score (RODS), ataxia score, anti-MAG titres, peak IgM dosage, neurofilament light chain levels, motor and sensory amplitudes, motor unit index (MUNIX) and motor unit size index (MUSIX) sum scores. Efficacy of RTX was evaluated at 12 months in 26 patients. RESULTS: Malignant haematological disorders were discovered in 17 patients (22%): 13 Waldenstrom macroglobulinemia, 3 marginal zone lymphoma and one mantle cell lymphoma. MYD88L265P mutation was detected in 29/60 (48%) patients and CXCR4 in 1 single patient. Disease severity, biological and electrophysiological data and response to RTX were comparable in patients with MGUS/lymphoma and patients with/without MYD88L265P mutation. ISS was lower and MUSIX higher in patients improved by RTX. CONCLUSIONS: MYD88L265P mutation and underlying haemopathies are not predictive of a more severe disease. However, in cases of resistant and progressive neuropathy, they provide an opportunity to prescribe newly available drugs such as Bruton tyrosine kinase inhibitors.

Yellow fever vaccine-associated neurologic and viscerotropic disease: a 10-year case series of the French National Reference Center for Arboviruses with clinical and immunological insights.

BACKGROUND: Immunization against the Yellow fever virus (YFV) with the 17D live-attenuated vaccine is the most effective way to prevent the disease. However, unexpected severe adverse events can occur. They consist in a neurological impairment - neurological disease (YEL-AND), a YF-like illness - viscerotropic disease (YEL-AVD) or anaphylaxis. In this article, we describe the epidemiology, clinical and biological features of YEL-AND and YEL-AVD cases reported to the French National Reference Center for Arboviruses (NRCA) in the past 10 years. METHODS: We conducted a national, retrospective study using the database of the NRCA from June 2012 to June 2022. All patients whose biological samples were sent to the NRCA for detection of YFV by serology and/or RT-qPCR for a suspected vaccine-associated adverse event were included. We collected data by reading medical records and conducted complementary neuro-immunological analysis, followed by a search for autoimmunity against type-1-interferon when samples were available at the NRCA. RESULTS: There were 10 cases of YEL-AND and 2 cases of YEL-AVD reported to the NRCA in the past 10 years, which represented an overall incidence of 0.6 for 100 000 doses. A total of 6/12 cases were previously healthy patients (50%, mean age 31 years), and 4/12 cases had cardiovascular co-morbidities (42%, mean age 56 years). The majority of YEL-AND had a favourable outcome at 6 months of follow up. One YEL-AVD patient passed. In secondary analyses, we evidenced a significant blood cerebrospinal fluid (CSF) barrier dysfunction, without intrathecal synthesis of immunoglobulin and without argument for a neuron damage. We further detected a significant rate of anti-type-1alpha interferon antibodies in 3/10 tested patients (2 YEL-AND and 1 YEL-AVD). CONCLUSION: YEL-AND and YEL-AVD are rare events that can underlie defect in the innate immunity of apparently healthy or mild co-morbid subjects. Outcome was generally favourable in the YEL-AND cases of our series, but still life-threatening or even fatal in the YEL-AVD cases.

Validation of ELISA assays for the calculation of FLC indices for the diagnosis of intrathecal immunoglobulin synthesis.

OBJECTIVES: Define the cutoff thresholds of the Kappa (K) and Lambda (L) free light chains (FLC) indices for the detection of intrathecal immunoglobulin synthesis (IIS) using the new K and L FLC ELISA from SEBIA. The reference technique, which is not readily standardized between laboratories, is based on the demonstration of oligoclonal banding (OCB) in cerebrospinal fluid (CSF) which is absent in serum. For the past 6 years, we have also routinely calculated the K FLC index using The Binding Site (TBS) reagents on an Optilite instrument, an approach increasingly used as an alternative and/or a complement to electrophoretic analysis. METHODS: We analyzed 391 serum/CSF pairs divided into three groups. The first group were cases without OCB and with normal albumin CSF/serum ratio (n=174). The second group were cases with specific OCB (n=73). The last group included patients with increased albumin CSF/sera ratio without OCB (n=142). RESULTS: Analysis of the first group determined that the cutoffs for detection of IIS are respectively 2.55 and 1.02 for the K FLC and L FLC indices. Of the 73 cases with IIS, only 2 had a K FLC index below this threshold (sensitivity of 97.26%), while 16 out of 73 cases (78.08%) and 13 out of 72 cases (81.94%) had an IgG and L FLC index below the cutoffs, respectively. Additionally, we illustrate equivalent performances for prediction of the presence of OCB between SEBIA and TBS methods. CONCLUSIONS: Sebia K FLC and L FLC assays are adequate alternative methods for the diagnosis of IIS.

Rituximab Responsive Relapsing-Remitting IgG4 Anticontactin 1 Chronic Inflammatory Demyelinating Polyradiculoneuropathy Associated With Membranous Nephropathy: A Case Description and Brief Review.

ABSTRACT: Nodal/paranodal IgG4-related chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) rarely involves anticontactin (CNTN1) subtype and exceptionally complicates with nephrotic syndrome. A 65-year-old man developed weakness, facial palsy, and balance impairment; after spontaneous recovery, he severely relapsed 1 month later. Electroneuromyography confirmed CIDP. Proteinorachy (462 mg/dL; N < 45), proteinuria (3.5 g/g creatine), and biopsy-proven membranous nephropathy were identified. Intravenous immunoglobulins, corticosteroids, and plasmaphereses did not allow recovery. Anti-CNTN1 immunoglobulin G4 (IgG4) assay was positive. Rituximab (375 mg/m2/week, 4 weeks) provided obvious improvement. Relapsing-remitting anti-CNTN1-CIDP co-occurring with nephrotic syndrome is exceptional, and its identification is essential because efficient therapies such as rituximab are available for this severe condition.

Decrease in the cortex/striatum metabolic ratio on [18F]-FDG PET: a biomarker of autoimmune encephalitis.

PURPOSE: The aim of this [18F]-FDG PET study was to determine the diagnostic value of the cortex/striatum metabolic ratio in a large cohort of patients suffering from autoimmune encephalitis (AE) and to search for correlations with the course of the disease. METHODS: We retrospectively collected clinical and paraclinical data of patients with AE, including brain 18F-FDG PET/CT. Whole-brain statistical analysis was performed using SPM8 software after activity parametrization to the striatum in comparison to healthy subjects. The discriminative performance of this metabolic ratio was evaluated in patients with AE using receiver operating characteristic curves against 44 healthy subjects and a control group of 688 patients with MCI. Relationship between cortex/striatum metabolic ratios and clinical/paraclinical data was assessed using univariate and multivariate analysis in patients with AE. RESULTS: Fifty-six patients with AE were included. In comparison to healthy subjects, voxel-based statistical analysis identified one large cluster (p-cluster < 0.05, FWE corrected) of widespread decreased cortex/striatum ratio in patients with AE. The mean metabolic ratio was significantly lower for AE patients (1.16 ± 0.13) than that for healthy subjects (1.39 ± 0.08; p < 0.001) and than that for MCI patients (1.32 ± 0.11; p < 0.001). A ratio threshold of 1.23 allowed to detect AE patients with a sensitivity of 71% and a specificity of 82% against MCI patients, and 98% against healthy subjects. A lower cortex/striatum metabolic ratio had a trend towards shorter delay before 18F-FDG PET/CT (p = 0.07) in multivariate analysis. CONCLUSION: The decrease in the cortex/striatal metabolic ratio has a good early diagnostic performance for the differentiation of AE patients from controls.

A clinical, aetiological, and public health perspective on central nervous system infections in Bolivia, 2017-2018.

Central nervous system (CNS) infections are important causes of morbidity and mortality worldwide. In Bolivia, aetiologies, case fatality, and determinants of outcome are poorly characterised. We attempted to investigate such parameters to guide diagnosis, treatment, prevention, and health policy. From Nov-2017 to Oct-2018, we prospectively enrolled 257 inpatients (20.2% HIV-positive patients) of all ages from healthcare centers of Cochabamba and Santa Cruz, Bolivia with a suspected CNS infection and a lumbar puncture performed. Biological diagnosis included classical microbiology, molecular, serological and immunohistochemical tests. An infectious aetiology was confirmed in 128/257 (49.8%) inpatients, including, notably among confirmed single and co-infections, Cryptococcus spp. (41.7%) and Mycobacterium tuberculosis (27.8%) in HIV-positive patients, and Mycobacterium tuberculosis (26.1%) and Streptococcus pneumoniae (18.5%) in HIV-negative patients. The total mortality rate was high (94/223, 42.1%), including six rabies cases. In multivariate logistic regression analysis, mortality was associated with thrombocytopenia (Odds ratio (OR) 5.40, 95%-CI 2.40-11.83) and hydrocephalus (OR 4.07, 95%-CI 1.35-12.23). The proportion of untreated HIV patients, late presentations of neurotuberculosis, the rate of pneumococcal cases, and rabies patients who did not benefit from a post-exposure prophylaxis, suggest that decreasing the burden of CNS infections requires reinforcing health policy regarding tuberculosis, rabies, S. pneumoniae vaccination, and HIV-infections.

Combination of serum and CSF neurofilament-light and neuroinflammatory biomarkers to evaluate ALS.

This monocentric prospective study of patient suffering from Amyotrophic lateral sclerosis (ALS) aims to evaluate the prognosis and diagnostic potential of both Neurofilament-Light (Nf-L) and neuroinflammatory biomarkers in serum and CSF. Candidate markers levels were measured using multiplex method in serum of 60 ALS patients, 94 healthy controls of 43 patients suffering from Inflammatory Peripheral Neuropathies (IPN). A comparative CSF analysis was performed for 20 ALS and 17 IPN patients. Among the altered biomarkers, CSF Nf-L level remains the best marker of ALS severity, while serum levels correlate strongly with disease progression. The combination of Nf-L and ICAM-1 concentrations in the CSF and IFN-γ concentration in the serum differentiate ALS patients from IPN patients with improved sensibility and specificity relative to individual biomarkers. A cutoff value of 0.49 for the fitted values of these 3 biomarkers discriminate ALS from IPN patients with a specificity of 100% (78.20-100%) and a sensibility of 85.71% (57.19-98.22%) with an AUC of 0.99 ± 0.01. The measure of Nf-L and neuroinflammatory biomarkers in CSF and serum can be useful biomarkers panel in the differential diagnosis of ALS.

CD146/sCD146 in the Pathogenesis and Monitoring of Angiogenic and Inflammatory Diseases.

CD146 is a cell adhesion molecule expressed on endothelial cells, as well as on other cells such as mesenchymal stem cells and Th17 lymphocytes. This protein also exists in a soluble form, whereby it can be detected in biological fluids, including the serum or the cerebrospinal fluid (CSF). Some studies have highlighted the significance of CD146 and its soluble form in angiogenesis and inflammation, having been shown to contribute to the pathogenesis of many inflammatory autoimmune diseases, such as systemic sclerosis, mellitus diabetes, rheumatoid arthritis, inflammatory bowel diseases, and multiple sclerosis. In this review, we will focus on how CD146 and sCD146 contribute to the pathogenesis of the aforementioned autoimmune diseases and discuss the relevance of considering it as a biomarker in these pathologies.

Antibodies against the node of Ranvier: a real-life evaluation of incidence, clinical features and response to treatment based on a prospective analysis of 1500 sera.

INTRODUCTION: IgG4 antibodies against neurofascin (Nfasc155 and Nfasc140/186), contactin (CNTN1) and contactin-associated protein (Caspr1) are described in specific subtypes of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Our objective was to assess, in a real-life practice, the incidence, the clinical features and the response to treatment of these forms of CIDP. METHODS: 1500 sera of patients suspected of having CIDP from France, Belgium and Switzerland were prospectively tested using a flow cytometry technique. The characteristics of patients with antibodies against the node of Ranvier were compared to 100 seronegative CIDP from our department. RESULTS: IgG4 antibodies against Nfasc155, CNTN1, and Caspr1 were, respectively, detected in 15 (prevalence 1%), 10 (0.7%) and 2 (0.2%) sera. Antibodies specific of the Nfasc140/186 were not detected. All subjects with antibodies against the node of Ranvier fulfilled diagnostic criteria for CIDP. CIDP with anti-Nfasc155 were younger, had more sensory ataxia and postural tremor than seronegative CIDP. CIDP with anti-CNTN1 had more frequent subacute onset and facial paralysis, commoner renal involvement with membranous glomerulonephritis and greater disability, than seronegative CIDP. CIDP with anti-Caspr1 had more frequent respiratory failure and cranial nerve involvement but not more neuropathic pain than seronegative CIDP. Intravenous immunoglobulins were ineffective in most seropositive patients. Rituximab produced dramatic improvement in disability and decreased antibodies titres in 13 seropositive patients (8 with anti-Nfasc155 and 5 with anti-CNTN1 antibodies). CONCLUSIONS: Although rare, anti-paranodal antibodies are clinically valuable, because they are associated with specific phenotypes and therapeutic response.

Autoimmune Encephalitis Concomitant with SARS-CoV-2 Infection: Insight from 18F-FDG PET Imaging and Neuronal Autoantibodies.

We report the case of a 72-y-old man with concomitant autoimmune encephalitis and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The patient presented with subacute cerebellar syndrome and myoclonus several days after general infectious symptoms began. Methods: Clinical examination, CT, PET, MRI, and autoantibody testing were performed. Results: The oropharyngeal swab test was positive for SARS-CoV-2. The brain MRI results were normal. Cerebrospinal fluid testing showed normal cell counts, a negative result on reverse-transcription polymerase chain reaction testing, and no oligoclonal banding. Brain 18F-FDG PET showed diffuse cortical hypometabolism associated with putaminal and cerebellum hypermetabolism, compatible with encephalitis and especially cerebellitis. The immunologic study revealed high titers of IgG autoantibodies in serum and cerebrospinal fluid directed against the nuclei of Purkinje cells, striatal neurons, and hippocampal neurons. Whole-body 18F-FDG PET and CT scans did not show neoplasia. Treatment with steroids allowed a rapid improvement in symptoms. Conclusion: This clinical case argues for a possible relationship between SARS-CoV-2 infection and autoimmune encephalitis and for the use of 18F-FDG PET in such a context.

Selective inhibition of anti-MAG IgM autoantibody binding to myelin by an antigen-specific glycopolymer.

Anti-myelin-associated glycoprotein (MAG) neuropathy is a disabling autoimmune peripheral neuropathy that is caused by circulating monoclonal IgM autoantibodies directed against the human natural killer-1 (HNK-1) epitope. This carbohydrate epitope is highly expressed on adhesion molecules such as MAG, a glycoprotein present in myelinated nerves. We previously showed the therapeutic potential of the glycopolymer poly(phenyl disodium 3-O-sulfo-ß-d-glucopyranuronate)-(1→3)-ß-d-galactopyranoside (PPSGG) in selectively neutralizing anti-MAG IgM antibodies in an immunological mouse model and ex vivo with sera from anti-MAG neuropathy patients. PPSGG is composed of a biodegradable backbone that multivalently presents a mimetic of the HNK-1 epitope. In this study, we further explored the pharmacodynamic properties of the glycopolymer and its ability to inhibit the binding of anti-MAG IgM to peripheral nerves. The polymer selectively bound anti-MAG IgM autoantibodies and prevented the binding of patients' anti-MAG IgM antibodies to myelin of non-human primate sciatic nerves. Upon PPSGG treatment, neither activation nor inhibition of human and murine peripheral blood mononuclear cells nor alteration of systemic inflammatory markers was observed in mice or ex vivo in human peripheral blood mononuclear cells. Intravenous injections of PPSGG to mice immunized against the HNK-1 epitope removed anti-MAG IgM antibodies within less than 1 hr, indicating a fast and efficient mechanism of action as compared to a B-cell depletion with anti-CD20. In conclusion, these observations corroborate the therapeutic potential of PPSGG for an antigen-specific treatment of anti-MAG neuropathy. Read the Editorial Highlight for this article on page 465.

Electrophysiological features of chronic inflammatory demyelinating polyradiculoneuropathy associated with IgG4 antibodies targeting neurofascin 155 or contactin 1 glycoproteins.

OBJECTIVE: Chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) with antibodies against neurofascin 155 (Nfasc155) or contactin-1 (CNTN1) have distinctive clinical features. Knowledge on their electrophysiological characteristics is still scarce. In this study, we are investigating whether these patients have specific electrophysiological characteristics. METHODS: The electrophysiological data from 13 patients with anti-Nfasc155 IgG4 antibodies, 9 with anti-CNTN1 IgG4 antibodies were compared with those of 40 consecutive CIDP patients without antibodies. RESULTS: All the patients with antibodies against Nfasc155 or CNTN1 fulfilled the EFNS/PNS electrodiagnostic criteria for definite CIDP. There was no electrophysiological difference between patients with anti-CNTN1 and anti-Nfasc155 antibodies. Nerve conduction abnormalities were heterogeneously distributed along nerves trunks and roots. They were more pronounced than in CIDP without antibodies. Motor conduction velocity on median nerve <24 m/s or motor velocity on ulnar nerve <26 m/s or motor distal latency on ulnar nerve >7.4 ms were predictive of positive antibodies against the node of Ranvier with a sensitivity of 59% and a specificity of 93%. CONCLUSIONS: Marked conduction abnormalities may suggest the presence of positive antibodies against the node of Ranvier. SIGNIFICANCE: Anti-Nfasc155 and anti-CNTN1 antibodies target the the paranodal axo-glial domain but are associated with nerve conduction abnormalities mimicking a "demyelinating" neuropathy.

Ageing stereotypes and prodromal Alzheimer's disease (AGING): study protocol for an ongoing randomised clinical study.

INTRODUCTION: The number of older people diagnosed with amnestic mild cognitive impairment (aMCI), the prodromal state of Alzheimer's disease (AD), is increasing worldwide. However, some patients with aMCI never convert to the AD type of dementia, with some remaining stable and others reverting to normal. This overdiagnosis bias has been largely overlooked and gone unexplained. There is ample evidence in the laboratory that negative ageing stereotypes (eg, the culturally shared belief that ageing inescapably causes severe cognitive decline) contribute to the deteriorating cognitive performances of healthy older adults, leading them to perform below their true abilities. The study described here is intended to test for the first time whether such stereotypes also impair patients' cognitive performances during neuropsychological examinations in memory clinics, resulting in overdiagnosis of aMCI. METHODS AND ANALYSIS: The ongoing study is a 4-year randomised clinical trial comparing patients' physiological stress and cognitive performances during neuropsychological testing in memory clinics. A total of 260 patients attending their first cognitive evaluation will be randomised to either a standard condition of test administration, assumed here to implicitly activate negative ageing stereotypes or a reduced-threat instruction condition designed to alleviate the anxiety arising from these stereotypes. Both groups will be tested with the same test battery and stress biomarkers. For 30 patients diagnosed with aMCI in each group (n=60), biomarkers of neurodegeneration and amyloidopathy will be used to distinguish between aMCI with normal versus abnormal AD biomarkers. A 9-month follow-up will be performed on all patients to identify those whose cognitive performances remain stable, deteriorate or improve. ETHICS AND DISSEMINATION: This protocol has been approved by the French National Agency for Medicines and Health Products Safety and the Sud-Est I French Ethics Committee (2017-A00946-47). Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03138018.

Relevance of anti-HNK1 antibodies in the management of anti-MAG neuropathies.

INTRODUCTION: In peripheral neuropathies with antibodies against Myelin Associated Glycoprotein (MAG), an IgM monoclonal gammopathy recognizes a specific epitope called Human Natural Killer 1 (HNK1) shared by NK lymphocytes and several components of the peripheral nerve myelin. Recently an ELISA test has been developed to detect antibodies against HNK1 epitope. Objectives were to determine the usefulness of this assay in the management of anti-MAG neuropathy. METHODS: Anti-HNK1 antibodies were assessed with the GanglioCombi™ MAG ELISA test (Buhlmann) in 41 anti-MAG neuropathies and in 118 controls: 34 chronic inflammatory demyelinating polyradiculoneuropathies, 3 Miller Fisher syndromes, 12 sensory neuronopathies, 63 length-dependent axonal sensory polyneuropathies, 6 healthy controls. Anti-HNK1 antibody was tested before and 1 year after rituximab therapy in seven patients with anti-MAG neuropathy. RESULTS: Anti-HNK1 antibodies were positive in 40/41 anti-MAG neuropathies, and in 1/118 controls (sensitivity 98%, specificity 99%). Only considering controls with IgM paraprotein, specificity was 96% (23/24). In anti-MAG neuropathies, anti-HNK1 titre was correlated with sensory deficiency evaluated with the INCAT sensory sum score (r = 0.4, p = 0.01) and with disability evaluated with the Rasch-built Overall Disability Scale (r = [Formula: see text] 0.4, p = 0.01) and Overall Neuropathy Limitation Scale (r = 0.4, p = 0.02). Anti-HNK1 titres were not related to age, disease duration, atypical clinical features and anti-MAG antibodies titres. Anti-MAG titres were not associated with disease severity. Anti-HNK1 titres were decreased by 18% 1 year after rituximab treatment. CONCLUSIONS: Anti-HNK1 antibodies have good sensitivity and specificity for the diagnosis of anti-MAG neuropathy. Interestingly, anti-HNK1 titres are related to the disease severity and decrease after rituximab infusions.

Cytotoxic CD8+ T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons.

Adaptive immune response is part of the dynamic changes that accompany motoneuron loss in amyotrophic lateral sclerosis (ALS). CD4+ T cells that regulate a protective immunity during the neurodegenerative process have received the most attention. CD8+ T cells are also observed in the spinal cord of patients and ALS mice although their contribution to the disease still remains elusive. Here, we found that activated CD8+ T lymphocytes infiltrate the central nervous system (CNS) of a mouse model of ALS at the symptomatic stage. Selective ablation of CD8+ T cells in mice expressing the ALS-associated superoxide dismutase-1 (SOD1)G93A mutant decreased spinal motoneuron loss. Using motoneuron-CD8+ T cell coculture systems, we found that mutant SOD1-expressing CD8+ T lymphocytes selectively kill motoneurons. This cytotoxicity activity requires the recognition of the peptide-MHC-I complex (where MHC-I represents major histocompatibility complex class I). Measurement of interaction strength by atomic force microscopy-based single-cell force spectroscopy demonstrated a specific MHC-I-dependent interaction between motoneuron and SOD1G93A CD8+ T cells. Activated mutant SOD1 CD8+ T cells produce interferon-γ, which elicits the expression of the MHC-I complex in motoneurons and exerts their cytotoxic function through Fas and granzyme pathways. In addition, analysis of the clonal diversity of CD8+ T cells in the periphery and CNS of ALS mice identified an antigen-restricted repertoire of their T cell receptor in the CNS. Our results suggest that self-directed immune response takes place during the course of the disease, contributing to the selective elimination of a subset of motoneurons in ALS.

A proliferation-inducing ligand-mediated anti-inflammatory response of astrocytes in multiple sclerosis.

OBJECTIVE: The two related tumor necrosis factor members a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS. METHODS: APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes. RESULTS: APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect. INTERPRETATION: Our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406-420.

Prevalence of autoantibodies in the course of Gaucher disease type 1: A multicenter study comparing Gaucher disease patients to healthy subjects.

OBJECTIVES: Type 1 Gaucher disease may be related to the presence of autoantibodies. Their clinical significance is questioned. Primary endpoint was to compare the prevalence of autoantibodies in type 1 Gaucher disease patients with healthy subjects, seeking correlations with autoimmune characteristics. Secondary endpoints were to determine whether patients with autoantibodies reported autoimmunity-related symptoms and if genotype, splenectomy or treatment influenced autoantibodies presence. METHODS: Type 1 Gaucher disease patients and healthy volunteers were included in this national multicenter exploratory study. Autoantibodies presence was compared in both groups and assessed regarding to genotype, splenectomy, Gaucher disease treatment and autoimmunity-related symptoms. RESULTS: Twenty healthy subjects and 40 type 1 Gaucher disease patients were included. Of the studied group: 15 patients undergone splenectomy, 37 were treated either with enzyme replacement therapy (34) or with substrate reduction therapy (3), 25 were homozygous/heterozygous for the N370S mutation. In type 1 Gaucher disease group (studied group), 52% had positive autoantibodies versus 26% in control group. Antiphospholipid antibodies were more frequent in the studied group (30% vs. 5%), but without correlation to thrombosis, osteonecrosis or bone infarcts. In the studied group, antinuclear antibodies were more frequent (25% vs. 16%). None of the patients with autoantibodies had clinical manifestations of autoimmune diseases. Autoantibodies were not correlated with treatment, genotype, or splenectomy, except for anticardiolipid, more frequent in splenectomized patients. CONCLUSIONS: In type 1 Gaucher disease, autoantibodies were more frequent compared to a healthy population. However, they were not associated with an increased prevalence of clinical active autoimmune diseases.

Motor unit number index (MUNIX) in patients with anti-MAG neuropathy.

OBJECTIVE: To investigate the relationship between Motor Unit Number Index (MUNIX) and functional scales in patients with anti-Myelin Associated Glycoprotein (MAG) neuropathy and to know if MUNIX is modify after rituximab (RTX) therapy. METHODS: 17 patients were enrolled, of whom 6 were prospectively evaluated during one year after RTX treatment. MUNIX technique was assessed in abductor digiti mini (ADM), abductor pollicis brevi (APB) and tibialis anterior (TA) muscles. MUNIX sum score was calculated by adding the results of ADM, APB and TA muscles. RESULTS: MUNIX sum score was correlated with overall neuropathy limitation scale (ONLS) (r=-0.55, p=0.02), grip strength in dominant hand (r=0.63, p=0.01) MRC testing (r=0.71, p<0.001) and CMAP sum score (r=0.71, p=0.001). Twelve months after RTX, four patients improved their disability measured on the ONLS score, five patients had improved MUNIX sum score with a median increase of 37% compared to initial evaluation. CONCLUSIONS: MUNIX is related to motor impairment and disability in anti-MAG neuropathy and MUNIX is modified after immunosuppressive treatment. SIGNIFICANCE: Considering its advantages, MUNIX may be a suitable test to evaluate anti-MAG neuropathy in clinical trials.