37 results on '"Jacobson, Leslie"'
Search Results
2. Thymus-derived B cell clones persist in the circulation after thymectomy in myasthenia gravis
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Jiang, Ruoyi, Hoehn, Kenneth B., Lee, Casey S., Pham, Minh C., Homer, Robert J., Detterbeck, Frank C., Aban, Inmaculada, Jacobson, Leslie, Vincent, Angela, Nowak, Richard J., Kaminski, Henry J., Kleinstein, Steven H., and O’Connor, Kevin C.
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- 2020
3. Multimodal electrophysiological analyses reveal that reduced synaptic excitatory neurotransmission underlies seizures in a model of NMDAR antibody-mediated encephalitis
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Wright, Sukhvir K., Rosch, Richard E., Wilson, Max A., Upadhya, Manoj A., Dhangar, Divya R., Clarke-Bland, Charlie, Wahid, Tamara T., Barman, Sumanta, Goebels, Norbert, Kreye, Jakob, Prüss, Harald, Jacobson, Leslie, Bassett, Danielle S., Vincent, Angela, Greenhill, Stuart D., and Woodhall, Gavin L.
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- 2021
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4. Screening for pathogenic neuronal autoantibodies in serum and CSF of patients with first-episode psychosis
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Theorell, Jakob, Ramberger, Melanie, Harrison, Ruby, Mgbachi, Victor, Jacobson, Leslie, Waters, Patrick, Erhardt, Sophie, Sellgren, Carl M., Cervenka, Simon, Piehl, Fredrik, and Irani, Sarosh R.
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- 2021
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5. The emerging spectrum of foetal acetylcholine receptor antibody-associated disorders (FARAD)
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Allen, Nicholas M, primary, O’Rahelly, Mark, additional, Eymard, Bruno, additional, Chouchane, Mondher, additional, Hahn, Andreas, additional, Kearns, Gerry, additional, Kim, Dae-Seong, additional, Byun, Shin Yun, additional, Nguyen, Cam-Tu Emilie, additional, Schara-Schmidt, Ulrike, additional, Kölbel, Heike, additional, Della Marina, Adela, additional, Schneider-Gold, Christiane, additional, Roefke, Kathryn, additional, Thieme, Andrea, additional, Van den Bergh, Peter, additional, Avalos, Gloria, additional, Álvarez-Velasco, Rodrigo, additional, Natera-de Benito, Daniel, additional, Cheng, Man Hin Mark, additional, Chan, Wing Ki, additional, Wan, Hoi Shan, additional, Thomas, Mary Ann, additional, Borch, Lauren, additional, Lauzon, Julie, additional, Kornblum, Cornelia, additional, Reimann, Jens, additional, Mueller, Andreas, additional, Kuntzer, Thierry, additional, Norwood, Fiona, additional, Ramdas, Sithara, additional, Jacobson, Leslie W, additional, Jie, Xiaobo, additional, Fernandez-Garcia, Miguel A, additional, Wraige, Elizabeth, additional, Lim, Ming, additional, Lin, Jean Pierre, additional, Claeys, Kristl G, additional, Aktas, Selma, additional, Oskoui, Maryam, additional, Hacohen, Yael, additional, Masud, Ameneh, additional, Leite, M Isabel, additional, Palace, Jacqueline, additional, De Vivo, Darryl, additional, Vincent, Angela, additional, and Jungbluth, Heinz, additional
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- 2023
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6. Antibodies to the human muscle acetylcholine receptor : their specificity and function in the foetus
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Jacobson, Leslie William
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610 ,Transmembrane proteins - Published
- 1998
7. Neuronal antibodies in pediatric epilepsy: Clinical features and long-term outcomes of a historical cohort not treated with immunotherapy
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Wright, Sukhvir, Geerts, Ada T., Jol-van der Zijde, Cornelia Maria, Jacobson, Leslie, Lang, Bethan, Waters, Patrick, van Tol, Maarten J. D., Stroink, Hans, Neuteboom, Rinze F., Brouwer, Oebele F., and Vincent, Angela
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- 2016
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8. Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis
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Pollak, Thomas A, Kempton, Matthew J, Iyegbe, Conrad, Vincent, Angela, Irani, Sarosh R, Coutinho, Ester, Menassa, David A, Jacobson, Leslie, de Haan, Lieuwe, Ruhrmann, Stephan, Sachs, Gabriele, Riecher-Roessler, Anita, Krebs, Marie-Odile, Amminger, Paul, Glenthoj, Birte, Barrantes-Vidal, Neus, van Os, Jim, Rutten, Bart PF, Bressan, Rodrigo A, van der Gaag, Mark, Yolken, Robert, Hotopf, Matthew, Valmaggia, Lucia, Stone, James, David, Anthony S, McGuire, Philip, Calem, Maria, Tognin, Stefania, Modinos, Gemma, Velthorst, Eva, Kraan, Tamar C, van Dam, Daniella S, Burger, Nadine, Nelson, Barnaby, McGorry, Patrick, Pantelis, Christos, Politis, Athena, Goodall, Joanne, Borgwardt, Stefan, Ittig, Sarah, Studerus, Erich, Smieskova, Renata, Gadelha, Ary, Brietzke, Elisa, Asevedo, Graccielle, Asevedo, Elson, Zugman, Andre, Rosa, Araceli, Racioppi, Anna, Monsonet, Manel, Hinojosa-Marques, Lidia, Kwapil, Thomas R, Kazes, Mathilde, Daban, Claire, Bourgin, Julie, Gay, Olivier, Mam-Lam-Fook, Celia, Nordholm, Dorte, Randers, Lasse, Krakauer, Kristine, Glenthoj, Louise, Nordentoft, Merete, Gebhard, Dominika, Arnhold, Julia, Klosterkoetter, Joachim, Lasser, Iris, Winklbaur, Bernadette, Delespaul, Philippe A, Clinical Psychology, APH - Mental Health, RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), Psychiatrie & Neuropsychologie, RS: MHeNs - R3 - Neuroscience, Adult Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep
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Psychosis ,Biochemistry & Molecular Biology ,NEURONAL AUTOANTIBODIES ,Verbal learning ,Prognostic markers ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,ASPARTATE RECEPTOR AUTOANTIBODIES ,medicine ,1ST-EPISODE PSYCHOSIS ,LIMBIC ENCEPHALITIS ,RATING-SCALE ,BRAIN ,Molecular Biology ,Autoimmune disease ,Autoimmune encephalitis ,Psychiatry ,Science & Technology ,HIPPOCAMPAL ,business.industry ,Limbic encephalitis ,Case-control study ,Autoantibody ,Neurosciences ,medicine.disease ,030227 psychiatry ,Psychiatry and Mental health ,INDIVIDUALS ,nervous system ,Immunology ,ANTIBODIES ,Schizophrenia ,MENTAL STATE ,Neurosciences & Neurology ,business ,Life Sciences & Biomedicine ,030217 neurology & neurosurgery ,Neuroscience ,Psychopathology - Abstract
Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case–control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens implicated in CNS autoimmune disorders, using fixed and live cell-based assays (CBAs). Within the CHR group, the relationship between NMDAR antibodies and symptoms, cognitive function and clinical outcomes over 24 month follow-up was examined. CHR subjects were not more frequently seropositive for neuronal autoantibodies than controls (8.3% vs. 5.2%; OR = 1.50; 95% CI: 0.58–3.90). The NMDAR was the most common target antigen and NMDAR IgGs were more sensitively detected with live versus fixed CBAs (p p p p p
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- 2021
9. Inhibition of Maternal-to-Fetal Transfer of IgG Antibodies by FcRn Blockade in a Mouse Model of Arthrogryposis Multiplex Congenita
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Coutinho, Ester, primary, Jacobson, Leslie, additional, Shock, Anthony, additional, Smith, Bryan, additional, Vernon, Anthony, additional, and Vincent, Angela, additional
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- 2021
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10. Investigation of neuronal autoantibodies in two different focal epilepsy syndromes
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Ekizoglu, Esme, Tuzun, Erdem, Woodhall, Mark, Lang, Bethan, Jacobson, Leslie, Icoz, Sema, Bebek, Nerses, Gurses, Candan, Gokyigit, Aysen, Waters, Patrick, Vincent, Angela, and Baykan, Betul
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- 2014
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11. Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis The EUGEI High-Risk Study
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Pollak, Thomas, Kempton, Matthew, Iyegbe, Conrad, Vincent, Angela, Irani, Sarosh R, Coutinho, Ester, Menassa, David A, Jacobson, Leslie, De Haan, Lieuwe, Ruhrmann, Stephan, Sachs, Gabriele, Riecher-Rössler, Anita, Krebs, Marie-Odile, Amminger, Paul, Glenthøj, Birte, Barrantes-Vidal, Neus, Van Os, Jim, Rutten, Bart, Bressan, Rodrigo, Van Der Gaag, Mark, Yolken, Robert, Hotopf, Matthew, Valmaggia, Lucia, Stone, James, David, Anthony S, McGuire, Philip, Martinez Rico, Clara, King‘s College London, South London and Maudsley NHS Foundation Trust, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital [Oxford University Hospital], University of Southampton, University of Amsterdam [Amsterdam] (UvA), University of Cologne, Medizinische Universität Wien = Medical University of Vienna, University of Basel (Unibas), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Melbourne, IT University of Copenhagen (ITU), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Brain Centre Rudolf Magnus [Utrecht], University Medical Center [Utrecht], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Universidade Federal de São Paulo, Vrije Universiteit Amsterdam [Amsterdam] (VU), Johns Hopkins University School of Medicine [Baltimore], University College of London [London] (UCL), EUGEI High-Risk Study: Maria Calem, Stefania Tognin, Gemma Modinos, Lieuwe de Haan, Mark van der Gaag, Eva Velthorst, Tamar C Kraan, Daniella S van Dam, Nadine Burger, Barnaby Nelson, Patrick McGorry, Christos Pantelis, Athena Politis, Joanne Goodall, Stefan Borgwardt, Sarah Ittig, Erich Studerus, Renata Smieskova, Ary Gadelha, Elisa Brietzke, Graccielle Asevedo, Elson Asevedo, Andre Zugman, Araceli Rosa, Anna Racioppi, Manel Monsonet, Lídia Hinojosa-Marqués, Thomas R Kwapil, Mathilde Kazes, Claire Daban, Julie Bourgin, Olivier Gay, Célia Mam-Lam-Fook, Dorte Nordholm, Lasse Randers, Kristine Krakauer, Louise Glenthøj, Merete Nordentoft, Dominika Gebhard, Julia Arnhold, Joachim Klosterkötter, Iris Lasser, Bernadette Winklbaur, Philippe A Delespaul, Jim van Os, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), IT University of Copenhagen, VU University Amsterdam, and Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU)
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[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,nervous system ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case-control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens implicated in CNS autoimmune disorders, using fixed and live cell-based assays (CBAs). Within the CHR group, the relationship between NMDAR antibodies and symptoms, cognitive function and clinical outcomes over 24 month follow-up was examined. CHR subjects were not more frequently seropositive for neuronal autoantibodies than controls (8.3% vs. 5.2%; OR = 1.50; 95% CI: 0.58-3.90). The NMDAR was the most common target antigen and NMDAR IgGs were more sensitively detected with live versus fixed CBAs (p < 0.001). Preliminary phenotypic analyses revealed that within the CHR sample, the NMDAR antibody seropositive subjects had higher levels of current depression, performed worse on the Rey Auditory Verbal Learning Task (p < 0.05), and had a markedly lower IQ (p < 0.01). NMDAR IgGs were not more frequent in subjects who later became psychotic than those who did not. NMDAR antibody serostatus and titre was associated with poorer levels of functioning at follow-up (p < 0.05) and the presence of a neuronal autoantibody was associated with larger amygdala volumes (p < 0.05). Altogether, these findings demonstrate that NMDAR autoantibodies are detectable in a subgroup of CHR subjects at equal rates to controls. In the CHR group, they are associated with affective psychopathology, impairments in verbal memory, and overall cognitive function: these findings are qualitatively and individually similar to core features of autoimmune encephalitis and/or animal models of NMDAR antibody-mediated CNS disease. Overall the current work supports further evaluation of NMDAR autoantibodies as a possible prognostic biomarker and aetiological factor in a subset of people already meeting CHR criteria.
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- 2020
12. Autoantibodies to the N-Methyl-D-Aspartate Receptor in Adolescents With Early Onset Psychosis and Healthy Controls
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Engen, Kristine, primary, Wortinger, Laura Anne, additional, Jørgensen, Kjetil Nordbø, additional, Lundberg, Mathias, additional, Bohman, Hannes, additional, Smelror, Runar Elle, additional, Myhre, Anne Margrethe, additional, Jacobson, Leslie, additional, Vincent, Angela, additional, and Agartz, Ingrid, additional
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- 2020
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13. Glycine receptor autoantibodies disrupt inhibitory neurotransmission
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Crisp, Sarah J, primary, Dixon, Christine L, additional, Jacobson, Leslie, additional, Chabrol, Elodie, additional, Irani, Sarosh R, additional, Leite, M Isabel, additional, Leschziner, Guy, additional, Slaght, Sean J, additional, Vincent, Angela, additional, and Kullmann, Dimitri M, additional
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- 2019
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14. Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis
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Lee, Jae-Yun, Stathopoulos, Panos, Gupta, Sasha, Bannock, Jason M., Barohn, Richard J., Cotzomi, Elizabeth, Dimachkie, Mazen M., Jacobson, Leslie, Lee, Casey S., Morbach, Henner, Querol, Luis, Shan, Jing-Li, Vander Heiden, Jason A., Waters, Patrick, Vincent, Angela, Nowak, Richard J., O'Connor, Kevin C., and Universitat Autònoma de Barcelona
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0301 basic medicine ,biology ,General Neuroscience ,Autoantibody ,Peripheral tolerance ,Neurotransmission ,medicine.disease ,Myasthenia gravis ,Subclass ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Immunology ,medicine ,biology.protein ,Neurology (clinical) ,Antibody ,030217 neurology & neurosurgery ,B cell ,Research Articles ,Acetylcholine receptor ,Research Article - Abstract
Objective Myasthenia gravis (MG) is an autoimmune condition in which neurotransmission is impaired by binding of autoantibodies to acetylcholine receptors (AChR) or, in a minority of patients, to muscle specific kinase (MuSK). There are differences in the dominant IgG subclass, pathogenic mechanisms, and treatment responses between the two MG subtypes (AChR or MuSK). The antibodies are thought to be T‐cell dependent, but the mechanisms underlying their production are not well understood. One aspect not previously described is whether defects in central and peripheral tolerance checkpoints, which allow autoreactive B cells to accumulate in the naive repertoire, are found in both or either form of MG. Methods An established set of assays that measure the frequency of both polyreactive and autoreactive B cell receptors (BCR) in naive populations was applied to specimens collected from patients with either AChR or MuSK MG and healthy controls. Radioimmuno‐ and cell‐based assays were used to measure BCR binding to AChR and MuSK. Results The frequency of polyreactive and autoreactive BCRs (n = 262) was higher in both AChR and MuSK MG patients than in healthy controls. None of the MG‐derived BCRs bound AChR or MuSK. Interpretation The results indicate that both these MG subtypes harbor defects in central and peripheral B cell tolerance checkpoints. Defective B cell tolerance may represent a fundamental contributor to autoimmunity in MG and is of particular importance when considering the durability of myasthenia gravis treatment strategies, particularly biologics that eliminate B cells.
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- 2019
15. Characterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patients
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Takata, Kazushiro, Stathopoulos, Panos, Cao, Michelangelo, Mané-Damas, Marina, Fichtner, Miriam L., Benotti, Erik S., Jacobson, Leslie, Waters, Patrick, Irani, Sarosh R., Martinez-Martinez, Pilar, Beeson, David, Losen, Mario, Vincent, Angela, Nowak, Richard J., O’Connor, Kevin C., Promovendi MHN, Psychiatrie & Neuropsychologie, and RS: MHeNs - R3 - Neuroscience
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Adult ,Male ,Autoimmune diseases ,Immunology ,PROTEIN 4 ,Autoimmunity ,MUSK ANTIBODIES ,Myasthenia Gravis ,ANTIGEN PRESENTATION ,Humans ,Receptors, Cholinergic ,CRYSTAL-STRUCTURE ,IGG4 AUTOANTIBODIES ,Autoantibodies ,ACETYLCHOLINE-RECEPTORS ,B cells ,Antibodies, Monoclonal ,Receptor Protein-Tyrosine Kinases ,Neuromuscular disease ,Middle Aged ,Recombinant Proteins ,HEK293 Cells ,IMMUNOGLOBULIN G4 ,PASSIVE TRANSFER ,PLASMA-CELLS ,Immunoglobulin G ,B-CELLS ,Female ,Epitope Mapping ,Research Article - Abstract
Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by muscle weakness and caused by pathogenic autoantibodies that bind to membrane proteins at the neuromuscular junction. Most patients have autoantibodies against the acetylcholine receptor (AChR), but a subset of patients have autoantibodies against muscle-specific tyrosine kinase (MuSK) instead. MuSK is an essential component of the pathway responsible for synaptic differentiation, which is activated by nerve-released agrin. Through binding MuSK, serum-derived autoantibodies inhibit agrin-induced MuSK autophosphorylation, impair clustering of AChRs, and block neuromuscular transmission. We sought to establish individual MuSK autoantibody clones so that the autoimmune mechanisms could be better understood. We isolated MuSK autoantibody-expressing B cells from 6 MuSK MG patients using a fluorescently tagged MuSK antigen multimer, then generated a panel of human monoclonal autoantibodies (mAbs) from these cells. Here we focused on 3 highly specific mAbs that bound quantitatively to MuSK in solution, to MuSK-expressing HEK cells, and at mouse neuromuscular junctions, where they colocalized with AChRs. These 3 IgG isotype mAbs (2 IgG4 and 1 IgG3 subclass) recognized the Ig-like domain 2 of MuSK. The mAbs inhibited AChR clustering, but intriguingly, they enhanced rather than inhibited MuSK phosphorylation, which suggests an alternative mechanism for inhibiting AChR clustering., A fluorescent tetrameric antigen allows isolation of human myasthenia gravis monoclonal antibodies that interrupt acetylcholine receptor signaling.
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- 2019
16. Plasma from human mothers of fetuses with severe arthrogryposis multiplex congenita causes deformities in mice
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Jacobson, Leslie, Polizzi, Agata, Morriss-Kay, Gillian, and Vincent, Angela
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- 1999
17. Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability
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Dawes, John M., Weir, Greg A., Middleton, Steven J., Patel, Ryan, Chisholm, Kim I., Pettingill, Philippa, Peck, Liam J., Sheridan, Joseph, Shakir, Akila, Jacobson, Leslie, Gutierrez-Mecinas, Maria, Galino, Jorge, Walcher, Jan, Kühnemund, Johannes, Kuehn, Hannah, Sanna, Maria D., Lang, Bethan, Clark, Alex J., Themistocleous, Andreas C., Iwagaki, Noboru, West, Steven J., Werynska, Karolina, Carroll, Liam, Trendafilova, Teodora, Menassa, David A., Giannoccaro, Maria P., Coutinho, Ester, Cervellini, Ilaria, Tewari, Damini, Leite, M. Isabel, Wildner, Hendrik, Zeilhofer, Hanns U., Peles, Elior, McMahon, Stephen B., Dickenson, Anthony H., Lewin, Gary R., Vincent, Angela, and Bennett, David L.
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nervous system - Abstract
Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2−/−) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2−/− mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability., Neuron, 97 (4)
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- 2018
18. Behaviour and neuropathology in mice injected with human contactin-associated protein 2 antibodies
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Giannoccaro, Maria Pia, primary, Menassa, David A, additional, Jacobson, Leslie, additional, Coutinho, Ester, additional, Prota, Gennaro, additional, Lang, Bethan, additional, Leite, M Isabel, additional, Cerundolo, Vincenzo, additional, Liguori, Rocco, additional, and Vincent, Angela, additional
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- 2019
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19. Thymus-derived B cell clones persist in the circulation after thymectomy in myasthenia gravis.
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Ruoyi Jiang, Hoehn, Kenneth B., Lee, Casey S., Pham, Minh C., Homer, Robert J., Detterbeck, Frank C., Aban, Inmaculada, Jacobson, Leslie, Vincent, Angela, Nowak, Richard J., Kaminski, Henry J., Kleinstein, Steven H., and O'Connor, Kevin C.
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T cells ,MYASTHENIA gravis ,CLONE cells ,THYMECTOMY ,PLASMA cells - Abstract
Myasthenia gravis (MG) is a neuromuscular, autoimmune disease caused by autoantibodies that target postsynaptic proteins, primarily the acetylcholine receptor (AChR) and inhibit signaling at the neuromuscular junction. The majority of patients under 50 y with AChR autoantibody MG have thymic lymphofollicular hyperplasia. The MG thymus is a reservoir of plasma cells that secrete disease-causing AChR autoantibodies and although thymectomy improves clinical scores, many patients fail to achieve complete stable remission without additional immunosuppressive treatments. We speculate that thymus-associated B cells and plasma cells persist in the circulation after thymectomy and that their persistence could explain incomplete responses to resection. We studied patients enrolled in a randomized clinical trial and used complementary modalities of B cell repertoire sequencing to characterize the thymus B cell repertoire and identify B cell clones that resided in the thymus and circulation before and 12 mo after thymectomy. Thymus-associated B cell clones were detected in the circulation by both mRNA-based and genomic DNA-based sequencing. These antigen-experienced B cells persisted in the circulation after thymectomy. Many circulating thymus-associated B cell clones were inferred to have originated and initially matured in the thymus before emigration from the thymus to the circulation. The persistence of thymus-associated B cells correlated with less favorable changes in clinical symptom measures, steroid dose required to manage symptoms, and marginal changes in AChR autoantibody titer. This investigation indicates that the diminished clinical response to thymectomy is related to persistent circulating thymus-associated B cell clones. [ABSTRACT FROM AUTHOR]
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- 2020
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20. Cell- and single molecule-based methods to detect Anti-N-Methyl-D-Aspartate receptor autoantibodies in first episode psychosis patients from the OPTiMiSE project
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Jézéquel, Julie, Rogemond, Véronique, Pollak, Thomas, Lepleux, Marilyn, Jacobson, Leslie, Gréa, Hélène, Iyegbe, Conrad, Kahn, Rene, McGuire, Philip, Vincent, Angela, Honnorat, Jérôme, Leboyer, Marion, and Groc, Laurent
- Abstract
Circulating autoantibodies against glutamatergic N-methyl-D-aspartate receptor (NMDAR-Ab) have been reported in a proportion of patients with psychotic disorders, raising hopes for more appropriate treatment for these antibody-positive patients. However, the prevalence of circulating NMDAR-Ab in psychotic disorders remains controversial with detection prevalence rates, and immunoglobulin (Ig) classes, varying considerably between studies, perhaps because of different detection methods. Here, we compared the results of serum assays for a large cohort of first episode psychosis patients (FEP) using classical cell-based assays in three labs and a single molecule-based imaging method. Most assays and single molecule imaging in live hippocampal neurons revealed the presence of circulating NMDAR-Ab in approximately 5% of FEP patients. However, some heterogeneity between cell-based assays was clearly observed, highlighting the urgent need of new sensitive methods to detect the presence of low-titer NMDAR-Ab in seropositive patients that cannot be clinically identified from seronegative ones.
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- 2017
21. Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability
- Author
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Dawes, John M., primary, Weir, Greg A., additional, Middleton, Steven J., additional, Patel, Ryan, additional, Chisholm, Kim I., additional, Pettingill, Philippa, additional, Peck, Liam J., additional, Sheridan, Joseph, additional, Shakir, Akila, additional, Jacobson, Leslie, additional, Gutierrez-Mecinas, Maria, additional, Galino, Jorge, additional, Walcher, Jan, additional, Kühnemund, Johannes, additional, Kuehn, Hannah, additional, Sanna, Maria D., additional, Lang, Bethan, additional, Clark, Alex J., additional, Themistocleous, Andreas C., additional, Iwagaki, Noboru, additional, West, Steven J., additional, Werynska, Karolina, additional, Carroll, Liam, additional, Trendafilova, Teodora, additional, Menassa, David A., additional, Giannoccaro, Maria Pia, additional, Coutinho, Ester, additional, Cervellini, Ilaria, additional, Tewari, Damini, additional, Buckley, Camilla, additional, Leite, M. Isabel, additional, Wildner, Hendrik, additional, Zeilhofer, Hanns Ulrich, additional, Peles, Elior, additional, Todd, Andrew J., additional, McMahon, Stephen B., additional, Dickenson, Anthony H., additional, Lewin, Gary R., additional, Vincent, Angela, additional, and Bennett, David L., additional
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- 2018
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22. Neuronal antibodies in pediatric epilepsy:Clinical features and long-term outcomes of a historical cohort not treated with immunotherapy
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Wright, Sukhvir, Geerts, Ada T., Jol-Van Der Zijde, Cornelia Maria, Jacobson, Leslie, Lang, Bethan, Waters, Patrick, Van Tol, Maarten J.D., Stroink, Hans, Neuteboom, Rinze F., Brouwer, Oebele F., and Vincent, Angela
- Abstract
Objective In autoimmune encephalitis the etiologic role of neuronal cell-surface antibodies is clear; patients diagnosed and treated early have better outcomes. Neuronal antibodies have also been described in patients with pediatric epilepsy without encephalitis. The aim was to assess whether antibody presence had any effect on long-term outcomes in these patients. Methods Patients (n = 178) were recruited between 1988 and 1992 as part of the prospective Dutch Study of Epilepsy in Childhood; none received immunotherapy. Healthy age-matched bone-marrow donors served as controls (n = 112). All sera were tested for serum N-methyl-d-aspartate receptor (NMDAR), alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, leucine rich glioma inactivated 1, contactin associated protein like 2 (CASPR2), contactin-2, glutamic acid decarboxylase, and voltage gated potassium channel (VGKC)-complex antibodies by standard techniques. No cerebrospinal fluid (CSF) samples were available. Results were correlated with clinical data collected over 15 years. Results Seventeen patients (9.5%) were positive for VGKC complex (n = 3), NMDAR (n = 7), CASPR2 (n = 4), and contactin-2 (n = 3), compared to three (3/112; 2.6%) healthy controls (VGKC complex [n = 1], NMDAR [n = 2]; p = 0.03; Fisher's exact test). Titers were relatively low (≤1:100 for cell-surface antibodies), but 8 (47%) of the 17 positive samples bound to the surface of live hippocampal neurons consistent with a potential pathogenic antibody. Preexisting cognitive impairment was more frequent in antibody-positive patients (9/17 vs. 33/161; p = 0.01). Fourteen antibody-positive patients were treated with standard antiepileptic drugs (AEDs); three (17%) became intractable but this was not different from the 16 (10%) of 161 antibody-negative patients. In 96 patients with available follow-up samples at 6 and/or 12 months, 6 of 7 positive antibodies had disappeared and, conversely, antibodies had appeared for the first time in a further 7 patients. Significance Neuronal antibodies were found at low levels in 9.5% of patients with new-onset pediatric epilepsy but did not necessarily persist over time, and the development of antibodies de novo in later samples suggests they could be due to a secondary response to neuronal damage or inflammation. Moreover, as the response to standard AEDs and the long-term outcome did not differ from those of antibody-negative pediatric patients, these findings suggest that routine neuronal antibody testing is unlikely to be helpful in pediatric epilepsy. However, the higher incidence of preexisting cognitive problems in the antibody-positive group, the CASPR2 and contactin-2 antibodies in 7 of 17 patients, and the binding of 8 of 17 of serum samples to live hippocampal neurons suggest that neuronal antibodies, even if secondary, could contribute to the comorbidities of pediatric epilepsy.
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- 2016
23. IgG-specific cell-based assay detects potentially pathogenic MuSK-Abs in seronegative MG
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Huda, Saif, primary, Waters, Patrick, additional, Woodhall, Mark, additional, Leite, Maria Isabel, additional, Jacobson, Leslie, additional, De Rosa, Anna, additional, Maestri, Michelangelo, additional, Ricciardi, Roberta, additional, Heckmann, Jeannine M., additional, Maniaol, Angelina, additional, Evoli, Amelia, additional, Cossins, Judy, additional, Hilton-Jones, David, additional, and Vincent, Angela, additional
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- 2017
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24. N-methyl-D-aspartate receptor antibody-mediated neurological disease:results of a UK-based surveillance study in children
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Wright, Sukhvir, Hacohen, Yael, Jacobson, Leslie, Agrawal, Shakti, Gupta, Rajat, Philip, Sunny, Smith, Martin, Lim, Ming, Wassmer, Evangeline, and Vincent, Angela
- Abstract
OBJECTIVE: N-methyl-D-aspartate receptor antibody (NMDAR-Ab) encephalitis is a well-recognised clinico-immunological syndrome that presents with neuropsychiatric symptoms cognitive decline, movement disorder and seizures. This study reports the clinical features, management and neurological outcomes of paediatric NMDAR-Ab-mediated neurological disease in the UK. DESIGN: A prospective surveillance study. Children with NMDAR-Ab-mediated neurological diseases were voluntarily reported to the British Neurological Surveillance Unit (BPNSU) from November 2010 to December 2011. Initial and follow-up questionnaires were sent out to physicians. RESULTS: Thirty-one children fulfilled the criteria for the study. Eight presented during the study period giving an incidence of 0.85 per million children per year (95% CI 0.64 to 1.06); 23 cases were historical. Behavioural change and neuropsychiatric features were present in 90% of patients, and seizures and movement disorders both in 67%. Typical NMDAR-Ab encephalitis was reported in 24 children and partial phenotype without encephalopathy in seven, including predominantly psychiatric (four) and movement disorder (three). All patients received steroids, 22 (71%) received intravenous immunoglobulin, 9 (29%) received plasma exchange,and 10 (32%) received second-line immunotherapy. Of the 23 patients who were diagnosed early, 18 (78%) made a full recovery compared with only 1 of 8 (13%) of the late diagnosed patients (p=0.002, Fisher's exact test). Seven patients relapsed, with four needing additional second-line immunotherapy. CONCLUSIONS: Paediatric NMDAR-Ab-mediated neurological disease appears to be similar to adult NMDAR-Ab encephalitis, but some presented with a partial phenotype. Early treatment was associated with a quick and often full recovery.
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- 2015
25. Compromised fidelity of B‐cell tolerance checkpoints in AChR and MuSK myasthenia gravis
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Lee, Jae‐Yun, primary, Stathopoulos, Panos, additional, Gupta, Sasha, additional, Bannock, Jason M., additional, Barohn, Richard J., additional, Cotzomi, Elizabeth, additional, Dimachkie, Mazen M., additional, Jacobson, Leslie, additional, Lee, Casey S., additional, Morbach, Henner, additional, Querol, Luis, additional, Shan, Jing‐Li, additional, Vander Heiden, Jason A., additional, Waters, Patrick, additional, Vincent, Angela, additional, Nowak, Richard J., additional, and O'Connor, Kevin C., additional
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- 2016
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26. Fetal acetylcholine receptor inactivation syndrome
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Hacohen, Yael, primary, Jacobson, Leslie W., additional, Byrne, Susan, additional, Norwood, Fiona, additional, Lall, Abhimanu, additional, Robb, Stephanie, additional, Dilena, Robertino, additional, Fumagalli, Monica, additional, Born, Alfred Peter, additional, Clarke, Debbie, additional, Lim, Ming, additional, Vincent, Angela, additional, and Jungbluth, Heinz, additional
- Published
- 2014
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27. NMDA receptor antibodies associated with distinct white matter syndromes
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Hacohen, Yael, primary, Absoud, Michael, additional, Hemingway, Cheryl, additional, Jacobson, Leslie, additional, Lin, Jean-Pierre, additional, Pike, Mike, additional, Pullaperuma, Sunil, additional, Siddiqui, Ata, additional, Wassmer, Evangeline, additional, Waters, Patrick, additional, Irani, Sarosh R., additional, Buckley, Camilla, additional, Vincent, Angela, additional, and Lim, Ming, additional
- Published
- 2014
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28. Lipopolysaccharide Upregulates α7 Acetylcholine Receptors
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Khan, Mohammed Abdul Sattar, primary, Farkhondeh, Mina, additional, Crombie, Jennifer, additional, Jacobson, Leslie, additional, Kaneki, Masao, additional, and Martyn, J.A. Jeevendra, additional
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- 2012
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29. Lipopolysaccharide Upregulates 7 Acetylcholine Receptors
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Khan, Mohammed Abdul Sattar, Farkhondeh, Mina, Crombie, Jennifer, Jacobson, Leslie, Kaneki, Masao, and Martyn, J.A. Jeevendra
- Abstract
Nicotinic stimulation of the 7 acetylcholine receptors (7AChRs) mitigates the lipopolysaccharide (LPS)–induced tumor necrosis factor (TNF-) and other cytokines release in macrophages. This effect is blocked by 7AChR antagonist, -bungarotoxin (BTX). We tested and confirmed the hypotheses that LPS upregulates 7AChRs, and the prototypical 7AChR antagonists, vecuronium and BTX, do not block the effects of GTS-21, a specific 7AChR agonist, on TNF- release. With the knockdown of 7AChR expression by short interference RNA, GTS-21 effects on inhibition of TNF- release were not demonstrable. In addition, GTS-21 mitigated the LPS-induced growth arrest of macrophages in vitroin J774A.1 cells and ex vivoin peritoneal macrophages obtained from mice at 3 days after burn. Moreover, GTS-21 reduced mortality after burn injury in mice. These results indicate that (i) LPS upregulates 7AChRs; (ii) the therapeutic beneficial effects of GTS-21 on cytokine release are specifically mediated via 7AChRs and are preserved even when cotreated with prototypical antagonist, BTX, or clinically used muscle nicotinic antagonist, vecuronium; (iii) activation of 7AChRs by GTS-21 partially reverses the LPS-induced proliferation arrest; and (iv) GTS-21 reduces mortality in mice with burn injury. The in vivobeneficial effects of GTS-21 in burn injury warrant further studies.
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- 2012
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30. Diverse Fab specific for acetylcholine receptor epitopes from a myasthenia gravis thymus combinatorial library.
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Farrar, Jeremy, Portolano, Stefano, Willcox, Nick, Vincent, Angela, Jacobson, Leslie, Newsom-Davis, John, Rapoport, Basil, and McLachlan, Sandra M.
- Abstract
The muscle weakness in myasthenia gravis (MG) is caused by heterogeneous high-affinity IgG autoantibodies to the nicotinic acetylcholine receptor (AChR), a complex ion channel glycoprotein. These antibodies are clearly responsible for reducing AChR numbers at the neuromuscular junction in myasthenia; however, the origins, diversity, specificity and pathogenicity of individual antibodies have not yet been established. We have cloned and characterized four different AChR-specific Fab from an MG patient’s thymus by screening an IgG1/k gene combinatorial lambda phage library with soluble human AChR labeled with [
125 I]α-bungarotoxin. Unlike most previously cloned human antibodies, all four Fab immunoprecipitated soluble human muscle AChR. Two Fab strongly inhibited binding of mAb to the main immunogenic region on the α subunits and one Fab bound to an epitope on the fetal-specific γ subunit. In sensitivity and fine specificity, these Fab resembled the anti-AChR antibodies found in many MG patients, including the donor. The closest germline counterparts for their heavy chains were in VH families 1, 3 and 4; however, there were many differences consistent with an antigen-driven response of diverse B cell clones. The combinatorial approach holds promise for further analysis of human autoantibodies. [ABSTRACT FROM AUTHOR]- Published
- 1997
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31. Disentangling etiologies of CNS infections in Singapore using multiple correspondence analysis and random forest.
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Zellweger, Raphaël M., Yacoub, Sophie, Chan, Yvonne F. Z., Soon, Derek, Shafi, Humaira, Ooi, Say Tat, Chan, Monica, Jacobson, Leslie, Sessions, October M., Vincent, Angela, Low, Jenny Guek Hong, Ooi, Eng Eong, Wang, Linfa, Wijaya, Limin, and Tan, Kevin
- Subjects
CENTRAL nervous system ,EPIDEMIOLOGY ,MORTALITY ,GENE expression ,HOMEOSTASIS - Abstract
Central nervous system (CNS) infections cause substantial morbidity and mortality worldwide, with mounting concern about new and emerging neurologic infections. Stratifying etiologies based on initial clinical and laboratory data would facilitate etiology-based treatment rather than relying on empirical treatment. Here, we report the epidemiology and clinical outcomes of patients with CNS infections from a prospective surveillance study that took place between 2013 and 2016 in Singapore. Using multiple correspondence analysis and random forest, we analyzed the link between clinical presentation, laboratory results, outcome and etiology. Of 199 patients, etiology was identified as infectious in 110 (55.3%, 95%-CI 48.3–62.0), immune-mediated in 10 (5.0%, 95%-CI 2.8–9.0), and unknown in 79 patients (39.7%, 95%-CI 33.2–46.6). The initial presenting clinical features were associated with the prognosis at 2 weeks, while laboratory-related parameters were related to the etiology of CNS disease. The parameters measured were helpful to stratify etiologies in broad categories, but were not able to discriminate completely between all the etiologies. Our results suggest that while prognosis of CNS is clearly related to the initial clinical presentation, pinpointing etiology remains challenging. Bio-computational methods which identify patterns in complex datasets may help to supplement CNS infection diagnostic and prognostic decisions. [ABSTRACT FROM AUTHOR]
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- 2020
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32. Virustat, a Device for Continuous Production of Viruses
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Jacobson, Homer and Jacobson, Leslie S.
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Methods for continuous production of viruses, and operation of the virustat, an apparatus in which such production was accomplished, were studied. Continuous production requires a separate continuous host growth chamber, such as the chemostat, and a multiunit virus growth chamber into which the virus-inoculated host cells are led. Successful continuous output of MS-2 and ϕX174 viruses, the latter in lysates, over periods of several days and at titers approximating those of batch lysates, was observed. Design problems include chamber sizes and flow rates, growth of resistant mutants within both virus and host growth chambers, clogging by lysis debris, and the phenomenon of self-inoculation. The latter represents virus growth in the first section of the chamber in excess of the washout rate, leading to lack of need for virus inoculation after an initial period. Use of the virustat for production and research purposes will require some attention to the formation of resistant bacterial colonies at pockets and surface sites of limited washout. With the virustat as a continuous virus production device, continuous purification methods are desirable. Research use of the virustat in continuous mutagenic population studies would require suppression of self-inoculation by use of many sections in the chamber, and improved servo control of host populations at low concentrations.
- Published
- 1966
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33. Behaviour and neuropathology in mice injected with human contactin-associated protein 2 antibodies
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Leslie Jacobson, Gennaro Prota, Maria Pia Giannoccaro, Angela Vincent, Vincenzo Cerundolo, Maria Isabel Leite, Rocco Liguori, Ester Coutinho, David A. Menassa, Bethan Lang, Giannoccaro, Maria Pia, Menassa, David A, Jacobson, Leslie, Coutinho, Ester, Prota, Gennaro, Lang, Bethan, Leite, M Isabel, Cerundolo, Vincenzo, Liguori, Rocco, Vincent, Angela, and Kullmann, D
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Lipopolysaccharides ,Male ,0301 basic medicine ,medicine.medical_specialty ,Cell Adhesion Molecules, Neuronal ,microglia activation ,Hippocampus ,Neuropathology ,Hippocampal formation ,Blood–brain barrier ,Open field ,Immunoglobulin G ,Mice ,03 medical and health sciences ,0302 clinical medicine ,astrocyte ,Cell Movement ,Internal medicine ,medicine ,Animals ,Humans ,Lymphocytes ,Cells, Cultured ,Autoantibodies ,Neurons ,passive transfer ,Behavior, Animal ,biology ,Microglia ,animal model ,Brain ,Spontaneous alternation ,CASPR2 antibodie ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Blood-Brain Barrier ,biology.protein ,Female ,Neurology (clinical) ,Neuroglia ,Proto-Oncogene Proteins c-fos ,Injections, Intraperitoneal ,030217 neurology & neurosurgery - Abstract
Serum antibodies that bind to the surface of neurons or glia are associated with a wide range of rare but treatable CNS diseases. In many, if not most instances, the serum levels are higher than CSF levels yet most of the reported attempts to reproduce the human disease in mice have used infusion of antibodies into the mouse cerebral ventricle(s) or intrathecal space. We used the intraperitoneal route and injected purified plasma IgG from either a CASPR2-antibody-positive patient (n = 10 mice) or healthy individual (n = 9 mice) daily for 8 days. Lipopolysaccharide was injected intraperitoneally on Day 3 to cause a temporary breach in the blood brain barrier. A wide range of baseline behaviours, including tests of locomotion, coordination, memory, anxiety and social interactions, were established before the injections and tested from Day 5 until Day 11. At termination, brain tissue was analysed for human IgG, CASPR2 and c-fos expression, lymphocyte infiltration, and neuronal, astrocytic and microglial markers. Mice exposed to CASPR2-IgG, compared with control-IgG injected mice, displayed reduced working memory during the continuous spontaneous alternation test with trends towards reduced short-term and long-term memories. In the open field tests, activities were not different from controls, but in the reciprocal social interaction test, CASPR2-IgG injected mice showed longer latency to start interacting, associated with more freezing behaviour and reduced non-social activities of rearing and grooming. At termination, neuropathology showed more IgG deposited in the brains of CASPR2-IgG injected mice, but a trend towards increased CASPR2 expression; these results were mirrored in short-term in vitro experiments where CASPR2-IgG binding to hippocampal neurons and to CASPR2-transfected HEK cells led to some internalization of the IgG, but with a trend towards higher surface CASPR2 expression. Despite these limited results, in the CASPR2-IgG injected mouse brains there was increased c-fos expression in the piriform-entorhinal cortex and hypothalamus, and a modest loss of Purkinje cells. There was also increased microglia density, morphological changes in both microglia and astrocytes and raised complement C3 expression on astrocytes, all consistent with glial activation. Patients with CASPR2 antibodies can present with a range of clinical features reflecting central, autonomic and peripheral dysfunction. Although the behavioural changes in mice were limited to social interactions and mild working-memory defects, the neuropathological features indicate potentially widespread effects of the antibodies on different brain regions.
- Published
- 2019
34. Inhibition of Maternal-to-Fetal Transfer of IgG Antibodies by FcRn Blockade in a Mouse Model of Arthrogryposis Multiplex Congenita.
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Coutinho E, Jacobson L, Shock A, Smith B, Vernon A, and Vincent A
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- Animals, Animals, Newborn, Disease Models, Animal, Female, Humans, Immunoglobulin G, Mice, Mice, Inbred ICR, Pregnancy, Receptors, Cholinergic immunology, Antibodies, Blocking administration & dosage, Antibodies, Monoclonal administration & dosage, Arthrogryposis prevention & control, Autoantibodies drug effects, Histocompatibility Antigens Class I drug effects, Maternal-Fetal Exchange, Receptors, Fc drug effects
- Abstract
Objective: To determine whether blocking the neonatal Fc receptor (FcRn) during gestation with an anti-FcRn monoclonal antibody (mAb) reduces transfer of pathogenic maternal antibodies in utero and decreases the likelihood of maternal antibody-mediated neonatal disease in the offspring., Methods: Using a previously established maternal-to-fetal transfer mouse model of arthrogryposis multiplex congenita (AMC), we assessed the effect of 4470, an anti-FcRn mAb, on the transfer of total human immunoglobulin G (IgG) and specific acetylcholine receptor (AChR)-antibodies from mother to fetus, as well as its effect on the prevention of neurodevelopmental abnormalities in the offspring., Results: Offspring of pregnant dams treated with 4470 during gestation showed a substantial reduction in total human IgG and AChR antibody levels compared with those treated with the isotype mAb control. Treatment with 4470 was also associated with a significant reduction in AMC-IgG-induced deformities (limb or spinal curve malformations) when compared with mAb control-exposed embryos and a nonsignificant increase in the percentage of fetuses showing spontaneous movements. 4470 exposure during pregnancy was not associated with changes in general parameters of maternal well-being or fetal development; indeed, male neonates showed faster weight gain and shorter time to reach developmental milestones., Conclusions: FcRn blockade is a promising therapeutic strategy to prevent the occurrence of AMC and other human maternal autoantibody-related diseases in the offspring., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
- Published
- 2021
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35. IgG-specific cell-based assay detects potentially pathogenic MuSK-Abs in seronegative MG.
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Huda S, Waters P, Woodhall M, Leite MI, Jacobson L, De Rosa A, Maestri M, Ricciardi R, Heckmann JM, Maniaol A, Evoli A, Cossins J, Hilton-Jones D, and Vincent A
- Abstract
Objective: To increase the detection of MuSK-Abs using a CBA and test their pathogenicity., Methods: Sera from 69 MuSK-RIA-positive patients with myasthenia gravis (MG) (Definite MuSK-MG), 169 patients negative for MuSK-RIA and AChR-RIA (seronegative MG, SNMG), 35 healthy individuals (healthy controls, HCs), and 16 NMDA receptor-Ab-positive (NMDAR-Ab) disease controls were tested for binding to MuSK on a CBA using different secondary antibodies., Results: Initially, in addition to 18% of SNMG sera, 11% of HC and 19% of NMDAR-Ab sera showed positive binding to MuSK-transfected cells; this low specificity was due to anti-IgG(H+L) detection of IgM bound nonspecifically to MuSK. Using an IgG Fc gamma-specific secondary antibody, MuSK-Abs were detected by CBA in 68/69 (99%) of Definite MuSK-MG, 0/35 HCs, 0/16 NMDAR-Ab, and 14/169 (8%) of SNMG sera, providing increased sensitivity with high specificity. The RIA-negative, CBA-positive MuSK-IgG sera, but not IgM-MuSK-binding sera, reduced agrin-induced AChR clustering in C2C12 myotubes, qualitatively similar to RIA-positive MuSK-Abs., Conclusions: An IgG-specific MuSK-CBA can reliably detect IgG MuSK-Abs and increase sensitivity. In the MuSK-CBA, IgG specificity is essential. The positive sera demonstrated pathogenic potential in the in vitro AChR-clustering assay, although less effective than Definite MuSK-MG sera, and the patients had less severe clinical disease. Use of IgG-specific secondary antibodies may improve the results of other antibody tests., Classification of Evidence: This study provides Class III evidence that an IgG-specific MuSK-CBA identifies patients with MG.
- Published
- 2017
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36. Fetal acetylcholine receptor inactivation syndrome: A myopathy due to maternal antibodies.
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Hacohen Y, Jacobson LW, Byrne S, Norwood F, Lall A, Robb S, Dilena R, Fumagalli M, Born AP, Clarke D, Lim M, Vincent A, and Jungbluth H
- Abstract
Background: Transient neonatal myasthenia gravis (TNMG) affects a proportion of infants born to mothers with myasthenia gravis (MG). Symptoms usually resolve completely within the first few months of life, but persistent myopathic features have been reported in a few isolated cases., Methods: Here we report 8 patients from 4 families born to mothers with clinically manifest MG or mothers who were asymptomatic but had elevated acetylcholine receptor (AChR) antibody levels., Results: Clinical features in affected infants ranged from a mild predominantly facial and bulbar myopathy to arthrogryposis multiplex congenita. Additional clinical findings included hearing impairment, pyloric stenosis, and mild CNS involvement. In all cases, antibodies against the AChR were markedly elevated, although not always specific for the fetal AChR γ subunit. There was a correlation between maternal symptoms; the timing, intensity, and frequency of maternal treatment; and neonatal outcome., Conclusions: These findings suggest that persistent myopathic features following TNMG may be more common than currently recognized. Fetal AChR inactivation syndrome should be considered in the differential diagnosis of infants presenting with unexplained myopathic features, in particular marked dysarthria and velopharyngeal incompetence. Correct diagnosis requires a high degree of suspicion if the mother is asymptomatic but is crucial considering the high recurrence risk for future pregnancies and the potentially treatable nature of this condition. Infants with a history of TNMG should be followed up for subtle myopathic signs and associated complications.
- Published
- 2014
- Full Text
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37. NMDA receptor antibodies associated with distinct white matter syndromes.
- Author
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Hacohen Y, Absoud M, Hemingway C, Jacobson L, Lin JP, Pike M, Pullaperuma S, Siddiqui A, Wassmer E, Waters P, Irani SR, Buckley C, Vincent A, and Lim M
- Abstract
Objective: To report the clinical and radiologic findings of children with NMDA receptor (NMDAR) antibodies and white matter disorders., Method: Ten children with significant white matter involvement, with or without anti-NMDAR encephalitis, were identified from 46 consecutive NMDAR antibody-positive pediatric patients. Clinical and neuroimaging features were reviewed and the treatment and outcomes of the neurologic syndromes evaluated., Results: THREE DISTINCT CLINICORADIOLOGIC PHENOTYPES WERE RECOGNIZED: brainstem encephalitis (n = 3), leukoencephalopathy following herpes simplex virus encephalitis (HSVE) (n = 2), and acquired demyelination syndromes (ADS) (n = 5); 3 of the 5 with ADS had myelin oligodendrocyte glycoprotein as well as NMDAR antibodies. Typical NMDAR antibody encephalitis was seen in 3 patients remote from the first neurologic syndrome (2 brainstem, 1 post-HSVE). Six of the 7 patients (85%) who were treated acutely, during the original presentation with white matter involvement, improved following immunotherapy with steroids, IV immunoglobulin, and plasma exchange, either individually or in combination. Two patients had escalation of immunotherapy at relapse resulting in clinical improvement. The time course of clinical features, treatments, and recoveries correlated broadly with available serum antibody titers., Conclusion: Clinicoradiologic evidence of white matter involvement, often distinct, was identified in 22% of children with NMDAR antibodies and appears immunotherapy responsive, particularly when treated in the acute phase of neurologic presentation. When observed, this clinical improvement is often mirrored by reduction in NMDAR antibody levels, suggesting that these antibodies may mediate the white matter disease.
- Published
- 2014
- Full Text
- View/download PDF
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