Manuel Comabella

VHIR Vall d’Hebron Research Institute, Barcino, Catalonia, Spain

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Publications (180)920.19 Total impact

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    ABSTRACT: We aimed to investigate the ability of natalizumab (NTZ)-treated patients to assume treatment-associated risks and the factors involved in such risk acceptance. From a total of 185 patients, 114 patients on NTZ as of July 2011 carried out a comprehensive survey. We obtained disease severity perception scores, personality traits' scores, and risk-acceptance scores (RAS) so that higher RAS indicated higher risk acceptance. We recorded JC virus status (JCV+/-), prior immunosuppression, NTZ treatment duration, and clinical characteristics. NTZ patients were split into subgroups (A-E), depending on their individual PML risk. Some 22 MS patients on first-line drugs (DMD) acted as controls. No differences between treatment groups were observed in disease severity perception and personality traits. RAS were higher in NTZ than in DMD patients (p<0.01). Perception of the own disease as a more severe condition tended to predict higher RAS (p=0.07). Higher neuroticism scores predicted higher RAS in the NTZ group as a whole (p=0.04), and in high PML-risk subgroups (A-B) (p=0.02). In low PML-risk subgroups (C-E), higher RAS were associated with a JCV+ status (p=0.01). Neither disability scores nor pre-treatment relapse rate predicted RAS in either group. Risk acceptance is a multifactorial phenomenon, which might be partly explained by an adaptive process, in light of the higher risk acceptance amongst NTZ-treated patients and, especially, amongst those who are JCV seropositive but still have low PML risk, but which seems also intimately related to personality traits.
    PLoS ONE 01/2013; 8(12):e82796. · 3.53 Impact Factor
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    ABSTRACT: A relatively large proportion of relapsing-remitting multiple sclerosis (RRMS) patients do not respond to interferon-beta (IFNb) treatment. In previous studies with peripheral blood mononuclear cells (PBMC), we identified a subgroup of IFNb non-responders that was characterized by a baseline over-expression of type I IFN inducible genes. Additional mechanistic experiments carried out in IFNb non-responders suggested a selective alteration of the type I IFN signaling pathway in the population of blood monocytes. Here, we aimed (i) to investigate whether the type I IFN signaling pathway is up-regulated in isolated monocytes from IFNb non-responders at baseline; and (ii) to search for additional biological pathways in this cell population that may be implicated in the response to IFNb treatment. Twenty RRMS patients classified according to their clinical response to IFNb treatment and 10 healthy controls were included in the study. Monocytes were purified from PBMC obtained before treatment by cell sorting and the gene expression profiling was determined with oligonucleotide microarrays. Purified monocytes from IFNb non-responders were characterized by an over-expression of type I IFN responsive genes, which confirms the type I IFN signature in monocytes suggested from previous studies. Other relevant signaling pathways that were up-regulated in IFNb non-responders were related with the mitochondrial function and processes such as protein synthesis and antigen presentation, and together with the type I IFN signaling pathway, may also be playing roles in the response to IFNb.
    PLoS ONE 01/2013; 8(4):e60994. · 3.53 Impact Factor
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    Dataset: Byun et al
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    ABSTRACT: Type I interferons (IFNs) are known to enhance humoral immunity. Here, we investigated the prevalence and titer of anti-nuclear and anti-neuronal IgG autoantibodies in 71 relapsing-remitting MS patients classified based on their clinical response to IFNβ in paired sera obtained at baseline and after 12months of treatment. All samples were negative for antibodies against cytoplasmic rods/rings, synaptic proteins and paraneoplastic antibodies. Regarding anti-nuclear, anti-filament and anti-myelin antibodies, pre- and post-treatment prevalence and titers did not differ significantly between IFNβ responders and non-responders. Thus, pattern of anti-nuclear and anti-neuronal autoantibodies does not predict the response to IFNβ in MS patients.
    Journal of neuroimmunology 11/2012; · 2.84 Impact Factor
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    ABSTRACT: BACKGROUND AND AIM: Several studies have highlighted the association of the 12q13.3-12q14.1 region with coeliac disease, type 1 diabetes, rheumatoid arthritis and multiple sclerosis (MS); however, the causal variants underlying diseases are still unclear. The authors sought to identify the functional variant of this region associated with MS. METHODS: Tag-single nucleotide polymorphism (SNP) analysis of the associated region encoding 15 genes was performed in 2876 MS patients and 2910 healthy Caucasian controls together with expression regulation analyses. RESULTS: rs6581155, which tagged 18 variants within a region where 9 genes map, was sufficient to model the association. This SNP was in total linkage disequilibrium (LD) with other polymorphisms that associated with the expression levels of FAM119B, AVIL, TSFM, TSPAN31 and CYP27B1 genes in different expression quantitative trait loci studies. Functional annotations from Encyclopedia of DNA Elements (ENCODE) showed that six out of these rs6581155-tagged-SNPs were located in regions with regulatory potential and only one of them, rs10877013, exhibited allele-dependent (ratio A/G=9.5-fold) and orientation-dependent (forward/reverse=2.7-fold) enhancer activity as determined by luciferase reporter assays. This enhancer is located in a region where a long-range chromatin interaction among the promoters and promoter-enhancer of several genes has been described, possibly affecting their expression simultaneously. CONCLUSIONS: This study determines a functional variant which alters the enhancer activity of a regulatory element in the locus affecting the expression of several genes and explains the association of the 12q13.3-12q14.1 region with MS.
    Journal of Medical Genetics 11/2012; · 5.70 Impact Factor
  • MULTIPLE SCLEROSIS JOURNAL. 10/2012; 18:342.
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    ABSTRACT: BACKGROUND: Sialic acid binding immunoglobulin-like lectins (Siglecs) are cell surface receptors that recognize sialic acids and may attenuate immune responses and reduce inflammation. OBJECTIVE: The purpose of this study was to investigate the role of two members of the Siglec family, SIGLEC1 and SIGLEC7, in the clinical course and disease activity of patients with multiple sclerosis (MS). METHODS: SIGLEC1 and SIGLEC7 expression was determined by flow cytometry in the blood monocytes of 16 healthy controls and 55 untreated MS patients (13 primary progressive MS (PPMS) patients, 13 secondary progressive MS (SPMS) patients and 29 relapsing-remitting MS (RRMS) patients (18 during clinical remission and 11 during relapse)). RESULTS: SIGLEC1 expression by CD14+ monocytes was significantly increased in MS patients compared with controls (p=0.025 for percentage of positive cells; p=0.007 for mean fluorescence intensity (MFI)). Stratification of patients into different clinical forms revealed increased SIGLEC1 expression in patients with progressive forms of the disease, particularly in those with PPMS (p=0.003 for percentage of positive cells and p=0.001 for MFI when compared with controls; p=0.031 for percentage of positive cells when compared with RRMS patients). Both inflammatory and resident monocytes contributed to the increase in SIGLEC1 expression observed in PPMS patients. SIGLEC7 expression was significantly up-regulated in blood monocytes from RRMS during relapse compared with patients during clinical remission (p=0.001 for MFI). CONCLUSIONS: These findings suggest roles for SIGLEC1 in the chronic progressive phases of MS and for SIGLEC7 in acute disease activity.
    Multiple Sclerosis 08/2012; · 4.47 Impact Factor
  • Carme Costa, Manuel Comabella, Xavier Montalban
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    ABSTRACT: Therapeutic strategies based on stem cells are being increasingly used to treat a wide range of neurological diseases. Although these strategies were initially designed to replace dead cells in injured tissue, the potential of stem cells to migrate, secrete trophic factors, and immunomodulate allows their therapeutic use as a vehicle for gene therapy, as in Parkinson's disease, or as immunomodulators and neuroprotectors in diseases such as multiple sclerosis. This review will focus on current clinical and experimental evidence on the treatment of neurological disorders with strategies based on stem cells.
    Medicina Clínica. 07/2012; 139(5):208–214.
  • Genes and immunity 07/2012; 13(5):443. · 4.22 Impact Factor
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    ABSTRACT: DNA vaccines represent promising therapeutic strategies in autoimmune disorders such as multiple sclerosis (MS). However, the precise mechanisms by which DNA vaccines induce immune regulation remain largely unknown. Here, we aimed to expand previous knowledge existing on the mechanisms of action of DNA vaccines in the animal model of MS, experimental autoimmune encephalomyelitis (EAE), by treating EAE mice with a DNA vaccine encoding the myelin oligodendrocyte glycoprotein (MOG), and exploring the therapeutic effects on the disease-induced inflammatory and neurodegenerative changes. EAE was induced in C57BL6/J mice by immunization with MOG₃₅₋₅₅ peptide. Mice were intramuscularly treated with a MOG-DNA vaccine or vehicle in prophylactic and therapeutic approaches. Histological studies were performed in central nervous system (CNS) tissue. Cytokine production and regulatory T cell (Treg) quantification were achieved by flow cytometry. Gene expression patterns were determined using microarrays, and the main findings were validated by real-time PCR. MOG-DNA treatment reduced the clinical and histopathological signs of EAE when administered in both prophylactic and therapeutic settings. Suppression of clinical EAE was associated with dampening of antigen (Ag)-specific proinflammatory Th1 and Th17 immune responses and, interestingly, expansion of Treg in the periphery and upregulation in the CNS of genes encoding neurotrophic factors and proteins involved in remyelination. These results suggest for the first time that the beneficial effects of DNA vaccines in EAE are not limited to anti-inflammatory mechanisms, and DNA vaccines may also exert positive effects through hitherto unknown neuroprotective mechanisms.
    Journal of Neuroinflammation 06/2012; 9:139. · 4.35 Impact Factor
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    ABSTRACT: The new insights presented at the 5th Joint Triennial Congress of the European and Americas Committees on Treatment and Research in Multiple Sclerosis (ECTRIMS and ACTRIMS) held in Amsterdam, the Netherlands, 19-22 October 2011, have been summarized at the fourth edition of Post-ECTRIMS meeting held in Madrid in November 2011. Regional grey-matter atrophy is more sensitive to cognitive impairment than global grey-matter atrophy measures. In patients with clinically isolated syndrome cognitive impairment does not predict conversion to multiple sclerosis (MS) after 5-years of follow-up. Focusing on central nervous system plasticity and functional reorganization in MS, an early intervention can improve clinical aspects and enhances brain plasticity. Preservation of a potential for plasticity provides a rationale for rehabilitation interventions even in later stages of disease. Therapeutical strategies have focused on stem cell-mediated remyelination and immunomodulation functions, on cellular infiltration into the brain, and on new ways for immuno-modulation for the development of future therapies in MS. Encouraging findings from clinical trials with current and emerging disease-modifying therapy being developed was also a key theme at this edition. Positive results have been reported for rituximab, ocrelizumab, ofatumumab, daclizumab, alemtuzumab, teriflunomide, BG-12, and laquinimod, including a favorable safety profile. Since armamentarium for the treatment of MS is fast increasing, concerns exist about the risk of severe adverse events with their use. This aspect reinforces the importance of disease registries as a proactive tool for monitoring drug safety in the post-approval setting.
    Revista de neurologia 06/2012; 54(12):734-49. · 1.18 Impact Factor
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    ABSTRACT: Transcriptomics has emerged as a powerful approach for biomarker discovery. In the present review, the two main types of high throughput transcriptomic technologies - microarrays and next generation sequencing - that can be used to identify candidate biomarkers are briefly described. Microarrays, the mainstream technology of the last decade, have provided hundreds of valuable datasets in a wide variety of diseases including multiple sclerosis (MS), in which this approach has been used to disentangle different aspects of its complex pathogenesis. RNA-seq, the current next generation sequencing approach, is expected to provide similar power as microarrays but extending their capabilities to aspects up to now more difficult to analyse such as alternative splicing and discovery of novel transcripts.
    Journal of neuroimmunology 05/2012; 248(1-2):23-31. · 2.84 Impact Factor
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    ABSTRACT: Despite the availability of diagnostic criteria, an overlap between neuromyelitis optica (NMO) and multiple sclerosis (MS) exists, particularly in the early stage of the disease. To study the value of NMO-immunoglobulin G (IgG) determination in Caucasian patients with a first demyelinating episode who develop a relapsing form of optic neuritis or myelitis. This study was based on a prospectively acquired cohort of patients regarded as having a clinically isolated syndrome (CIS) at the time of presentation. From this cohort, 2 different groups were selected: group 1 (NMO phenotype), consisting of a first attack involving the optic nerve or the spinal cord, and at least a second event affecting either topography, and group 2 (negative control group), consisting of a first attack involving the brainstem or the cerebral hemispheres and at least 1 relapse in any topography. Group 3 was composed of patients with NMO according to the 2006 revised diagnostic criteria. Serum NMO-IgG was determined by indirect immunofluorescence. A total of 3.1 of the group 1 patients were positive for NMO-IgG in comparison to 3.9% of group 2 and 44.5% of group 3, NMO. One of the positive patients in group 1 evolved to NMO. NMO-IgG determination is crucial in detecting patients who will develop NMO; however, its value as a routine test in cases presenting with symptoms of the type seen in MS is low, and should only be performed in those patients in which the initial diagnosis is not clear.
    Neurology 05/2012; 78(20):1608-11. · 8.30 Impact Factor
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    ABSTRACT: Multifocal progressive leukoencephalopathy (PML) is associated with JC virus (JCV) seropositivity, past immunosuppression, and natalizumab treatment for two years or more. The aim of our study was to investigate the rate of treatment discontinuation after stratifying for the three risk factors in a group of 104 natalizumab-treated patients with relapsing-remitting multiple sclerosis. We investigated JCV serological status in our population. We then divided patients into groups according to their PML risk. Treatment indication was reassessed. Of the patients, 64 (61.5%) were JCV seropositive. Amongst seropositive patients on natalizumab for 2 years or more, 10 had received immunosuppression (group A), and 38 had not (group B). After an informed and shared decision-making process, 6/10 (60%) from group A compared with 9/38 (23.7%) from group B discontinued treatment (p=0.027). In groups A and B, discontinuation also depended upon doctors' views (p=0.019, group A; p=0.010, group B) and clinical outcomes (p=0.021, group A). No-one from low-intermediate risk groups discontinued. The decision to discontinue natalizumab treatment is complex, even when clear PML risk rates are described. Clinical outcomes and doctors' idiosyncrasies play a crucial part in patients' final choice.
    Multiple Sclerosis 03/2012; 18(8):1193-6. · 4.47 Impact Factor
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    ABSTRACT: Recently, we reported an association between a SNP in IL28RA and MS. Here, we performed a fine-mapping of the IL28RA locus by genotyping 10 haplotype-tagging SNPs in a Basque-Spanish population. In addition, based on shared genetic risk loci between autoimmune diseases, a psoriasis-associated SNP located at this locus, rs4649203, was genotyped in four independent populations, comprising a total of 2582 cases and 2614 controls. We did not find any consistent association between IL28RA and MS in these populations, suggesting that, although it may play a role in other autoimmune diseases, this gene is unlikely of general relevance to MS pathogenesis.
    Journal of neuroimmunology 03/2012; 245(1-2):98-101. · 2.84 Impact Factor
  • Carme Costa, Manuel Comabella, Xavier Montalban
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    ABSTRACT: Therapeutic strategies based on stem cells are being increasingly used to treat a wide range of neurological diseases. Although these strategies were initially designed to replace dead cells in injured tissue, the potential of stem cells to migrate, secrete trophic factors, and immunomodulate allows their therapeutic use as a vehicle for gene therapy, as in Parkinson's disease, or as immunomodulators and neuroprotectors in diseases such as multiple sclerosis. This review will focus on current clinical and experimental evidence on the treatment of neurological disorders with strategies based on stem cells.
    Medicina Clínica 02/2012; 139(5):208-14. · 1.25 Impact Factor
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    ABSTRACT:   Therapy for multiple sclerosis (MS) has a partial efficacy, and a significant proportion of treated patients will develop a suboptimal response with first-line disease-modifying drugs (DMD). Therapy switch in patients with MS can be a strategy after a treatment failure. We studied the change in clinical activity after switching of first-line DMD because of a treatment failure.   Relapsing-remitting multiple sclerosis (RRMS) patients treated with interferon-beta (IFNB) or glatiramer acetate (GA) were divided into (i) patients without change in DMD, (ii) patients with a change in DMD because of a poor response, and (iii) those with a change in DMD without relation with response. Annualized relapse rate (ARR) and relapse-free proportions were analyzed.   We identified 923 patients with RRMS. Of the 180 who experienced a change because of suboptimal response, 90 switched to another first-line DMT, 38 to mitoxantrone, and 52 to natalizumab. Median ARR in the pre-DMD period on first DMD and second DMD was the following: 1, 1, and 0 for switchers from IFNB to another IFNB (P = 0.0001); 0.67, 1, and 0 for switchers from GA to IFNB (P = 0.01); 1, 1, and 0 for switchers from an IFNB to GA (P = 0.02); 1.1, 1.5, 0.2 for switchers from IFNB or GA to mitoxantrone (P = 0.0001); 0.9, 1, 0 for switchers from IFNB or GA to natalizumab (P = 0.0001).   In patients with RRMS who have a poor response, switch to another DMD may reduce the clinical activity of the disease.
    European Journal of Neurology 01/2012; 19(6):899-904. · 4.16 Impact Factor
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    ABSTRACT: Ten genes previously showing different evidence of association with multiple sclerosis have been selected to validate. Eleven polymorphisms were genotyped with the iPLEX™ Sequenom in a well-powered collection of Spanish origin including 2863 multiple sclerosis cases and 2930 controls. Replication extended to the following polymorphisms: PKN2 (rs305217), GTF2B (rs7538427), EPHA4 (rs1517440), YTHDF3 (rs12115114), ANKFN1 (rs17758761) and PTPRM (rs4798571), which did not reach the threshold of significance in a follow-up of the first genome-wide association study (GWAS) conducted in multiple sclerosis; TMEM39A (rs1132200), which appeared as a newly identified susceptibility gene in the same study; a gene previously reaching GWAS significance in Italy, CBLB (rs9657904); IL12B (rs6887695, rs10045431), a susceptibility gene shared by diverse autoimmune diseases and, finally, another gene showing inconclusive association with multiple sclerosis, CNR1 (rs1049353). Pooled analysis corroborated the effect on MS predisposition of three genes: TMEM39A [rs1132200: p(M-H)=0.001; OR(M-H) (95% CI)= 0.84 (0.75-0.93)], IL12B [rs6887695: p(M-H)=0.03; OR(M-H) (95% CI)= 1.09 (1.01-1.17)] and CBLB [rs9657904: p(M-H)=0.01; OR(M-H) (95% CI)= 0.89 (0.81-0.97)].
    Multiple Sclerosis 12/2011; 18(7):959-65. · 4.47 Impact Factor
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    ABSTRACT: Chitinase 3-like 1 (CHI3L1) is upregulated in a wide variety of inflammatory conditions. Recent studies have pointed to a role of CHI3L1 in multiple sclerosis (MS) pathogenesis. The objective of this study was to investigate the role of plasma CHI3L1 in MS clinical course and disease activity and to evaluate the effect of interferon-beta (IFNβ) treatment on protein levels. Plasma CHI3L1 levels were determined by ELISA in 57 healthy controls (HC), 220 untreated MS patients [66 primary progressive MS patients (PPMS), 30 secondary progressive MS patients (SPMS), and 124 relapsing-remitting MS patients (RRMS), 94 during clinical remission and 30 during relapse], and 32 MS patients receiving IFNβ treatment. A polymorphism of the CHI3L1 gene, rs4950928, was genotyped in 3274 MS patients and 3483 HC. Plasma CHI3L1 levels were significantly increased in patients with progressive forms of MS compared with RRMS patients and HC. CHI3L1 levels were similar between RRMS patients in relapse and remission. A trend towards decreased CHI3L1 levels was observed in IFNβ-treated patients. Allele C of rs4950928 was significantly associated with PPMS patients and with higher plasma CHI3L1 levels. These findings point to a role of CHI3L1 in patients with progressive forms of MS, particularly in those with PPMS.
    Multiple Sclerosis 12/2011; 18(7):983-90. · 4.47 Impact Factor
  • Manuel Comabella, Samia J Khoury
    Clinical Immunology 12/2011; 142(1):1. · 3.77 Impact Factor

Publication Stats

3k Citations
920.19 Total Impact Points

Institutions

  • 2012–2014
    • VHIR Vall d’Hebron Research Institute
      Barcino, Catalonia, Spain
  • 1995–2014
    • University Hospital Vall d'Hebron
      • Department of Neurology
      Barcino, Catalonia, Spain
  • 2005–2013
    • Autonomous University of Barcelona
      • Department of Medicine
      Cerdanyola del Vallès, Catalonia, Spain
  • 2011–2012
    • Hospital Virgen del Camino
      Cádiz, Andalusia, Spain
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
    • IMIM Hospital del Mar Medical Research Institute
      Barcino, Catalonia, Spain
  • 2009–2012
    • University of Barcelona
      • • Departament d'Estadística
      • • Departament de Medicina
      Barcelona, Catalonia, Spain
    • University of Zurich
      • Institut für Experimentelle Immunologie
      Zürich, ZH, Switzerland
  • 2010
    • Universidad del País Vasco / Euskal Herriko Unibertsitatea
      Leioa, Basque Country, Spain
    • Instituto de Salud Carlos III
      Madrid, Madrid, Spain
    • Catalan Institution for Research and Advanced Studies
      Barcino, Catalonia, Spain
  • 2005–2008
    • University of California, San Francisco
      • • Department of Neurology
      • • Division of Hospital Medicine
      San Francisco, CA, United States
  • 2007
    • Vall d’Hebron Institute of Oncology
      Barcino, Catalonia, Spain
  • 2004
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 1998–2004
    • Brigham and Women's Hospital
      • • Department of Medicine
      • • Center for Neurologic Diseases
      Boston, MA, United States