La reseqüenciació dirigida revela variants rares enriquides en gens susceptibles d'Esclerosi Múltiple

Per tal d'eixamplar el mapa de les variants genètiques implicades amb la malaltia de l'Esclerosi Múltiple (EM) i així explorar l'origen d'aquesta, el grup del Servei de Neurologia- Neuroimmunologia del Centre d'Esclerosi Múltiple de Catalunya (Cemcat) i de l'Institut de Recerca Vall d'Hebron (VHIR) de l'Hospital Universitari Vall d'Hebron ha estudiat el paper de les variants rarament associades a contreure EM, específicament ubicades a 4 dels 14 gens analitzats i vinculats amb EM. Sobretot és rellevant el comportament de les variants rares localitzades al gen RGS1, ja que són les úniques que generen canvis funcionals a pacients portadors d'aquestes variants.Con el fin de ampliar el mapa de las variantes genéticas implicadas con enfermedad de la Esclerosis Múltiple (EM) y así explorar el origen de ésta, el grupo del Servicio de Neurologia- Neuroinmunología del Centro de Esclerosis Múltiple de Cataluña (Cemcat) y del Instituto de Investigación Vall d'Hebron (VHIR) del Hospital Universitario Vall d'Hebron ha estudiado el papel de las variantes raramente asociadas a contraer EM, específicamente ubicadas en 4 de los 14 genes analizados y vinculados con EM. Sobre todo es relevante el comportamiento de las variantes raras localizadas en el gen RGS1, ya que son las únicas que generan cambios funcionales en pacientes portadores de estas variantes.In order to broaden the map of the genetic variants involved in Multiple Sclerosis (MS) disease and thus explore its origin, the group of the Neurology-Neuroimmunology Service from the Multiple Sclerosis Center of Catalonia (Cemcat) and from the Research Institute Vall d'Hebron (VHIR) of the University Hospital Vall d'Hebron has studied the role of the variants rarely associated with contracting MS, specifically located in 4 of the 14 genes analyzed and linked to MS. Is relevant the behavior of the rare variants located in the RGS1 gene, as they are the only ones that cause functional changes in patients carrying these variants

Multiple sclerosis: Immunopathological heterogeneity and its implications

Biomarkers; Brain barriers immunotherapy; Multiple sclerosisBiomarcadores; Inmunoterapia de barreras cerebrales; Esclerosis múltipleBiomarcadors; Immunoteràpia de barreres cerebrals; Esclerosi múltipleMS is the most common autoimmune demyelinating disease of the CNS. For the past decades, several immunomodulatory disease-modifying treatments with multiple presumed mechanisms of action have been developed, but MS remains an incurable disease. Whereas high efficacy, at least in early disease, corroborates underlying immunopathophysiology, there is profound heterogeneity in clinical presentation as well as immunophenotypes that may also vary over time. In addition, functional plasticity in the immune system as well as in the inflamed CNS further contributes to disease heterogeneity. In this review, we will highlight immune-pathophysiological and associated clinical heterogeneity that may have an implication for more precise immunomodulatory therapeutic strategies in MS.We thank our lab teams and clinical coworkers for their dedication. We thank people with MS that we have the privilege to counsel for their continuous support. Part of the work cited was funded by the Swiss National Fund (SNF no. 310030_172952) to AC. Open access funding provided by Inselspital Universitatsspital Ber

Chitinases and chitinase-like proteins as biomarkers in neurologic disorders

Esclerosi múltiple; Malaltia d'Alzheimer; Esclerosi lateral amiotròficaEsclerosis múltiple; Enfermedad de alzheimer; Esclerosis lateral amiotróficaMultiple sclerosis; Alzheimer's disease; Amyotrophic lateral sclerosisChitinases are hydrolytic enzymes widely distributed in nature. Despite their physiologic and pathophysiologic roles are not well understood, chitinases are emerging as biomarkers in a broad range of neurologic disorders, where in many cases, protein levels measured in the CSF have been shown to correlate with disease activity and progression. In this review, we will summarize the structural features of human chitinases and chitinase-like proteins and their potential physiologic and pathologic functions in the CNS. We will also review existing evidence for the role of chitinases and chitinase-like proteins as diagnostic and prognostic biomarkers in inflammatory, neurodegenerative diseases, and psychiatric disorders. Finally, we will comment on future perspectives of chitinase studies in neurologic conditions.No targeted funding reported

Liquid Biopsy in Neurological Diseases

Liquid biopsy; MicroRNA; Neurological diseasesBiòpsia líquida; MicroARN; Malalties neurològiquesBiopsia líquida; MicroARN; Enfermedades neurológicasThe most recent and non-invasive approach for studying early-stage biomarkers is liquid biopsy. This implies the extraction and analysis of non-solid biological tissues (serum, plasma, saliva, urine, and cerebrospinal fluid) without undergoing invasive procedures to determine disease prognosis. Liquid biopsy can be used for the screening of several components, such as extracellular vesicles, microRNAs, cell-free DNA, cell-free mitochondrial and nuclear DNA, circulating tumour cells, circulating tumour DNA, transfer RNA, and circular DNA or RNA derived from body fluids. Its application includes early disease diagnosis, the surveillance of disease activity, and treatment response monitoring, with growing evidence for validating this methodology in cancer, liver disease, and central nervous system (CNS) disorders. This review will provide an overview of mentioned liquid biopsy components, which could serve as valuable biomarkers for the evaluation of complex neurological conditions, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, stroke, traumatic brain injury, CNS tumours, and neuroinfectious diseases. Furthermore, this review highlights the future directions and potential limitations associated with liquid biopsy.S.M. was supported by the grant from Instituto Salud Carlos III (PI20/01697)

Classification of multiple sclerosis clinical forms by 1H magnetic ressonance spectroscopy of cerebrospinal fluid

Postprint (published version

Transcriptome and Function of Novel Immunosuppressive Autoreactive Invariant Natural Killer T Cells That Are Absent in Progressive Multiple Sclerosis

Progressive Multiple Sclerosis; T CellsCélulas T; Esclerosis múltiple progresivaCèl·lules T; Esclerosi múltiple progressivaBackground and Objective The aim of this study was to determine whether natural killer T (NKT) cells, including invariant (i) NKT cells, have clinical value in preventing the progression of multiple sclerosis (MS) by examining the mechanisms by which a distinct self-peptide induces a novel, protective invariant natural killer T cell (iNKT cell) subset. Methods We performed a transcriptomic and functional analysis of iNKT cells that were reactive to a human collagen type II self-peptide, hCII707-721, measuring differentially induced genes, cytokines, and suppressive capacity. Results We report the first transcriptomic profile of human conventional vs novel hCII707-721–reactive iNKT cells. We determined that hCII707-721 induces protective iNKT cells that are found in the blood of healthy individuals but not progressive patients with MS (PMS). By transcriptomic analysis, we observed that hCII707-721 promotes their development and proliferation, favoring the splicing of full-length AKT serine/threonine kinase 1 (AKT1) and effector function of this unique lineage by upregulating tumor necrosis factor (TNF)-related genes. Furthermore, hCII707-721–reactive iNKT cells did not upregulate interferon (IFN)-γ, interleukin (IL)-4, IL-10, IL-13, or IL-17 by RNA-seq or at the protein level, unlike the response to the glycolipid alpha-galactosylceramide. hCII707-721–reactive iNKT cells increased TNFα only at the protein level and suppressed autologous-activated T cells through FAS-FAS ligand (FAS-FASL) and TNFα-TNF receptor I signaling but not TNF receptor II. Discussion Based on their immunomodulatory properties, NKT cells have a potential value in the treatment of autoimmune diseases, such as MS. These significant findings suggest that endogenous peptide ligands can be used to expand iNKT cells, without causing a cytokine storm, constituting a potential immunotherapy for autoimmune conditions, including PMS.This work was supported by grants from the Lundbeck Foundation, Danish MS Society, Independent Research Fund Denmark-Medical and Health Sciences (DFF-M), and Foundation for Research in Neurology (to S.I.-N.). B. Carrion received a PhD fellowship from CONACYT-Mexico and the Lundbeck Foundation. M. Hadi was the recipient of a McDonald fellowship from the MSIF program

Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe: A descriptive study of test results

Antibodies; Interferon beta; Multiple sclerosisAnticossos; Interferó beta; Esclerosi múltipleAnticuerpos; Interferón beta; Esclerosis múltipleAntibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFNβ) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries. A common database platform (tranSMART) for querying, analyzing and storing retrospective data of MS cohorts was set up to harmonize the data and compare results of ADA tests between different countries. Retrospective data from six countries (Sweden, Austria, Spain, Switzerland, Germany and Denmark) on 20,695 patients and on 42,555 samples were loaded into tranSMART including data points of age, gender, treatment, samples, and ADA results. The previously observed immunogenic difference among the four IFNβ preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFNβ-1a subcutaneous (s.c.) and IFNβ-1b s.c. in favor of the least immunogenic preparation IFNβ-1a intramuscular (i.m.) was observed. The median time from treatment start to first ADA test correlated with time to first positive test. Shorter times were observed for IFNβ-1b-Extavia s.c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFNβ-1a i.m. (1.41 and 2.27 years), IFNβ-1b-Betaferon s.c. (2.51 and 1.96 years) and IFNβ-1a s.c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFNβ ADA was observed in test samples taken from older patients. Testing for ADA varies between different European countries and is highly dependent on the policy within each country. For drugs where routine monitoring of ADA is not in place, there is a risk that some patients remain on treatment for several years despite ADA positivity. For drugs where a strategy of ADA testing is introduced with the release of the drug, there is a reduced risk of having ADA positive patients and thus of less efficient treatment. This indicates that potential savings in health cost might be achieved by routine analysis of ADA

Serum Neurofilament Levels and PML Risk in Patients With Multiple Sclerosis Treated With Natalizumab

Natalizumab; Neurofilamento séricoNatalizumab; Neurofilament sèricNatalizumab; Serum NeurofilamentObjectives The study aimed to assess the potential for serum neurofilament light chain (NFL) levels to predict the risk of progressive multifocal leukoencephalopathy (PML) in natalizumab (NTZ)-treated patients with multiple sclerosis (MS) and to discriminate PML from MS relapses. Methods NFL levels were measured with single molecule array (Simoa) in 4 cohorts: (1) a prospective cohort of patients with MS who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr); (2) a cohort of patients whose blood was collected during PML; (3) an independent cohort of non-PML NTZ-treated patients with serum NFL determinations at 2 years (replication cohort); and (4) a cohort of patients whose blood was collected during exacerbations. Results Serum NFL levels were significantly increased after 2 years of NTZ treatment in pre-PML patients compared with NTZ-ctr. The prognostic performance of serum NFL levels to predict PML development at 2 years was similar in the NTZ-ctr group and replication cohort. Serum NFL levels also distinguished PML from MS relapses and were 8-fold higher during PML compared with relapses. Conclusions These results support the use of serum NFL levels in clinical practice to identify patients with relapsing-remitting MS at higher PML risk and to differentiate PML from clinical relapses in NTZ-treated patients. Classification of Evidence This study provides Class I evidence that serum NFL levels can identify NTZ-treated patients with MS who will develop PML with a sensitivity of 67% and specificity of 80%

Chitinase 3-like 1 is neurotoxic in primary cultured neurons

Chitinase 3-like 1 (CHI3L1) is known to play a role as prognostic biomarker in the early stages of multiple sclerosis (MS), and patients with high cerebrospinal fluid CHI3L1 levels have an increased risk for the development of neurological disability. Here, we investigated its potential neurotoxic effect by adding recombinant CHI3L1 in vitro to primary cultures of mouse cortical neurons and evaluating both neuronal functionality and survival by immunofluorescence. CHI3L1 induced a significant neurite length retraction after 24 and 48 hours of exposure and significantly reduced neuronal survival at 48 hours. The cytotoxic effect of CHI3L1 was neuron-specific and was not observed in mouse immune or other central nervous system cells. These results point to a selective neurotoxic effect of CHI3L1 in vitro and suggest a potential role of CHI3L1 as therapeutic target in MS patients

Increased NLRP3 Inflammasome Activation and Pyroptosis in Patients With Multiple Sclerosis With Fingolimod Treatment Failure

Inflammasome; Pyroptosis; Multiple sclerosisInflamasoma; Piroptosis; Esclerosis múltipleInflamasoma; Piroptosi; Esclerosi múltipleBackground and Objectives Inflammasomes are involved in the pathogenesis of different neuroimmune and neurodegenerative diseases, including multiple sclerosis (MS). In a previous study by our group, the nucleotide-binding oligomerization domain, leucine-rich repeat receptor and pyrin-domain–containing 3 (NLRP3) inflammasome was reported to be associated with the response to interferon-beta in MS. Based on recent data showing the potential for the oral therapy fingolimod to inhibit NLRP3 inflammasome activation, here we investigated whether fingolimod could also be implicated in the response to this therapy in patients with MS. Methods NLRP3 gene expression levels were measured by real-time PCR in peripheral blood mononuclear cells at baseline and after 3, 6, and 12 months in a cohort of patients with MS treated with fingolimod (N = 23), dimethyl fumarate (N = 21), and teriflunomide (N = 21) and classified into responders and nonresponders to the treatment according to clinical and radiologic criteria. In a subgroup of fingolimod responders and nonresponders, the percentage of monocytes with an oligomer of ASC was determined by flow cytometry, and the levels of interleukin (IL)-1β, IL-18, IL-6, tumor necrosis factor (TNF)α, and galectin-3 were quantified by ELISA. Results NLPR3 expression levels were significantly increased in fingolimod nonresponders after 3 (p = 0.03) and 6 months (p = 0.008) of treatment compared with the baseline but remained similar in responders at all time points. These changes were not observed in nonresponders to the other oral therapies tested. The formation of an oligomer of ASC in monocytes after lipopolysaccharide and adenosine 5′-triphosphate stimulation was significantly decreased in responders (p = 0.006) but increased in nonresponders (p = 0.0003) after 6 months of fingolimod treatment compared with the baseline. Proinflammatory cytokine release from stimulated peripheral blood mononuclear cells was comparable between responders and nonresponders, but galectin-3 levels on cell supernatants, as a marker of cell damage, were significantly increased in fingolimod nonresponders (p = 0.02). Discussion The differential effect of fingolimod on the formation of an inflammasome-triggered ASC oligomer in monocytes between responders and nonresponders could be used as a response biomarker after 6 months of fingolimod treatment and suggests that fingolimod may exert their beneficial effects by reducing inflammasome signaling in a subset of patients with MS.MCIN/AEI/10.13039/501100011033 (grant PID2020-116709RB-I00)—Fundación Séneca (grant 20859/PI/18) and the Instituto Salud Carlos III (grant DTS21/00080). L. Hurtado-Navarro was supported by the fellowship 21214/FPI/19 (Fundación Séneca, Región de Murcia, Spain)