Olivier Boyer

Université de Rouen, Mont-Saint-Aignan, Upper Normandy, France

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Publications (115)437.25 Total impact

  • Clinical & Experimental Immunology 11/2014; · 3.41 Impact Factor
  • Leukemia. 08/2014;
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    ABSTRACT: ADP-ribosyltransferases comprise a family of enzymes originally discovered as bacterial toxins and later characterised also in mammals. In mice, the ADP-ribosyltransferase ARTC2.2 is expressed at the surface of T lymphocytes and has been studied extensively. In the presence of extracellular NAD(+), ARTC2.2 ADP-ribosylates several cell surface target proteins and thereby regulates their function. P2X7, an ATP-gated cation channel, has been discovered as a prominent ARTC2.2 target at the surface of mouse T cells. ADP-ribosylation of P2X7 in the presence of low micromolar extracellular NAD(+) induces long-lasting P2X7 activation and triggers cell death. Regulatory T cell subsets (Tregs and NKT cells) are remarkably sensitive to NAD(+)-induced cell death (NICD). Thus, liberation of endogenous NAD(+) by stressed cells is now viewed as a danger signal promoting immune responses by hindering regulatory T cells. This review will highlight the recent discoveries on the in vivo role of the ARTC2.2/P2X7 pathway triggered by the endogenous release of extracellular NAD(+), the relative sensitivity of lymphocytes subsets to this regulatory pathway and its pharmacological manipulation using camelid-derived ARTC2.2-blocking nanobodies.
    Current topics in microbiology and immunology 07/2014; · 4.86 Impact Factor
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    ABSTRACT: Objective. To assess the role of Toll-like receptors (TLRs) in antiphospholipid antibody (aPL)-mediated vascular abnormalities in patients with primary arterial antiphospholipid syndrome (APS).Methods. Forty eight subjects participated in the study. Arterial function and structure and TLR pathway activation were determined in primary arterial APS patients and frequency-matched controls. The pathogenic effects of aPL isolated from patients were assessed in wild-type and TLR knockout mice.Results. APS patients displayed endothelial dysfunction, arterial stiffening and hypertrophy, as shown by decreased brachial artery endothelium-dependent flow-mediated dilatation (FMD) and increased aortic pulse wave velocity and carotid intima-media thickness (IMT) as compared with controls. Plasma samples from APS patients revealed decreased NO availability and a pro-oxidative, pro-inflammatory and pro-thrombotic state illustrated by a decrease in nitrite and an increase in lipid peroxidation, TNF-α and tissue factor (TF) levels. Furthermore, TLR pathway activation was demonstrated in APS patients with increased TLR2 and TLR4 mRNA expression and protein levels of activated TLR transduction protein IRAK1 in peripheral blood mononuclear cells. Moreover, agonist-stimulated cell-surface expression of TLR2 and TLR4 in circulating monocytes was higher in APS patients than in controls. These changes were positively associated with IMT and negatively with FMD. Finally, aPL injection decreased mesenteric endothelium-dependent relaxations and increased TF expression in wild-type but not in TLR2 or TLR4 knockout mice.Conclusion. This translational study supports the role of TLR2 and TLR4 in mediating vascular abnormalities in primary arterial APS patients. TLRs, thus constitute a promising pharmacological target to prevent the cardiovascular complications in APS. © 2014 American College of Rheumatology.
    Arthritis & Rheumatology. 07/2014;
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    ABSTRACT: Necrotizing autoimmune myopathy (NAM) is a group of acquired myopathies characterized by prominent myofiber necrosis with little or no muscle inflammation. Recently, researchers identified autoantibodies (aAb) against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in patients with NAM, especially in statin-exposed patients. Here we report what is to our knowledge the first European cohort of patients with NAM.The serum of 206 patients with suspicion of NAM was tested for detection of anti-HMGCR aAb using an addressable laser bead immunoassay. Forty-five patients were found to be anti-HMGCR positive. Their mean age was 48.9 ± 21.9 years and the group was predominantly female (73.3%). Statin exposure was recorded in 44.4% of patients. Almost all patients had a muscular deficit (97.7%), frequently severe (Medical Research Council [MRC] 5 ≤3 in 75.5%). Subacute onset (<6 mo) was noted for most of them (64.4%). Nevertheless, 3 patients (6.6%) had a slowly progressive course over more than 10 years. Except for weight loss (20%), no extramuscular sign was observed. The mean CK level was high (6941 ± 8802 IU/L) and correlated with muscle strength evaluated by manual muscle testing (r = -0.37, p = 0.03). Similarly, anti-HMGCR aAb titers were correlated with muscular strength (r = -0.31; p = 0.03) and CK level (r = 0.45; p = 0.01). Mean duration of treatment was 34.1 ± 40.8 months, and by the end of the study no patient had been able to stop treatment.This study confirms the observation and description of anti-HMGCR aAb associated with NAM. The majority of patients were statin naive and needed prolonged treatments. Some patients had a dystrophic-like presentation. Anti-HMGR aAb titers correlated with CK levels and muscle strength, suggesting their pathogenic role.
    Medicine 05/2014; 93(3):150-7. · 4.35 Impact Factor
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    ABSTRACT: Necrotizing autoimmune myopathies (NAM) have recently been defined as a distinct group of severe acquired myopathies, characterized by prominent myofiber necrosis without significant muscle inflammation. Because of the lack of appropriate biomarkers, these diseases have been long misdiagnosed as atypical forms of myositis. NAM may be associated to autoantibodies directed against signal recognition particle (SRP) or 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). The objective of this work was to quantify anti-HMGCR autoantibodies in patients with suspicion of NAM through the development of a new addressable laser bead immunoassay (ALBIA). Recombinant HMGCR C-domain was bound to fluorescent beads. After incubation with serum, autoantibodies were revealed using class- or subclass-specific anti-human immunoglobulin G (IgG) antibodies. Anti-HMGCR levels were assayed in 150 patients with suspicion of NAM, 142 controls with different inflammatory/autoimmune diseases and 100 healthy donors. Inhibition with free recombinant HMGCR and immunoprecipitation experiments confirmed test specificity. Reproducibility and repeatability were determined from sera with various levels of anti-HMGCR autoantibodies. A multiplex assay (ALBIA-NAM) was also developed to permit the simultaneous quantification of anti-HMGCR and anti-signal recognition particle autoantibodies. No controls scored positive. Of 150 patients with suspicion of NAM, 24% were positive for anti-HMGCR autoantibodies with levels ranging from 24 to 2,656 AU/mL. Anti-HMGCR positivity could be associated to a cytoplasmic pattern in immunofluorescence assay on HEp-2 cells. Anti-HMGCR-positive patients had high creatine kinase (CK) levels (mean 6,630 IU/L) and only 40% of them had been exposed to statins. Multiplex ALBIA-NAM was equally as effective as monoplex anti-HMGCR and anti-SRP ALBIA. Both monoplex ALBIA-HMGCR and multiplex ALBIA-NAM reliably detect and quantify anti-HMGCR autoantibodies. A positive result allows ascribing patients with a necrotizing myopathy to an autoimmune form. Anti-HMGCR autoantibodies may be found in patients who have not taken statins.
    Arthritis research & therapy 02/2014; 16(1):R39. · 4.27 Impact Factor
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    ABSTRACT: Diagnostic tests are needed to aid in the diagnosis of necrotizing myopathies associated with statin use. This study aimed to compare different technologies for the detection of anti-HMGCR antibodies and analyze the clinical phenotype and autoantibody profile of the patients. Twenty samples from myositis patients positive for anti-HMGCR antibodies using a research addressable laser bead assay and 20 negative controls were tested for autoantibodies to HMGCR: QUANTA Lite HMGCR ELISA and QUANTA Flash HMGCR CIA. All patients were also tested for antibodies to extractable nuclear antigens and myositis related antibodies. To verify the specificity of the ELISA, 824 controls were tested. All three assays showed qualitative agreements of 100% and levels of anti-HMGCR antibodies showed significant correlation: Spearman's rho > 0.8. The mean age of the anti-HMGCR antibody positive patients was 54.4 years, 16/20 were females, and 18/20 had necrotizing myopathy (two patients were not diagnosed). Nine out of 20 anti-HMGCR positive patients were on statin. All patients with anti-HMGCR antibodies were negative for all other autoantibodies tested. Testing various controls showed high specificity (99.3%). Anti-HMGCR antibodies are not always associated with the use of statin and appear to be the exclusive autoantibody specificity in patients with statin associated myopathies.
    Journal of Immunology Research 01/2014; 2014:405956. · 2.93 Impact Factor
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    ABSTRACT: Fecal incontinence (FI) remains a socially isolating condition with profound impact on quality of life for which autologous myoblast cell therapy represents an attractive treatment option. We developed an animal model of FI and investigated the possibility of improving sphincter function by intra-sphincteric injection of syngeneic myoblasts. Several types of anal cryoinjuries were evaluated on anesthetized Fischer rats receiving analgesics. The minimal lesion yielding sustainable anal sphincter deficiency was a 90° cryoinjury of the sphincter, repeated after a 24h interval. Anal sphincter pressure was evaluated longitudinally by anorectalmanometry under local electro-stimulation. Myoblasts were prepared using a protocol mimicking a clinical-grade process and further transduced with a GFP-encoding lentiviral vector before intra-sphincteric injection. Experimental groups were: uninjured controls; cryoinjured + PBS; and cryoinjured + myoblasts (different doses or injection site). Myoblast injection was well tolerated. Transferred myoblasts expressing GFP integrated into the sphincter and differentiated in situinto dystrophin-positive mature myofibers. Posttreatment sphincter pressures increased overtime.At D60, pressures in the treated group were significantly higher than those ofPBS-injected controls and notsignificantly different from those of normal rats. Longitudinal follow-up showed stability of the therapeutic effect on sphincter function over a period of 6 months. Intra-sphincteric myoblast injections at the lesion borders were equally as effective as intra-lesion administration, but an injection opposite to the lesion was not. These results provide proof of principle for myoblast cell therapy in fecal incontinence in a rat model. This strategy is currently being evaluated in humans in a randomized double-blind placebo-controlled clinical trial.
    Cell Transplantation 10/2013; · 4.42 Impact Factor
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    ABSTRACT: Immune-mediated necrotizing myopathy (IMNM) associated with statin use and anti 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibody is a new and emerging entity that supports a link between statin use and IMNM and raises the questions of distinct clinical phenotypes and treatment strategy. We describe the clinical and histopathological characteristics of a patient and discuss the spectrum of IMNM and statin-induced myopathies. A 65-year-old man was suffering from proximal muscle weakness and elevated CK levels, following exposure to statin therapy. The symptoms worsened despite discontinuation of the drug. At that point, no myositis-specific or -associated antibodies were detected. Malignancy screening did not reveal abnormalities. Muscle biopsy demonstrated a predominantly necrotizing myopathy with minimal lymphocytic infiltrates, MHC class I expression in necrotic muscle fibers, and complement deposition on scattered non-necrotic muscle fibers. Muscle protein analysis by western blot was normal. The patient did not improve with steroid and methotrexate and required monthly intravenous immunoglobulin (IVIG) therapy. Muscle strength gradually improved, CK levels normalized and IVIG were stopped 1year later. Screening for anti-HMGCR antibodies, not available at the time of presentation, was highly positive. Identification of anti-HMGCR antibodies in statin-exposed patients with myopathy appears to be helpful both for differential diagnosis and for treatment strategy. In patients who did not improve after discontinuation of the statin treatment, a muscle biopsy should be performed as well as screening for anti-HMGCR antibodies. Patients with this disorder require aggressive immunosuppressive treatment.
    Joint, bone, spine: revue du rhumatisme 08/2013; · 2.25 Impact Factor
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    ABSTRACT: Genetic alterations have recently been described as emerging during the culture of embryonic stem cells or induced pluripotent stem cells, raising concerns about their safety in future clinical use. Myoblasts are adult stem cells with important therapeutic potential that have been used in clinical trials for almost twenty years but their genome integrity has not yet been established. Here, we produced 10 human myoblast preparations and investigated their genomic stability. At the third passage, half of the preparations had a normal karyotype and half showed 1-4 alterations/30 metaphases. Chromosome 2 trisomy was found in 1-2/30 metaphases and/or 2/100 nuclei by FISH in 3/10 samples, and there was no other recurrent anomaly. When prolonging cultures, these erratic abnormalities were never associated with a growth advantage. Cellular senescence was manifested in all samples by growth arrest before passage 15. Expression of hTERT was always negative. Molecular analysis of individual p53 transcripts did not reveal tumorigenic mutations. CGH array (10 samples) and exome sequencing (1 sample) failed to detect copy number variations or accumulation of mutations, respectively. Myoblasts did not grow either in soft agar or in vivo after injection in immuno-deficient mice. Hence, occasional genomic abnormalities may occur during myoblast culture but are not associated with risk of transformation.
    Cell Transplantation 07/2013; · 4.42 Impact Factor
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    ABSTRACT: Muscle fibers do not normally express major histocompatibility complex class I (MHC-I) molecules, and their reexpression is a hallmark of inflammatory myopathies. It has been shown in mice that overexpression of MHC-I induces a poorly inflammatory myositis accompanied by the unfolded protein response (UPR), but it is unclear whether it is attributable to T-cell-mediated MHC-I-dependent immune responses or to MHC-I forced expression per se. Indeed, besides presenting antigenic peptides to CD8(+) T cells, MHC-I may also possibly exert nonimmunologic, yet poorly understood pathogenic effects. Thus, we investigated the pathogenicity of MHC-I expression in muscle independently of its immune functions. HT transgenic mice that conditionally overexpress H-2K(b) in muscle were bred to an immunodeficient Rag2(-/-) background. The muscle proteome was analyzed by label-free high-resolution protein quantitation and Western blot. Despite the absence of adaptive immunity, HT Rag2(-/-) mice developed a very severe myopathy associated with the cytoplasmic accumulation of H-2K(b) molecules. The UPR was manifest by up-regulation of characteristic proteins. In humans, we found that HLA class I molecules not only were expressed at the sarcolemma but also could accumulate intracellularly in some patients with inclusion body myositis. Accordingly, the UPR was triggered as a function of the degree of HLA accumulation in myofibers. Hence, reexpression of MHC-I in normally negative myofibers exerts pathogenic effects independently of its immune function.
    American Journal Of Pathology 07/2013; · 4.60 Impact Factor
  • I. Marie, O. Boyer
    La Revue de Médecine Interne. 06/2013; 34(6):333–336.
  • I Marie, O Boyer
    La Revue de Médecine Interne 01/2013; · 0.90 Impact Factor
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    ABSTRACT: La myopathie nécrosante auto-immune (MNAI) associée à l’utilisation des statines et à la présence d’anticorps anti-3-hydroxy-3-méthylglutaryl-coenzyme A réductase (HMGCR) est une entité nouvelle et émergeante qui renforce le lien entre l’exposition aux statines et la survenue de MNAI et soulève la question d’éventuels phénotypes cliniques et de stratégies thérapeutiques distincts. Nous décrivons les caractéristiques cliniques et histologiques d’un patient et discutons le spectre des MNAI et des myopathies induites par les statines. Un homme âgé de 65 ans avait souffert d’une faiblesse musculaire proximale et d’un taux élevé de CPK, après avoir reçu un traitement par statines. Les symptômes se sont aggravés malgré l’arrêt de ces dernières. À ce moment, aucun anticorps spécifique ou associé aux myosites n’a été détecté. La recherche de néoplasies était négative. La biopsie musculaire avait montré un aspect de myopathie nécrosante avec un infiltrat lymphocytaire minime, une expression du CMH de classe I dans les fibres musculaires nécrosées et des dépôts de complément sur quelques fibres musculaires non nécrosées dispersées. L’analyse des protéines musculaires par Western Blot était normale. Le patient n’était pas amélioré par les corticoïdes et le méthotrexate et avait nécessité des perfusions d’immunoglobulines IV (IGIV). La force musculaire s’est améliorée progressivement, le taux des CPK s’est normalisé et les IGIV étaient arrêtés un an plus tard. La recherche d’anticorps anti-HMGCR, non disponible au moment de la présentation clinique, était fortement positive. L’identification des anticorps anti-HMGCR chez les patients sous statines présentant une myopathie semble intéressante afin d’aider au diagnostic différentiel et de guider le traitement. Chez les patients ne s’améliorant pas à l’arrêt du traitement par statines, une biopsie musculaire doit être réalisée ainsi que la recherche d’anticorps anti-HMGCR. Les patients présentant ces anomalies nécessitent des traitements immunosuppresseurs agressifs.
    Revue du Rhumatisme 01/2013;
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    ABSTRACT: Spinal cord injury (SCI) induces a permanent disability in patients. To this day no curative treatment can be proposed to restore lost functions. Therefore, extensive experimental studies have been conducted to induce recovery after SCI. One of the most promising therapies is based on the use of olfactory ensheathing cells (OECs). OECs can be obtained from either the olfactory bulbs (OB-OECs) or from olfactory mucosa (OM-OECs), involving a less invasive approach for autotransplantation. However the vast majority of experimental transplantations have been focusing on OB-OECs although the OM represents a more accessible source of OECs. Importantly, the ability of OM-OECs in comparison to OB-OECs to induce spinal cord recovery in the same lesion paradigm has never been described. We here present data using a multiparametric approach, based on electrophysiological, behavioral, histological and magnetic resonance imaging experiments on the repair potential of OB-OECs and OM-OECs from either primary or purified cultures after a severe model of SCI. Our data demonstrate that transplantation of OECs obtained from OB or OM induces electrophysiological and functional recovery, reduces astrocyte reactivity and glial scar formation and improves axonal regrowth. We also show that the purification step is essential for OM-OECs while not required for OB-OECs. Altogether, our study strongly indicates that transplantation of OECs from OM represents the best benefit/risk ratio according to the safety of access of OM and the results induced by transplantations of OM-OECs. Indeed, purified OM-OECs in addition to induce recovery can integrate and survive up to 60 days into the spinal cord. Therefore, our results provide strong support for these cells as a viable therapy for SCI.
    PLoS ONE 01/2013; 8(4):e62860. · 3.53 Impact Factor
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    ABSTRACT: We describe the effectiveness of combinatorial therapy with plasma exchanges and methylprednisolone pulses followed by intravenous cyclophosphamide in a young girl with anti-signal recognition particle 54 (SRP54) antibody-associated myopathy. We also use a newly described quantitative assay to demonstrate the close association between the titers of anti-SRP54 antibodies and disease activity. This is the first report of a pediatric patient indicating that the serum levels of anti-SRP54 antibodies are also beneficial for monitoring the disease activity of progressive necrotizing myopathy.
    Modern Rheumatology 11/2012; · 1.72 Impact Factor
  • Journal des Maladies Vasculaires 09/2012; 33:S54. · 0.24 Impact Factor
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    ABSTRACT: To investigate the influence of myoinjury on antigen presentation to T cells in draining lymph nodes (LNs). Muscle crush was performed in mice injected with exogenous ovalbumin (OVA) and in transgenic SM-OVA mice expressing OVA as a muscle-specific self antigen. Antigen exposure and the resulting stimulation of T cell proliferation in draining LNs was assessed by transferring carboxyfluorescein succinimidyl ester (CFSE)-labeled OVA-specific CD8+ and CD4+ T cells from OT-I and OT-II mice and by measuring the dilution of CFSE, which directly reflects their proliferation. The role of monocyte-derived dendritic cells (DCs) in T cell priming was assessed using pharmacologic blockade of DC migration. Immunofluorescence was used to detect CD8+ T cells, inflammatory monocyte-derived DCs, and type I major histocompatibility complex (MHC)-expressing myofibers in crushed muscle, and to assess expression of perforin, interferon-γ (IFNγ), interleukin-2 (IL-2), IL-10, and transforming growth factor β1 (TGFβ1). OVA injection into intact muscle induced strong proliferation of CD4+ and CD8+ T cells, indicating efficient exposure of soluble antigens in draining LNs. OVA-specific CD8+ T cell proliferation in draining LNs of SM-OVA mice required myoinjury and was unaffected by pharmacologic inhibition of monocyte-derived DC migration. On day 7 postinjury, activated CD8+ T cells expressing perforin, IFNγ and IL-2 were transiently detected in crushed muscle, and these cells were in close contact with class I MHC-positive regenerating myofibers. Beginning on day 7, the immunosuppressive cytokines IL-10 and TGFβ1 were conspicuously expressed by CD11b+ cells, and CD8+ T cells rapidly disappeared from the healing muscle. Myofiber damage induces an episode of muscle antigen-specific CD8+ T cell proliferation in draining LNs. Activated CD8+ T cells transiently infiltrate the injured muscle, with prompt control by immunosuppressive cues. Inadequate control might favor sustained autoimmune myositis.
    Arthritis & Rheumatology 06/2012; 64(10):3441-51. · 7.48 Impact Factor
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    ABSTRACT: Endogenous danger signals released during cell damage contribute to alert the immune system. Typically, their release results in the activation and maturation of innate immune cells, and the production of pro-inflammatory cytokines. In addition, extracellular NAD(+) stimulates immune responses by hindering regulatory T cells (Tregs), and could, therefore, represent the prototype of a new category of danger signals.
    Microbes and Infection 05/2012; · 2.92 Impact Factor
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    Current Frontiers and Perspectives in Cell Biology, 04/2012; , ISBN: 978-953-51-0544-2

Publication Stats

1k Citations
437.25 Total Impact Points


  • 2008–2014
    • Université de Rouen
      Mont-Saint-Aignan, Upper Normandy, France
  • 2013
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2006–2013
    • Centre Hospitalier Universitaire Rouen
      • Service d'Urologie
      Rouen, Upper Normandy, France
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Angeles, CA, United States
  • 2009–2012
    • University of Hamburg
      • Department of Immunology
      Hamburg, Hamburg, Germany
  • 2003–2011
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
    • Cea Leti
      Grenoble, Rhône-Alpes, France
  • 2008–2010
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1995–2005
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2004
    • UPMC
      Pittsburgh, Pennsylvania, United States
  • 1997–2002
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      • Service de Médecine Interne 1
      Lutetia Parisorum, Île-de-France, France