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Patients 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.

There are an increasing number of treatments available for multiple sclerosis (MS). The early identification of optimal responders to individual treatments is important to achieve individualized therapy. With this aim, we performed a multicenter retrospective longitudinal study including 186 MS patients treated with natalizumab who were followed for 2 years. We analyzed the following variables at recruitment: sex, current age, age at disease onset, disease duration, EDSS, number of T2 and Gd + lesions, IgG and IgM oligoclonal bands, HLA class II (DR, DRB, DQA, DQB, and DRB1*15:01), IgG and IgM antibody titers against human herpesvirus 6 (HHV-6) and the antibody response to Epstein–Barr virus (EBV) through the measurement of the anti-EBNA-1 and anti-VCA IgG titers, in relation to clinical response (no relapses or disability progression), and to NEDA-3 (no evidence of disease activity in terms of clinical response and no changes in MRI scans either) after 2-years follow-up. Baseline EDSS score, baseline EBNA-1 IgG titers and percentage change of HHV6 IgG titers between baseline and 6 month visits were significantly different in clinical responders and in NEDA-3 status (all of them remained significant in the multivariate analysis). We identified three variables for the early identification of natalizumab optimal responders in a rapid and cost-effective approach.

Gut microbiota dysbiosis has been implicated in MS and other immune diseases, although it remains unclear how manipulating the gut microbiota may affect the disease course. Using a well-established model of progressive MS triggered by intracranial infection with Theiler's murine encephalomyelitis virus (TMEV), we sought to determine whether dysbiosis induced by oral antibiotics (ABX) administered on pre-symptomatic and symptomatic phases of the disease influences its course. We also addressed the effects of microbiota recolonization after ABX withdrawn in the presence or absence of probiotics. Central and peripheral immunity, plasma acetate and butyrate levels, axon damage and motor disability were evaluated. The cocktail of ABX prevented motor dysfunction and limited axon damage in mice, which had fewer CD4+ and CD8+ T cells in the CNS, while gut microbiota recolonization worsened motor function and axonal integrity. The underlying mechanisms of ABX protective effects seem to involve CD4+CD39+ T cells and CD5+CD1d+ B cells into the CNS. In addition, microglia adopted a round amoeboid morphology associated to an anti-inflammatory gene profile in the spinal cord of TMEV mice administered ABX. The immune changes in the spleen and mesenteric lymph nodes were modest, yet ABX treatment of mice limited IL-17 production ex vivo. Collectively, our results provide evidence of the functional relevance of gut microbiota manipulation on the neurodegenerative state and disease severity in a model of progressive MS and reinforce the role of gut microbiota as target for MS treatment.

La esclerosis múltiple (EM) es una enfermedad inflamatoria crónica del SNC de naturaleza autoinmune que produce desmielinización y daño axonal. Su etiología no es del todo conocida aunque se sabe que distintos factores genéticos y ambientales contribuyen a la susceptibilidad a esta enfermedad. Tampoco se conocen los mecanismos inmunológicos que juegan un papel importante en la EM. Aunque distintos trabajos han estudiado las diferencias entre la EM y otras patologías no inflamatorias, las diferencias con otras patologías inflamatorias no se han estudiado en profundidad. Tampoco se conocen los factores inmunológicos que se asocian con el daño axonal, la variable responsable de la discapacidad en la EM. Además, durante la evolución de la enfermedad, parecen existir dos fases. En al fase inicial predomina la inflamación, asociada a desmielinización y daño axonal. En la segunda fase, que en la un principio se solapa con la primera, habría una respuesta inflamatoria compartimentalizada, y una activación crónica de la respuesta inmune innata. Sin embargo, quedan por explorar las los cambios en distintas subpoblaciones celulares asociados a la edad en esta patología. Aproximadamente un tercio de los pacientes con EM muestra bandas oligoclonales IgM (BOC-M+) en LCR frente a lípidos. Múltiple trabajos han demostrado que estos anticuerpos son un biomarcador que se asocia con un mal pronóstico de la enfermedad. Sin embargo se desconoce su asociación con marcadores de inflamación y neurodegeneración en la enfermedad y si la presencia de estos anticuerpos condiciona la inmunosenescencia en la EM..., Multiple Sclerosis is a chronic inflammatory autoimmune disease of the central nervous system that causes demyelination and axonal damage. MS etiology remains unknown but genetic and environmental factors contribute to MS susceptibility. In addition, little is known about the immunological mechanisms playing an important role in the disease. Several reports have compared MS with non inflammatory diseases but differences with other inflammatory diseases have not been fully elucidated. The immunological mechanisms associated to axonal damage, the cause of the disability in MS, also remain unknown. On the other hand, it was suggested that MS is a two-phase disease. In the first one, the adaptive and innate immune responses mediate acute inflammation linked to demyelination and axonal damage. It is proposed that the second phase mainly show chronic activation of the innate immune response and a compartmentalized inflammation. However, aging effects in cell subsets remain unexplored. Around 30% of MS patients have oligoclonal IgM bands (OCB-M+) in the cerebrospinal fluid (CSF) that recognize lipids. Several reports have proven that these antibodies are a biomarker of poor disease outcome. However, little is known about it association with inflammatory and neurodegenerative markers in the disease and with immunosenescence...

[Background]: It remains unclear whether disease course in multiple sclerosis (MS) is influenced by genetic polymorphisms. Here, we aimed to identify genetic variants associated with benign and aggressive disease courses in MS patients., [Methods]: MS patients were classified into benign and aggressive phenotypes according to clinical criteria. We performed exome sequencing in a discovery cohort, which included 20 MS patients, 10 with benign and 10 with aggressive disease course, and genotyping in 2 independent validation cohorts. The first validation cohort encompassed 194 MS patients, 107 with benign and 87 with aggressive phenotypes. The second validation cohort comprised 257 patients, of whom 224 patients had benign phenotypes and 33 aggressive disease courses. Brain immunohistochemistries were performed using disease course associated genes antibodies., [Results]: By means of single-nucleotide polymorphism (SNP) detection and comparison of allele frequencies between patients with benign and aggressive phenotypes, a total of 16 SNPs were selected for validation from the exome sequencing data in the discovery cohort. Meta-analysis of genotyping results in two validation cohorts revealed two polymorphisms, rs28469012 and rs10894768, significantly associated with disease course. SNP rs28469012 is located in CPXM2 (carboxypeptidase X, M14 family, member 2) and was associated with aggressive disease course (uncorrected p value < 0.05). SNP rs10894768, which is positioned in IGSF9B (immunoglobulin superfamily member 9B) was associated with benign phenotype (uncorrected p value < 0.05). In addition, a trend for association with benign phenotype was observed for a third SNP, rs10423927, in NLRP9 (NLR family pyrin domain containing 9). Brain immunohistochemistries in chronic active lesions from MS patients revealed expression of IGSF9B in astrocytes and macrophages/microglial cells, and expression of CPXM2 and NLRP9 restricted to brain macrophages/microglia., [Conclusions]: Genetic variants located in CPXM2, IGSF9B, and NLRP9 have the potential to modulate disease course in MS patients and may be used as disease activity biomarkers to identify patients with divergent disease courses. Altogether, the reported results from this study support the influence of genetic factors in MS disease course and may help to better understand the complex molecular mechanisms underlying disease pathogenesis.

La esclerosis múltiple (EM) es una enfermedad inflamatoria crónica del SNC de naturaleza autoinmune que produce desmielinización y daño axonal. Su etiología no es del todo conocida aunque se sabe que distintos factores genéticos y ambientales contribuyen a la susceptibilidad a esta enfermedad. Tampoco se conocen los mecanismos inmunológicos que juegan un papel importante en la EM. Aunque distintos trabajos han estudiado las diferencias entre la EM y otras patologías no inflamatorias, las diferencias con otras patologías inflamatorias no se han estudiado en profundidad. Tampoco se conocen los factores inmunológicos que se asocian con el daño axonal, la variable responsable de la discapacidad en la EM. Además, durante la evolución de la enfermedad, parecen existir dos fases. En al fase inicial predomina la inflamación, asociada a desmielinización y daño axonal. En la segunda fase, que en la un principio se solapa con la primera, habría una respuesta inflamatoria compartimentalizada, y una activación crónica de la respuesta inmune innata. Sin embargo, quedan por explorar las los cambios en distintas subpoblaciones celulares asociados a la edad en esta patología. Aproximadamente un tercio de los pacientes con EM muestra bandas oligoclonales IgM (BOC-M+) en LCR frente a lípidos. Múltiple trabajos han demostrado que estos anticuerpos son un biomarcador que se asocia con un mal pronóstico de la enfermedad. Sin embargo se desconoce su asociación con marcadores de inflamación y neurodegeneración en la enfermedad y si la presencia de estos anticuerpos condiciona la inmunosenescencia en la EM...

La esclerosis múltiple (EM) es una enfermedad crónica del sistema nervioso central (SNC) que se caracteriza por presentar desmielinización, inflamación y daño axonal. El Interferón beta (IFN-beta) fue el primer fármaco inmunomodulador usado en el tratamiento de la esclerosis múltiple remitente-recidivante (EMRR). Es un fármaco seguro y eficaz, capaz de disminuir la actividad de la enfermedad. Sin embargo, la respuesta a este tratamiento no es uniforme en todos los pacientes de EM. Por ello, dado el gran abanico de opciones terapéuticas que existen en la actualidad, la búsqueda de biomarcadores que permitan identificar de manera precoz a los pacientes con alta probabilidad de mostrar una respuesta óptima al interferón beta es de gran relevancia para poder realizar una medicina personalizada en la EM. Hasta ahora son los marcadores clínicos y radiológicos los que más se utilizan para establecer la eficacia de las distintas opciones terapéuticas. Sin embargo, esto implica un cierto deterioro para los pacientes no respondedores que puede repetirse con distintas terapias. Objetivos El primer objetivo del estudio fue identificar antes del inicio del tratamiento, biomarcadores biológicos que predigan la respuesta a IFN-beta. En segundo lugar comparamos los niveles de todos los posibles marcadores incluidos en el estudio con los de los controles sanos. Nuestro último objetivo fue analizar los cambios que el tratamiento podría inducir en todos los factores estudiados..., Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by presenting with demyelination, axonal damage and inflammation. Interferon beta (IFN-beta) was the first immunomodulatory drug used in the treatment of relapsing-remitting multiple sclerosis (RRMS). It is a safe and effective treatment able to diminish the activity of the disease. However, the response to this treatment is not uniform in all MS patients. Therefore, given the wide range of therapeutic options existing actually in MS, the search for biomarkers that allow the early identification of patients with high probability of showing an optimal response to beta interferon is of great importance to perform a personalized medicine in MS. Actually, the most used markers to establish treatment efficacy are clinical and radiological data. However, this implies certain deterioration for non-responder patients, which may occur with different therapies. Objective The first objective of the study was to identify, before treatment initiation, biomarkers that predict patient response to IFN-beta. Secondly we compared the levels of the different molecules and cell subsets included in the study with healthy controls. Our ultimate goal was to analyse the changes induced by treatment in all the factors studied...

Recent studies have begun to point out the contribution of microbiota to multiple sclerosis (MS) pathogenesis. Theiler’s murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) is a model of progressive MS. Here, we first analyze the effect of intracerebral infection with TMEV on commensal microbiota and secondly, whether the early microbiota depletion influences the immune responses to TMEV on the acute phase (14 dpi) and its impact on the chronic phase (85 dpi). The intracranial inoculation of TMEV was associated with a moderate dysbiosis. The oral administration of antibiotics (ABX) of broad spectrum modified neuroimmune responses to TMEV dampening brain CD4+ and CD8+ T infiltration during the acute phase. The expression of cytokines, chemokines and VP2 capsid protein was enhanced and accompanied by clusters of activated microglia disseminated throughout the brain. Furthermore, ABX treated mice displayed lower levels of CD4+ and CD8+T cells in cervical and mesenteric lymph nodes. Increased mortality to TMEV was observed after ABX cessation at day 28pi. On the chronic phase, mice that survived after ABX withdrawal and recovered microbiota diversity showed subtle changes in brain cell infiltrates, microglia and gene expression of cytokines. Accordingly, the surviving mice of the group ABX-TMEV displayed similar disease severity than TMEV mice.

Prognostic molecular biomarkers for the conversion of clinically isolated syndrome (CIS) to multiple sclerosis (MS) are lacking. In a prospective longitudinal study of 813 individuals with CIS, Cantó et al. validate elevated CSF levels of chitinase 3-like 1 as a biomarker for conversion to MS and development of disability