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    Autoimmune encephalitis mediated by B-cell response against N-methyl-d-aspartate receptor. Wagnon Isabelle,Hélie Pauline,Bardou Isabelle,Regnauld Caroline,Lesec Léonie,Leprince Jerôme,Naveau Mikaël,Delaunay Barbara,Toutirais Olivier,Lemauff Brigitte,Etard Olivier,Vivien Denis,Agin Véronique,Macrez Richard,Maubert Eric,Docagne Fabian Brain : a journal of neurology Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a neuropsychiatric disease characterized by an antibody-mediated autoimmune response against NMDAR. Recent studies have shown that anti-NMDAR antibodies are involved in the pathophysiology of the disease. However, the upstream immune and inflammatory processes responsible for this pathogenic response are still poorly understood. Here, we immunized mice against the region of NMDA receptor containing the N368/G369 amino acids, previously implicated in a pathogenic response. This paradigm induced encephalopathy characterized by blood-brain barrier opening, periventricular T2-MRI hyperintensities and IgG deposits into the brain parenchyma. Two weeks after immunization, mice developed clinical symptoms reminiscent of encephalitis: anxiety- and depressive-like behaviours, spatial memory impairment (without motor disorders) and increased sensitivity to seizures. This response occurred independently of overt T-cell recruitment. However, it was associated with B220+ (B cell) infiltration towards the ventricles, where they differentiated into CD138+ cells (plasmocytes). Interestingly, these B cells originated from peripheral lymphoid organs (spleen and cervical lymphoid nodes). Finally, blocking the B-cell response using a depleting cocktail of antibodies reduced the severity of symptoms in encephalitis mice. This study demonstrates that the B-cell response can lead to an autoimmune reaction against NMDAR that drives encephalitis-like behavioural impairments. It also provides a relevant platform for dissecting encephalitogenic mechanisms in an animal model, and enables the testing of therapeutic strategies targeting the immune system in anti-NMDAR encephalitis. 10.1093/brain/awaa250
    Clinical Presentation and Outcomes of Severe Acute Respiratory Syndrome Coronavirus 2-Related Encephalitis: The ENCOVID Multicenter Study. Pilotto Andrea,Masciocchi Stefano,Volonghi Irene,Crabbio Massimo,Magni Eugenio,De Giuli Valeria,Caprioli Francesca,Rifino Nicola,Sessa Maria,Gennuso Michele,Cotelli Maria Sofia,Turla Marinella,Balducci Ubaldo,Mariotto Sara,Ferrari Sergio,Ciccone Alfonso,Fiacco Fabrizio,Imarisio Alberto,Risi Barbara,Benussi Alberto,Premi Enrico,Focà Emanuele,Caccuri Francesca,Leonardi Matilde,Gasparotti Roberto,Castelli Francesco,Zanusso Gianluigi,Pezzini Alessandro,Padovani Alessandro, The Journal of infectious diseases BACKGROUND:Several preclinical and clinical investigations have argued for nervous system involvement in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some sparse case reports have described various forms of encephalitis in coronavirus disease 2019 (COVID-19) disease, but very few data have focused on clinical presentations, clinical course, response to treatment, and outcomes. METHODS:The SARS-CoV-2 related encephalopaties (ENCOVID) multicenter study included patients with encephalitis with full infectious screening, cerebrospinal fluid (CSF), electroencephalography (EEG), and magnetic resonance imaging (MRI) data and confirmed SARS-CoV-2 infection recruited from 13 centers in northern Italy. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment, and outcomes were recorded. RESULTS:Twenty-five cases of encephalitis positive for SARS-CoV-2 infection were included. CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by reverse-transcription polymerase chain reaction resulted negative. Based on MRI, cases were classified as acute demyelinating encephalomyelitis (ADEM; n = 3), limbic encephalitis (LE; n = 2), encephalitis with normal imaging (n = 13), and encephalitis with MRI alterations (n = 7). ADEM and LE cases showed a delayed onset compared to the other encephalitis cases (P = .001) and were associated with previous, more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to those with other encephalitis. CONCLUSIONS:SARS-CoV-2 infection is associated with a wide spectrum of encephalitis characterized by different clinical presentation, response to treatment, and outcomes. 10.1093/infdis/jiaa609
    Exosomes expressing neuronal autoantigens induced immune response in antibody-positive autoimmune encephalitis. Gu Jiachen,Jin Tao,Li Zongshan,Chen Huimin,Xia Hongbo,Xu Xiaomin,Gui Yaxing Molecular immunology The immunological role of exosomes in autoimmune encephalitis (AE) remains uncharacterized and not examined. In this study we ought to determine whether exosomes are generated in AE and to define the presence of cell surface neuronal autoantigens (autoAgs) in the cargo. Exosomes were isolated from cerebrospinal fluid (CSF) from 12 patients with anti-N-methyl-d-aspartate (NMDA) receptor encephalitis, 8 patients with anti-gamma-aminobutyric acid-B (GABA) receptor encephalitis, 8 patients with anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis, 8 patients with anti-contactin-associated protein-like 2 (CASPR2) encephalitis, 10 patients with anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 1,2 (AMPA) receptor encephalitis and 30 control individuals negative of antibodies against neuronal autoAgs. Western blot demonstrated that CSF or sera derived exosomes from AE contained specific neuronal autoAgs in protein aggregates, however, control subjects had no detectable levels of these neuronal autoAgs. In addition, development of antibodies against NMDAR, GABAR, LGI1, CASPR2, and AMPAR were detected in the sera after 30 days immunization of C57BL/6 J mice with exosomes isolated from antibody positive AE patients; Enzyme-linked immunospot (ELISpot) assay demonstrated increased frequency of neuronal autoAgs-specific IL-17 and IFN-γ in splenocytes from AE derived exosomes immunized mice. We concluded that exosomes expressing neuronal autoAgs were present in CSF from antibody positive AE patients, and we propose these exosomes carrying neuronal autoAgs would play an important role in the immune pathogenesis of autoimmune encephalitis. 10.1016/j.molimm.2020.12.034