22 research outputs found
Multiple sclerosis: Immunopathological heterogeneity and its implications
Biomarkers; Brain barriers immunotherapy; Multiple sclerosisBiomarcadores; Inmunoterapia de barreras cerebrales; Esclerosis mĂșltipleBiomarcadors; ImmunoterĂ pia de barreres cerebrals; Esclerosi mĂșltipleMS 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 mĂșltiple; Malaltia d'Alzheimer; Esclerosi lateral amiotrĂČficaEsclerosis mĂșltiple; Enfermedad de alzheimer; Esclerosis lateral amiotrĂłficaMultiple 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 diseasesBiĂČpsia lĂquida; MicroARN; Malalties neurolĂČgiquesBiopsia lĂquida; MicroARN; Enfermedades neurolĂłgicasThe 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 Alzheimerâs disease, Parkinsonâs 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)
Transcriptome and Function of Novel Immunosuppressive Autoreactive Invariant Natural Killer T Cells That Are Absent in Progressive Multiple Sclerosis
Progressive Multiple Sclerosis; T CellsCĂ©lulas T; Esclerosis mĂșltiple progresivaCĂšl·lules T; Esclerosi mĂșltiple 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 hCII707-721âreactive 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, hCII707-721âreactive iNKT cells did not upregulate interferon (IFN)-Îł, 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. hCII707-721âreactive 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
Serum Neurofilament Levels and PML Risk in Patients With Multiple Sclerosis Treated With Natalizumab
Natalizumab; Neurofilamento séricoNatalizumab; Neurofilament sÚricNatalizumab; 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%
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; InterferĂł beta; Esclerosi mĂșltipleAnticuerpos; InterferĂłn beta; Esclerosis mĂșltipleAntibodies 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 (IFNÎČ) 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 IFNÎČ preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFNÎČ-1a subcutaneous (s.c.) and IFNÎČ-1b s.c. in favor of the least immunogenic preparation IFNÎČ-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 IFNÎČ-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 IFNÎČ-1a i.m. (1.41 and 2.27 years), IFNÎČ-1b-Betaferon s.c. (2.51 and 1.96 years) and IFNÎČ-1a s.c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFNÎČ 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
Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis
Immunitat adaptativa; Envelliment; Esclerosi mĂșltipleInmunidad adaptativa; Envejecimiento; Esclerosis mĂșltipleAdaptive immunity; Aging; Multiple sclerosisPatients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB. CSF cellular subsets and molecules implicated in immunosenescence were explored. In M- patients, aging induced remarkable decreases in absolute CSF counts of CD4+ and CD8+ T lymphocytes, including Th1 and Th17 cells, and of B cells, including those secreting TNF-alpha. It also increased serum anti-CMV IgG antibody titers (indicative of immunosenescence) and CSF CHI3L1 levels (related to astrocyte activation). In contrast, M+ patients showed an age-associated increase of TIM-3 (a biomarker of T cell exhaustion) and increased values of CHI3L1, independently of age. Finally, in both groups, age induced an increase in CSF levels of PD-L1 (an inductor of T cell tolerance) and activin A (part of the senescence-associated secretome and related to inflammaging). These changes were independent of the disease duration. Finally, this resulted in augmented disability. In summary, all MS patients experience with age a modest induction of T-cell tolerance and an activation of the innate immunity, resulting in increased disability. Additionally, M- patients show clear decreases in CSF lymphocyte numbers, which could increase the risk of infections. Thus, age and immunological status are important for tailoring effective therapies in MS.This work was supported by grants FIS-PI15/00513, FIS-PI18/00572 and RD16/0015/0001 from the Instituto de Salud Carlos III. Ministerio de Ciencia e InnovacioÌn, Spain and FEDER: "Una manera de hacer Europa"
Teriflunomide and EpsteinâBarr virus in a Spanish multiple sclerosis cohort: in vivo antiviral activity and clinical response
Biomarker; Multiple sclerosis; TeriflunomideBiomarcador; Esclerosi mĂșltiple; TeriflunomidaBiomarcador; Esclerosis mĂșltiple; TeriflunomidaBackground: EpsteinâBarr virus (EBV) and human herpesvirus 6 (HHV-6) have been associated with multiple sclerosis (MS). Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing forms of MS. In the preclinical Theilerâs murine encephalitis virus model of MS, the drug demonstrated an increased rate of viral clearance versus the vehicle placebo. Furthermore, teriflunomide inhibits lytic EBV infection in vitro.
Objective: 1. To evaluate the humoral response against EBV and HHV-6 prior to teriflunomide treatment and 6 months later. 2. To correlate the variation in the humoral response against EBV and HHV-6 with the clinical and radiological response after 24 months of treatment with teriflunomide. 3. To analyze the utility of different demographic, clinical, radiological, and environmental data to identify early biomarkers of response to teriflunomide.
Methods: A total of 101 MS patients (62 women; mean age: 43.4 years) with one serum prior to teriflunomide onset and another serum sample 6 months later were recruited. A total of 80 had been treated for at least 24 months, 13 had stopped teriflunomide before 24 months, and 8 were currently under teriflunomide therapy but with less than 24 months of follow-up. We analyzed the levels of the viral antibodies titers abovementioned in serum samples with ELISA commercial kits, and the levels of serum neurofilament light chain (Nf-L).
Results: Antiviral antibody titers decreased for EBNA-1 IgG (74.3%), VCA IgG (69%), HHV-6 IgG (60.4%), and HHV-6 IgM (73.3%) after 6 months of teriflunomide. VCA IgG titers at baseline correlated with Nf-L levels measured at the same time (r = 0.221; p = 0.028) and 6 months later (r = 0.240; p = 0.017). We found that higher EBNA-1 titers (p = 0.001) and a higher age (p = 0.04) at baseline were associated with NEDA-3 conditions. Thus, 77.8% of patients with EBNA-1 >23.0 AU and >42.8 years (P50 values) were NEDA-3.
Conclusion: Treatment with teriflunomide was associated with a reduction of the levels of IgG antibody titers against EBV and HHV-6. Furthermore, higher EBNA-1 IgG titers prior to teriflunomide initiation were associated with a better clinical response.AM has a technician contract from âREI: Red de Enfermedades Inflamatoriasâ (RD21/0002/0038). This work was financially supported by Ministerio de Ciencia e InnovaciĂłn (Proyectos de generaciĂłn de conocimiento)-Fondo Europeo de Desarrollo Regional (Feder) (PID2021-126041OB-I00) and âFundaciĂłn LAIRâ
Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis
Personalized medicine; Responder and non-responderMedicina personalizada; Respondedor y no respondedorMedicina personalitzada; Contestador i no contestadorBackground
The increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to develop biomarkers that can be used within the framework of individualized medicine. Fingolimod is a disease-modifying treatment that belongs to the sphingosine-1-phosphate receptor modulators. In addition to inhibiting T cell egress from lymph nodes, fingolimod promotes the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), whose monocytic subset (M-MDSCs) can be used as a biomarker of disease severity, as well as the degree of demyelination and extent of axonal damage in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the present study, we have assessed whether the abundance of circulating M-MDSCs may represent a useful biomarker of fingolimod efficacy in EAE and in the clinical context of MS patients.
Methods
Treatment with vehicle or fingolimod was orally administered to EAE mice for 14 days in an individualized manner, starting the day when each mouse began to develop clinical signs. Peripheral blood from EAE mice was collected previous to treatment and human peripheral blood mononuclear cells (PBMCs) were collected from fingolimod to treat MS patientsâ peripheral blood. In both cases, M-MDSCs abundance was analyzed by flow cytometry and its relationship with the future clinical affectation of each individual animal or patient was assessed.
Results
Fingolimod-treated animals presented a milder EAE course with less demyelination and axonal damage, although a few animals did not respond well to treatment and they invariably had fewer M-MDSCs prior to initiating the treatment. Remarkably, M-MDSC abundance was also found to be an important and specific parameter to distinguish EAE mice prone to better fingolimod efficacy. Finally, in a translational effort, M-MDSCs were quantified in MS patients at baseline and correlated with different clinical parameters after 12 months of fingolimod treatment. M-MDSCs at baseline were highly representative of a good therapeutic response to fingolimod, i.e., patients who met at least two of the criteria used to define non-evidence of disease activity-3 (NEDA-3) 12 months after treatment.
Conclusion
Our data indicate that M-MDSCs might be a useful predictive biomarker of the response of MS patients to fingolimod.This work was supported by the Instituto de Salud Carlos III (PI18/00357, RD16-0015/0019, PI21/00302, all co-funded by the European Union), the FundaciĂłn Merck Salud (FMS_2020_MS), Esclerosis MĂșltiple España (REEM-EME-S5 and REEM-EME_2018), ADEMTO, ATORDEM and AELEM. CC-T holds a predoctoral fellowship from the Instituto de Salud Carlos III (FI19/00132, co-funded by the European Union). LC and JG-A were hired under PI18/00357 and RD16/0015/0019, respectively. DC, MCO and IM-D were hired by SESCAM
Associations of sNfL with clinico-radiological measures in a large MS population
Esclerosi mĂșltiple; Cadena lleugera de neurofilaments sĂšricsEsclerosis mĂșltiple; Cadena ligera de neurofilamentos sĂ©ricosMultiple sclerosis; Serum neurofilament light chainObjective
Evaluation of serum neurofilament light chain (sNfL), measured using high-throughput assays on widely accessible platforms in large, real-world MS populations, is a critical step for sNfL to be utilized in clinical practice.
Methods
Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is a network of healthcare institutions in the United States and Europe collecting standardized clinical/imaging data and biospecimens during routine clinic visits. sNfL was measured in 6974 MS and 201 healthy control (HC) participants, using a high-throughput, scalable immunoassay.
Results
Elevated sNfL levels for age (sNfL-E) were found in 1238 MS participants (17.8%). Factors associated with sNfL-E included male sex, younger age, progressive disease subtype, diabetes mellitus, impaired renal function, and active smoking. Higher body mass index (BMI) was associated with lower odds of elevated sNfL. Active treatment with disease-modifying therapy was associated with lower odds of sNfL-E. MS participants with sNfL-E exhibited worse neurological function (patient-reported disability, walking speed, manual dexterity, and cognitive processing speed), lower brain parenchymal fraction, and higher T2 lesion volume. Longitudinal analyses revealed accelerated short-term rates of whole brain atrophy in sNfL-E participants and higher odds of new T2 lesion development, although both MS participants with or without sNfL-E exhibited faster rates of whole brain atrophy compared to HC. Findings were consistent in analyses examining age-normative sNfL Z-scores as a continuous variable.
Interpretation
Elevated sNfL is associated with clinical disability, inflammatory disease activity, and whole brain atrophy in MS, but interpretation needs to account for comorbidities including impaired renal function, diabetes, and smoking.Study funding was provided from the National Institutes of Health (K23NS117883 to E.S.S.; K01MH121582 to K.C.F.; U01NS111678 to P.A.C.), National Multiple Sclerosis Society (RG-1904-33834 to E.S.S.; RG-1904-33800 to P.A.C.), and Biogen