Publications by authors named "Béatrice Pignolet"

26 Publications

  • Page 1 of 1

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

Proc Natl Acad Sci U S A 2021 01;118(1)

Department of Neurology with Institute of Translational Neurology, University of Muenster, 48149 Muenster, Germany;

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies ( = 946, = 990). Additionally, effect-modification by medication and photosensitivity-associated variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β-treated patients. In carriers of :rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.
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http://dx.doi.org/10.1073/pnas.2018457118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817192PMC
January 2021

BEST-MS: A prospective head-to-head comparative study of natalizumab and fingolimod in active relapsing MS.

Mult Scler 2020 Oct 30:1352458520969145. Epub 2020 Oct 30.

Service de Neurologie, CRCSEP, Unité de Recherche Clinique Cote d'Azur (UR2CA), Centre Hospitalier Universitaire Pasteur 2, Nice, France.

Background: There are few head-to-head studies to compare highly active treatments in multiple sclerosis (MS).

Objective: The aim of this study was to compare the effectiveness between natalizumab (NTZ) and fingolimod (FTY) in active relapsing-remitting MS.

Method: Best Escalation STrategy in Multiple Sclerosis (BEST-MS) is a multicentric, prospective study with a 12-month follow-up including patients with active MS. Treatment choice was at the discretion of physician. Clinical and magnetic resonance imaging (MRI) data were collected at baseline and at 12 months. The primary outcome was the proportion of patients reaching no evidence of disease activity (NEDA) at 12 months. Secondary outcomes included annualized relapse rate and MRI activity.

Results: A total of 223 patients were included (NTZ: 109 and FTY: 114). Treatment groups were well balanced at baseline. Proportion of NEDA patients was 47.8% in NTZ group versus 30.4% in FTY group ( = 0.015). This superiority was driven by annualized relapse rate and MRI activity. In the multivariate analysis, treatment group was the only factor associated with NEDA at 12 months with a lower probability in FTY group (odds ratio (OR) = 0.49,  = 0.029).

Conclusion: BEST-MS is a prospective study that compared head-to-head the effectiveness of NTZ and FTY in active relapsing-remitting MS. Our results suggest a superiority of NTZ over FTY.
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http://dx.doi.org/10.1177/1352458520969145DOI Listing
October 2020

Prospective validation of the PML risk biomarker l-selectin and influence of natalizumab extended intervals.

Neurology 2019 09 22;93(12):550-554. Epub 2019 Aug 22.

From the Department of Neurology with Institute of Translational Neurology (N.S., T.S.-H., P.O., L.K., C.C.G., S.G.M., H.W.), University of Münster, Münster, Germany; CRC-SEP-Neurosciences Department (B.P., F.B., L.S., J.C., D. Biotti, D. Brassat), CHU Toulouse, Toulouse, France; CPTP-INSERM U1043-CNRS U5282-Université Toulouse III (B.P., F.B., L.S., D. Brassat), Toulouse, France; APHM (C.L.-F.), Hôpital de la Timone, Pôle de Neurosciences Cliniques, Marseille, France; CHU of Nice (G.M.), Nice, France; CHU Montpied, Neurology, Clermont-Ferrand, France (P.C.); APHM (J.P.), Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, CRCSEP Marseille, France; Institute of Clinical Neuroimmunology (I.M.), Ludwig-Maximilians University, Munich, Germany; Department of Neurology (S.W.), Clinics Osnabrück, Osnabrück, Germany; and Department of Neurology (F.G.), Innsbruck Medical University, Innsbruck, Austria.

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http://dx.doi.org/10.1212/WNL.0000000000008135DOI Listing
September 2019

Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects.

Sci Transl Med 2019 05;11(490)

University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany.

Interference with immune cell proliferation represents a successful treatment strategy in T cell-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis (MS). One prominent example is pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), which mediates de novo pyrimidine synthesis in actively proliferating T and B lymphocytes. Within the TERIDYNAMIC clinical study, we observed that the DHODH inhibitor teriflunomide caused selective changes in T cell subset composition and T cell receptor repertoire diversity in patients with relapsing-remitting MS (RRMS). In a preclinical antigen-specific setup, DHODH inhibition preferentially suppressed the proliferation of high-affinity T cells. Mechanistically, DHODH inhibition interferes with oxidative phosphorylation (OXPHOS) and aerobic glycolysis in activated T cells via functional inhibition of complex III of the respiratory chain. The affinity-dependent effects of DHODH inhibition were closely linked to differences in T cell metabolism. High-affinity T cells preferentially use OXPHOS during early activation, which explains their increased susceptibility toward DHODH inhibition. In a mouse model of MS, DHODH inhibitory treatment resulted in preferential inhibition of high-affinity autoreactive T cell clones. Compared to T cells from healthy controls, T cells from patients with RRMS exhibited increased OXPHOS and glycolysis, which were reduced with teriflunomide treatment. Together, these data point to a mechanism of action where DHODH inhibition corrects metabolic disturbances in T cells, which primarily affects profoundly metabolically active high-affinity T cell clones. Hence, DHODH inhibition may promote recovery of an altered T cell receptor repertoire in autoimmunity.
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http://dx.doi.org/10.1126/scitranslmed.aao5563DOI Listing
May 2019

IFN-γ is a therapeutic target in paraneoplastic cerebellar degeneration.

JCI Insight 2019 04 4;4(7). Epub 2019 Apr 4.

Centre de Physiopathologie Toulouse-Purpan (CPTP), Université de Toulouse, CNRS, Inserm, UPS, Toulouse, France.

Paraneoplastic neurological disorders result from an autoimmune response against neural self-antigens that are ectopically expressed in neoplastic cells. In paraneoplastic disorders associated to autoantibodies against intracellular proteins, such as paraneoplastic cerebellar degeneration (PCD), current data point to a major role of cell-mediated immunity. In an animal model, in which a neo-self-antigen was expressed in both Purkinje neurons and implanted breast tumor cells, immune checkpoint blockade led to complete tumor control at the expense of cerebellum infiltration by T cells and Purkinje neuron loss, thereby mimicking PCD. Here, we identify 2 potential therapeutic targets expressed by cerebellum-infiltrating T cells in this model, namely α4 integrin and IFN-γ. Mice with PCD were treated with anti-α4 integrin antibodies or neutralizing anti-IFN-γ antibodies at the onset of neurological signs. Although blocking α4 integrin had little or no impact on disease development, treatment using the anti-IFN-γ antibody led to almost complete protection from PCD. These findings strongly suggest that the production of IFN-γ by cerebellum-invading T cells plays a major role in Purkinje neuron death. Our successful preclinical use of neutralizing anti-IFN-γ antibody for the treatment of PCD offers a potentially new therapeutic opportunity for cancer patients at the onset of paraneoplastic neurological disorders.
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http://dx.doi.org/10.1172/jci.insight.127001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483638PMC
April 2019

Unexpected high multiple sclerosis activity after switching from fingolimod to alemtuzumab.

Mult Scler Relat Disord 2018 Oct 7;25:216-218. Epub 2018 Aug 7.

Centre for pathophysiology Toulouse Purpan, INSERM U1043, CNRS 5282, Université Toulouse III, Toulouse 31024, France; CRC-SEP, Pôle Neurosciences, CHU de Toulouse, Toulouse 31059, France. Electronic address:

Unexpected high disease activity (UHDA) after Fingolimod withdrawal has recently become a controversial concern for physicians. Here, we report the case of a patient with severe exacerbation of MS after switching from Fingolimod to Alemtuzumab treatment. This UHDA despite profound lymphopenia raised the question of the management of sequential use of biotherapies such as Fingolimod and Alemtuzumab in MS.
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http://dx.doi.org/10.1016/j.msard.2018.08.006DOI Listing
October 2018

Reply.

Ann Neurol 2017 10 4;82(4):647-648. Epub 2017 Oct 4.

Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

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http://dx.doi.org/10.1002/ana.25039DOI Listing
October 2017

Matrix metalloproteinase 9 is decreased in natalizumab-treated multiple sclerosis patients at risk for progressive multifocal leukoencephalopathy.

Ann Neurol 2017 Aug 22;82(2):186-195. Epub 2017 Jul 22.

Department of Neurology-Neuroimmunology, Multiple Sclerosis Center of Catalonia, Vall d'Hebron Research Institute, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain.

Objective: To identify biomarkers associated with the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab (NTZ).

Methods: Relapsing-remitting MS patients who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr) were included in the study. Cryopreserved peripheral blood mononuclear cells and serum samples collected at baseline, at 1- and 2-year treated time points, and during PML were analyzed for gene expression by RNA sequencing and for serum protein levels by Luminex and enzyme-linked immunosorbent assays, respectively.

Results: Among top differentially expressed genes in the RNA sequencing between pre-PML and NTZ-ctr patients, pathway analysis revealed a high representation of genes belonging to the following categories: proangiogenic factors (MMP9, VEGFA), chemokines (CXCL1, CXCL5, IL8, CCL2), cytokines (IL1B, IFNG), and plasminogen- and coagulation-related molecules (SERPINB2, PLAU, PLAUR, TFPI, THBD). Serum protein levels for these candidates were measured in a 2-step manner in a screening cohort and a validation cohort of pre-PML and NTZ-ctr patients. Only matrix metalloproteinase 9 (MMP9) was validated; in pre-PML patients, MMP9 protein levels were significantly reduced at baseline compared with NTZ-ctr patients, and levels remained lower at later time points during NTZ treatment.

Interpretation: The results from this study suggest that the proangiogenic factor MMP9 may play a role as a biomarker associated with the development of PML in MS patients treated with NTZ. Ann Neurol 2017;82:186-195.
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http://dx.doi.org/10.1002/ana.24987DOI Listing
August 2017

CD4+ and CD8+ T cells are both needed to induce paraneoplastic neurological disease in a mouse model.

Oncoimmunology 2017;6(2):e1260212. Epub 2016 Dec 9.

INSERM UMR1043 - CNRS U5282, Centre de Physiopathologie Toulouse-Purpan, Toulouse, France; Université Toulouse III, Tolouse, France.

Paraneoplastic neurological disorders (PNDs) are rare human autoimmune diseases that mostly affect the central nervous system (CNS). They are triggered by an efficient immune response against a neural self-antigen that is ectopically expressed in neoplastic tumors. Due to this shared antigenic expression, the immune system reacts not only to tumor cells but also to neural cells resulting in neurological damage. Growing data point to a major role of cell-mediated immunity in PNDs associated to autoantibodies against intracellular proteins. However, its precise contribution in the pathogenesis remains unclear. In this context, our study aimed at investigating the impact of anti-tumor cellular immune responses in the development of PND. To this end, we developed an animal model mimicking PND. We used a tumor cell line expressing the hemagglutinin (HA) of virus to induce an anti-tumor response in CamK-HA mice, which express HA in CNS neurons. To promote and track the T cell response against the HA antigen, naïve HA-specific CD8+ and/or CD4+ T cells, originating from TCR-transgenic animals, were transferred into these mice. We demonstrate that HA-expressing tumors, but not control tumors, induce activation, proliferation and differentiation of naïve HA-specific CD4+ and CD8+ T cells into effector cells. Moreover, both T cell subsets were needed to control tumor growth and induce CNS inflammation in CamK-HA mice. Thus, this new mouse model provides further insight into the cellular mechanisms whereby a potent anti-tumor immunity triggers a cancer-associated autoimmune disease, and may therefore help to develop new therapeutic strategies against PND.
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http://dx.doi.org/10.1080/2162402X.2016.1260212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353919PMC
December 2016

CD62L test at 2 years of natalizumab predicts progressive multifocal leukoencephalopathy.

Neurology 2016 12 4;87(23):2491-2494. Epub 2016 Nov 4.

From the CHU Toulouse Purpan (B.P., F.B., D.B., D.A.-P., D.B.), Pôle Neurosciences; INSERM U1043-CNRS UMR 5282 (B.P., F.B., D.B.), Université Toulouse III, Centre de Physiopathologie Toulouse Purpan, France; University of Münster (N.S., T.S.-H., H.W.), Germany; University of Lille (O.O., H.Z., P.V.); Hôpital Civil (J.-C. Ongagna, J.d.S.), Strasbourg; CHU Pellegrin (B.B., J.-C. Ouallet), Bordeaux; CHU Nancy (M.D., S.P.); CHU Caen (G.D., N.D.); CH St Vincent (P.H.), GHICL, Lille; CHU Reims (A.T.); CHU Montpellier (P.L.); CHU Nîmes (G.C., W.C., O.C.); CHRU Clermont Ferrand (P.C.); CHU Besançon (E.B.); Aix Marseille University (J.P., A.R.), APHM, CHU Timone, Marseille; CHU Nantes (D.L., S.W.); CHU Grenoble (E.T.); CHU Dijon (T.M., A.F.); CHU Lyon (S.V.), Bron; Hôpital de la Salpêtrière (C.P.), Paris, France; Centre d'Esclerosi Múltiple de Catalunya (CEMCAT) (M.C.), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain; and CHU Nice (C.L.-F.), France.

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http://dx.doi.org/10.1212/WNL.0000000000003401DOI Listing
December 2016

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice.

Proc Natl Acad Sci U S A 2016 09 12;113(39):10956-61. Epub 2016 Sep 12.

Center for Pathophysiology Toulouse Purpan, Université Toulouse III, INSERM U1043, CNRS UMR 5282, 31024 Toulouse, France; Department of Immunology, Toulouse University Hospitals, 31059 Toulouse, France

Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin(+) neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a "neo-self-antigen" specifically in hypothalamic orexin(+) neurons (called Orex-HA), which were transferred with effector neo-self-antigen-specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin(+) neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin(+) neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin(+) neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5047186PMC
http://dx.doi.org/10.1073/pnas.1603325113DOI Listing
September 2016

CTLA4 blockade elicits paraneoplastic neurological disease in a mouse model.

Brain 2016 11;139(11):2923-2934

INSERM UMR U1043 - CNRS U5282, Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, 31300, France.

CTLA4 is an inhibitory regulator of immune responses. Therapeutic CTLA4 blockade enhances T cell responses against cancer and provides striking clinical results against advanced melanoma. However, this therapy is associated with immune-related adverse events. Paraneoplastic neurologic disorders are immune-mediated neurological diseases that develop in the setting of malignancy. The target onconeural antigens are expressed physiologically by neurons, and aberrantly by certain tumour cells. These tumour-associated antigens can be presented to T cells, generating an antigen-specific immune response that leads to autoimmunity within the nervous system. To investigate the risk to develop paraneoplastic neurologic disorder after CTLA4 blockade, we generated a mouse model of paraneoplastic neurologic disorder that expresses a neo -self antigen both in Purkinje neurons and in implanted breast tumour cells. Immune checkpoint therapy with anti-CTLA4 monoclonal antibody in this mouse model elicited antigen-specific T cell migration into the cerebellum, and significant neuroinflammation and paraneoplastic neurologic disorder developed only after anti-CTLA4 monoclonal antibody treatment. Moreover, our data strongly suggest that CD8 + T cells play a final effector role by killing the Purkinje neurons. Taken together, we recommend heightened caution when using CTLA4 blockade in patients with gynaecological cancers, or malignancies of neuroectodermal origin, such as small cell lung cancer, as such treatment may promote paraneoplastic neurologic disorders.
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http://dx.doi.org/10.1093/brain/aww225DOI Listing
November 2016

Interleukin 17 alone is not a discriminant biomarker in early demyelinating spectrum disorders.

J Neurol Sci 2016 Sep 25;368:334-6. Epub 2016 Jul 25.

Neurology, Hopital Purpan, Toulouse, France.

Background: Radiologically isolated syndrome (RIS) is a sub clinical demyelinating neurological disorder and to date no biomarker that triggers the seminal event has been identified. As for multiple sclerosis (MS), disease activity and clinical course are unpredictable. In MS, exploratory studies reported increased IL-17 levels in CSF but results in detecting IL-17 in serum at different stage of the disease are controversial.

Objectives: We investigate levels of IL-17 in serum and CSF in patients diagnosed at different stages of demyelinating diseases (RIS, CIS, relapsing remitting (RR) or active multiple sclerosis patients:AMS) as a marker of inflammatory condition.

Methods: 1417 sera has been tested for IL-17A (1177 from active MS, 80 RRMS, 35 RIS, 35 CIS, 10 IIH: idiopathic intracranial hypertension, and 80 controls) and 240 CSF from RIS, CIS, IIH and controls.

Results: No difference has been found between RIS who early clinically converted and CIS patients who rapidly evolve in McDonald or clinically definite MS, nor active MS. No correlation was found with usual MRI or CSF criteria.

Conclusion: Our results do not confirm that IL-17 can be considerate as a reliable marker of inflammation in the demyelinating spectrum disorders, either in blood or CSF.
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http://dx.doi.org/10.1016/j.jns.2016.07.052DOI Listing
September 2016

Therapy with natalizumab is associated with high JCV seroconversion and rising JCV index values.

Neurol Neuroimmunol Neuroinflamm 2016 Feb 27;3(1):e195. Epub 2016 Jan 27.

Department of Neurology (N.S., T.S.-H., J.B., C.C.G., K.G., H.W.), University of Münster, Germany; and Pole des Neurosciences Centre Hospitalier Universitaire Toulouse (B.P., D.B.), CPTP INSERM UMR 1043 et Université de Toulouse, UPS, Toulouse, France. D.B. also represents the BioNAT Study Group.

Objective: The aim of the study was to analyze John Cunningham virus (JCV) serology in natalizumab-treated patients over time and assess whether they are influenced by natalizumab treatment.

Methods: German (n = 1,921; 525 longitudinally) and French (n = 1,259; 711 longitudinally) patients were assessed for JCV serology alongside their therapy with natalizumab.

Results: JCV serostatus changed in 69 of 525 longitudinally followed German patients (13.1%) over 14.8 months. Seroconversion according to serostatus was seen in 43 of 339 initially JCV- German patients (12.7% in 14.8 months; 10.3% per year) and 41 of 243 initially JCV- French patients (16.9% in 24 months; 8.5% per year). JCV index values could be reproduced (R (2) = 0.89) with the caveat of 8 of 50 samples (16%) being set into different risk categories between 2 assessments. Index values of JCV+ patients rose over time (p = 0.009) but not because of aging. Treatment with natalizumab was associated with a 15.9% increase of value in JCV+ patients in 14.8 months (12.9% per year).

Conclusions: JCV seroconversion and index values may be influenced by treatment with natalizumab. It is therefore important to monitor patients' JCV serology but also to incorporate additional risk factors into the progressive multifocal leukoencephalopathy risk stratification.
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http://dx.doi.org/10.1212/NXI.0000000000000195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733149PMC
February 2016

PML risk stratification using anti-JCV antibody index and L-selectin.

Mult Scler 2016 07 2;22(8):1048-60. Epub 2015 Oct 2.

Department of Neurology, University of Münster, Germany.

Background: Natalizumab treatment is associated with progressive multifocal leukoencephalopathy (PML) development. Treatment duration, prior immunosuppressant use, and JCV serostatus are currently used for risk stratification, but PML incidence stays high. Anti-JCV antibody index and L-selectin (CD62L) have been proposed as additional risk stratification parameters.

Objective: This study aimed at verifying and integrating both parameters into one algorithm for risk stratification.

Methods: Multicentric, international cohorts of natalizumab-treated MS patients were assessed for JCV index (1921 control patients and nine pre-PML patients) and CD62L (1410 control patients and 17 pre-PML patients).

Results: CD62L values correlate with JCV serostatus, as well as JCV index values. Low CD62L in natalizumab-treated patients was confirmed and validated as a biomarker for PML risk with the risk factor "CD62L low" increasing a patient's relative risk 55-fold (p < 0.0001). Validation efforts established 86% sensitivity/91% specificity for CD62L and 100% sensitivity/59% specificity for JCV index as predictors of PML. Using both parameters identified 1.9% of natalizumab-treated patients in the reference center as the risk group.

Conclusions: Both JCV index and CD62L have merit for risk stratification and share a potential biological relationship with implications for general PML etiology. A risk algorithm incorporating both biomarkers could strongly reduce PML incidence.
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http://dx.doi.org/10.1177/1352458515607651DOI Listing
July 2016

Migration of encephalitogenic CD8 T cells into the central nervous system is dependent on the α4β1-integrin.

Eur J Immunol 2015 Dec 6;45(12):3302-12. Epub 2015 Oct 6.

INSERM U1043 - CNRS UMR 5282, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.

Although CD8 T cells are key players in neuroinflammation, little is known about their trafficking cues into the central nervous system (CNS). We used a murine model of CNS autoimmunity to define the molecules involved in cytotoxic CD8 T-cell migration into the CNS. Using a panel of mAbs, we here show that the α4β1-integrin is essential for CD8 T-cell interaction with CNS endothelium. We also investigated which α4β1-integrin ligands expressed by endothelial cells are implicated. The blockade of VCAM-1 did not protect against autoimmune encephalomyelitis, and only partly decreased the CD8(+) T-cell infiltration into the CNS. In addition, inhibition of junctional adhesion molecule-B expressed by CNS endothelial cells also decreases CD8 T-cell infiltration. CD8 T cells may use additional and possibly unidentified adhesion molecules to gain access to the CNS.
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http://dx.doi.org/10.1002/eji.201545632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163664PMC
December 2015

[Migration and pathogenicity of CD8 T cells in central nervous system diseases].

Med Sci (Paris) 2015 Aug-Sep;31(8-9):748-55. Epub 2015 Sep 4.

Inserm U1043, CNRS UMR 5282, centre de physiopathologie Toulouse-Purpan, hôpital Purpan, place du Docteur Baylac, 31024 Toulouse, France - Université Toulouse III, Toulouse, F-31000, France.

The implication of CD8 T cells in infectious and inflammatory diseases of the central nervous system has received increasing attention. CD8 T cells are crucial players of the adaptive immune system against neurotropic infections, but can also trigger tissue damage. Here we review the molecular mechanisms used by CD8 T cells to migrate into the central nervous system, and describe diseases that imply CD8 T cell-mediated pathogenicity. We also suggest therapeutic strategies targeting this population.
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http://dx.doi.org/10.1051/medsci/20153108013DOI Listing
August 2016

Fingolimod treatment after natalizumab-related progressive multifocal leukoencephalopathy: three new cases.

Mult Scler 2015 Apr 10;21(5):671-2. Epub 2014 Oct 10.

Pole des neurosciences CHU Toulouse, France INSERM UMR 1043 et Université de Toulouse; UPS; France

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http://dx.doi.org/10.1177/1352458514549823DOI Listing
April 2015

Immunopathogenesis of paraneoplastic neurological syndromes associated with anti-Hu antibodies: A beneficial antitumor immune response going awry.

Oncoimmunology 2013 Dec 10;2(12):e27384. Epub 2013 Dec 10.

INSERM-UMR1043; Toulouse, France ; CNRS, U5282; Toulouse, France ; Universite de Toulouse; UPS; Centre de Physiopathologie Toulouse Purpan (CPTP); Toulouse, France ; CHU Toulouse Purpan; Toulouse, France.

Paraneoplastic neurological disorders (PNDs) are syndromes that develop in cancer patients when an efficient antitumor immune response, directed against antigens expressed by both malignant cells and healthy neurons, damages the nervous system. Herein, we analyze existing data on the mechanisms of loss of self tolerance and nervous tissue damage that underpin one of the most frequent PNDs, the anti-Hu syndrome. In addition, we discuss future directions and propose potential strategies aimed at blocking deleterious encephalitogenic immune responses while preserving the antineoplastic potential of treatment.
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http://dx.doi.org/10.4161/onci.27384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3913668PMC
December 2013

EVER proteins, key elements of the natural anti-human papillomavirus barrier, are regulated upon T-cell activation.

PLoS One 2012 28;7(6):e39995. Epub 2012 Jun 28.

Inserm, U1043, Toulouse, France.

Human papillomaviruses (HPV) cause a variety of mucosal and skin lesions ranging from benign proliferations to invasive carcinomas. The clinical manifestations of infection are determined by host-related factors that define the natural anti-HPV barrier. Key elements of this barrier are the EVER1 and EVER2 proteins, as deficiency in either one of the EVER proteins leads to Epidermodysplasia Verruciformis (EV), a genodermatosis associated with HPV-induced skin carcinoma. Although EVERs have been shown to regulate zinc homeostasis in keratinocytes, their expression and function in other cell types that may participate to the anti-HPV barrier remain to be investigated. In this work, we demonstrate that EVER genes are expressed in different tissues, and most notably in lymphocytes. Interestingly, in contrast to the skin, where EVER2 transcripts are hardly detectable, EVER genes are both abundantly expressed in murine and human T cells. Activation of CD4+ and CD8+ T cells via the TCR triggers a rapid and profound decrease in EVER expression, accompanied by an accumulation of free Zn(2+) ions. Thus, EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes. Consistent with this hypothesis, we show that the concentration of Zn(2+) ions is elevated in lymphoblastoid cells or primary T cells from EVER2-deficient patients. Interestingly, we also show that Zn(2+) excess blocks T-cell activation and proliferation. Therefore, EVER proteins appear as key components of the activation-dependent regulation of Zn(2+) concentration in T cells. However, the impact of EVER-deficiency in T cells on EV pathogenesis remains to be elucidated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0039995PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386272PMC
January 2013

Cutting edge: neuronal recognition by CD8 T cells elicits central diabetes insipidus.

J Immunol 2012 May 13;188(10):4731-5. Epub 2012 Apr 13.

INSERM, U1043, Toulouse F-31300, France.

An increasing number of neurologic diseases is associated with autoimmunity. The immune effectors contributing to the pathogenesis of such diseases are often unclear. To explore whether self-reactive CD8 T cells could attack CNS neurons in vivo, we generated a mouse model in which the influenza virus hemagglutinin (HA) is expressed specifically in CNS neurons. Transfer of cytotoxic anti-HA CD8 T cells induced an acute but reversible encephalomyelitis in HA-expressing recipient mice. Unexpectedly, diabetes insipidus developed in surviving animals. This robust phenotype was associated with preferential accumulation of cytotoxic CD8 T cells in the hypothalamus, upregulation of MHC class I molecules, and destruction of vasopressin-expressing neurons. IFN-γ production by the pathogenic CD8 T cells was necessary for MHC class I upregulation by hypothalamic neurons and their destruction. This novel mouse model, in combination with related human data, supports the concept that autoreactive CD8 T cells can trigger central diabetes insipidus.
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http://dx.doi.org/10.4049/jimmunol.1102998DOI Listing
May 2012

Transgenic mouse models of multiple sclerosis.

Cell Mol Life Sci 2010 Dec 17;67(23):4011-34. Epub 2010 Aug 17.

Institut National de la Santé et de la Recherche Médicale, Unité 563, Toulouse, France.

Multiple sclerosis (MS) is an inflammatory demyelinating disease affecting the central nervous system (CNS) and a frequent cause of neurological disability in young adults. Multifocal inflammatory lesions in the CNS white matter, demyelination, oligodendrocyte loss, axonal damage, as well as astrogliosis represent the histological hallmarks of the disease. These pathological features of MS can be mimicked, at least in part, using animal models. This review discusses the current concepts of the immune effector mechanisms driving CNS demyelination in murine models. It highlights the fundamental contribution of transgenesis in identifying the mediators and mechanisms involved in the pathophysiology of MS models.
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http://dx.doi.org/10.1007/s00018-010-0481-9DOI Listing
December 2010

Safety and immunogenicity of myxoma virus as a new viral vector for small ruminants.

J Gen Virol 2008 Jun;89(Pt 6):1371-1379

Université de Toulouse, ENVT, UMR 1225, F-31076 Toulouse, France.

Myxoma virus (MYXV), a leporide-specific poxvirus, represents an attractive candidate for the generation of safe and non-replicative vaccine vectors for other species. With the aim of developing new recombinant vaccines for ruminants, we evaluated the safety and the immunogenicity of recombinant MYXV in sheep. In vitro studies indicated that ovine primary fibroblasts were not permissive for MYXV and that infection of ovine peripheral blood mononuclear cells occurred at a low rate. Although non-specific activation significantly improved the susceptibility of lymphocytes, MYXV infection remained abortive. Histological and immunohistochemical examination at the inoculation sites revealed the development of an inflammatory process and allowed the detection of sparse infected cells in the dermis. In addition, inoculated sheep developed an antibody response directed against MYXV and the product of the transgene. Overall, these results provide the first line of evidence on the potential of MYXV as a viral vector for ruminants.
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http://dx.doi.org/10.1099/vir.0.83595-0DOI Listing
June 2008

In vitro permissivity of bovine cells for wild-type and vaccinal myxoma virus strains.

Virol J 2007 Sep 27;4:94. Epub 2007 Sep 27.

Laboratory Interactions Hôtes-Virus et Vaccinologie, UMR 1225 INRA-ENVT, Ecole Nationale Vétérinaire de Toulouse, 23 chemin des capelles, Toulouse F-31076, France.

Myxoma virus (MYXV), a leporide-specific poxvirus, represents an attractive candidate for the generation of safe, non-replicative vaccine vector for non-host species. However, there is very little information concerning infection of non-laboratory animals species cells with MYXV. In this study, we investigated interactions between bovine cells and respectively a wild type strain (T1) and a vaccinal strain (SG33) of MYXV. We showed that bovine KOP-R, BT and MDBK cell lines do not support MYXV production. Electron microscopy observations of BT-infected cells revealed the low efficiency of viral entry and the production of defective virions. In addition, infection of bovine peripheral blood mononuclear cells (PBMC) occurred at a very low level, even following non-specific activation, and was always abortive. We did not observe significant differences between the wild type strain and the vaccinal strain of MYXV, indicating that SG33 could be used for new bovine vaccination strategies.
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http://dx.doi.org/10.1186/1743-422X-4-94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2045666PMC
September 2007

A virulence factor of myxoma virus colocalizes with NF-kappaB in the nucleus and interferes with inflammation.

J Virol 2004 Mar;78(5):2510-6

UMR 1225 Interactions Hôtes Agents Pathogènes, INRA/ENVT, Ecole Nationale Vétérinaire de Toulouse, 31076 Toulouse Cedex, France.

NF-kappaB is one of the most important elements that coordinate stress-induced, immune, and inflammatory responses. Myxoma virus, a member of the Poxviridae family responsible for rabbit myxomatosis, codes for several factors that help its survival in the host. In this study, we focused on the product of the M150R gene. We show that the protein has nine ankyrin repeats (ANKs), with the eighth having a close similarity with the nuclear localization signal-containing ANK of I-kappaBalpha, which regulates NF-kappaB activity by sequestering it in the cytosol. Because the viral protein is targeted to the nucleus, it was named MNF, for myxoma nuclear factor. This localization was lost when the eighth ANK was removed. In tumor necrosis factor alpha-treated cells, MNF and NF-kappaB colocalized as dotted spots in the nucleus. In vivo experiments with a knockout virus showed that MNF is a critical virulence factor, with its deletion generating an almost apathogenic virus. Detailed histological examinations revealed an increase in the inflammatory process in the absence of MNF, consistent with the interference of MNF with the NF-kappaB-induced proinflammatory pathway. Because MNF has homologs in other poxviruses, such as vaccinia, cowpox, and variola viruses, this protein is probably part of a key mechanism that contributes to the immunogenic and pathogenic properties of these viruses.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC369233PMC
http://dx.doi.org/10.1128/jvi.78.5.2510-2516.2004DOI Listing
March 2004