High albumin level is a predictor of favorable response to immunotherapy in autoimmune encephalitis.
Jang Yoonhyuk,Lee Soon-Tae,Kim Tae-Joon,Jun Jin-Sun,Moon Jangsup,Jung Keun-Hwa,Park Kyung-Il,Chu Kon,Lee Sang Kun
There is no known biomarker that predicts the response to immune therapy in autoimmune synaptic encephalitis. Thus, we investigated serum albumin as a prognostic biomarker of early immune therapies in patients with autoimmune encephalitis. We enrolled patients who were diagnosed with definite autoimmune encephalitis and underwent IVIg treatment at Seoul National University Hospital from 2012 to 2017. Patients were dichotomized according to serum albumin prior to IVIg administration with a cut-off level of 4.0 g/dL, which was the median value of 50% of patients. Seventeen (53.1%) of the 32 patients with definite autoimmune encephalitis who received IVIg treatment in our hospital had low serum albumin (<4.0 g/dL). The initial disease severity (mRS ≥ 4) was the sole factor that predicted low albumin in autoimmune encephalitis patients using multivariate analysis (P = 0.013). The low albumin group exhibited a worse response to immune therapy at the third and fourth weeks from IVIg administration (P < 0.01 and P = 0.012, respectively), and recovery to activities of daily life without assistance was faster in the high albumin group (log-rank test for trend, P < 0.01). Our study found that pretreatment low serum albumin was a significant indicator of autoimmune encephalitis prognosis in the short-term and long-term.
Differing Outcome of Experimental Autoimmune Encephalitis in Macrophage/Neutrophil- and T Cell-Specific gp130-Deficient Mice.
Holz Kristian,Prinz Marco,Brendecke Stefanie M,Hölscher Alexandra,Deng Fengyuan,Mitrücker Hans-Willi,Rose-John Stefan,Hölscher Christoph
Frontiers in immunology
gp130 cytokines are differentially involved in regulating the T helper (H) 17-driven pathogenesis of experimental autoimmune encephalomyelitis (EAE), the animal model of human multiple sclerosis. Interleukin (IL)-6 directly promotes the development of TH17 cells through the gp130/IL-6R complex. By contrast, IL-27 has been shown to suppress a TH17 immune response by gp130/IL-27R-alpha (α) receptor ligation. The IL-27-dependent regulation of a TH17 development could be mediated on the level of CD4 T cells. However, because IL-27 also suppresses the secretion of the TH17-driving cytokines IL-6 and IL-12/23p40 in accessory cells, TH17 immune responses may also be controlled by IL-27 on the level of macrophages and/or neutrophils. To analyze these opposing effects of gp130 engagement on the pathogenesis of EAE, we immunized CD4 T cell-specific gp130-deficient (CD4cregp130) and macrophage/neutrophil-specific gp130-deficient (LysMcregp130) mice with the myelin-oligodendrocyte-glycoprotein peptide MOG. Whereas inflammatory immune responses, TH17 differentiation, and pathology in CD4cregp130 mice were mitigated, disease progression was eventually enhanced in LysMcregp130 mice. Exacerbated disease in MOG-immunized LysMcregp130 mice was associated with an elevated development of TH17 cells and increased infiltration of the central nervous system with leukocytes indicating a suppressive role of macrophage/neutrophil-gp130. To further prove IL-6 to be responsible for the control of inflammation during EAE through gp130 on macrophages/neutrophils, we immunized LysMcreIL-6R mice. In contrast to LysMcregp130 mice, neuropathology in MOG-immunized macrophage/neutrophil-specific IL-6R-deficient mice was not enhanced indicating that the alleviation of EAE through macrophage/neutrophil-gp130 is mediated independently of IL-6. Together, this different pathology in macrophage/neutrophil- and CD4 T cell-specific gp130-deficient mice suggests that gp130 cytokines modulate TH17 inflammation differentially by targeting distinct cell types.
NMDA Receptor Autoantibodies in Autoimmune Encephalitis Cause a Subunit-Specific Nanoscale Redistribution of NMDA Receptors.
Ladépêche Laurent,Planagumà Jesús,Thakur Shreyasi,Suárez Irina,Hara Makoto,Borbely Joseph Steven,Sandoval Angel,Laparra-Cuervo Lara,Dalmau Josep,Lakadamyali Melike
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe neuropsychiatric disorder mediated by autoantibodies against the GluN1 subunit of the NMDAR. Patients' antibodies cause cross-linking and internalization of NMDAR, but the synaptic events leading to depletion of NMDAR are poorly understood. Using super-resolution microscopy, we studied the effects of the autoantibodies on the nanoscale distribution of NMDAR in cultured neurons. Our findings show that, under control conditions, NMDARs form nanosized objects and patients' antibodies increase the clustering of synaptic and extrasynaptic receptors inside the nano-objects. This clustering is subunit specific and predominantly affects GluN2B-NMDARs. Following internalization, the remaining surface NMDARs return to control clustering levels but are preferentially retained at the synapse. Monte Carlo simulations using a model in which antibodies induce NMDAR cross-linking and disruption of interactions with other proteins recapitulated these results. Finally, activation of EphB2 receptor partially antagonized the antibody-mediated disorganization of the nanoscale surface distribution of NMDARs.
P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis.
Zabala Alazne,Vazquez-Villoldo Nuria,Rissiek Björn,Gejo Jon,Martin Abraham,Palomino Aitor,Perez-Samartín Alberto,Pulagam Krishna R,Lukowiak Marco,Capetillo-Zarate Estibaliz,Llop Jordi,Magnus Tim,Koch-Nolte Friedrich,Rassendren Francois,Matute Carlos,Domercq María
EMBO molecular medicine
Microglia survey the brain microenvironment for signals of injury or infection and are essential for the initiation and resolution of pathogen- or tissue damage-induced inflammation. Understanding the mechanism of microglia responses during pathology is hence vital to promote regenerative responses. Here, we analyzed the role of purinergic receptor P2X4 (P2X4R) in microglia/macrophages during autoimmune inflammation. Blockade of P2X4R signaling exacerbated clinical signs in the experimental autoimmune encephalomyelitis (EAE) model and also favored microglia activation to a pro-inflammatory phenotype and inhibited myelin phagocytosis. Moreover, P2X4R blockade in microglia halted oligodendrocyte differentiation and remyelination after lysolecithin-induced demyelination. Conversely, potentiation of P2X4R signaling by the allosteric modulator ivermectin (IVM) favored a switch in microglia to an anti-inflammatory phenotype, potentiated myelin phagocytosis, promoted the remyelination response, and ameliorated clinical signs of EAE Our results provide evidence that P2X4Rs modulate microglia/macrophage inflammatory responses and identify IVM as a potential candidate among currently used drugs to promote the repair of myelin damage.
Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis.
Armangue Thaís,Spatola Marianna,Vlagea Alexandru,Mattozzi Simone,Cárceles-Cordon Marc,Martinez-Heras Eloy,Llufriu Sara,Muchart Jordi,Erro María Elena,Abraira Laura,Moris German,Monros-Giménez Luis,Corral-Corral Íñigo,Montejo Carmen,Toledo Manuel,Bataller Luis,Secondi Gabriela,Ariño Helena,Martínez-Hernández Eugenia,Juan Manel,Marcos Maria Angeles,Alsina Laia,Saiz Albert,Rosenfeld Myrna R,Graus Francesc,Dalmau Josep,
The Lancet. Neurology
BACKGROUND:Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication. METHODS:We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis. FINDINGS:Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5-68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7-48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1-44·2]; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24-32] vs 43 days [25-54]; p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of 27 vs seven [23%] of 31; p<0·001), NMDAR antibodies (24 [89%] of 27 vs 19 [61%] of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 [IQR 4-4] vs 2 [2-3]; p<0·0010; seizures 12 [63%] of 19 vs three [13%] of 23; p=0·001). INTERPRETATION:The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy. FUNDING:Mutua Madrileña Foundation, Fondation de l'Université de Lausanne et Centre Hospitalier Universitaire Vaudois, Instituto Carlos III, CIBERER, National Institutes of Health, Generalitat de Catalunya, Fundació CELLEX.
Treatment strategies for autoimmune encephalitis.
Shin Yong-Won,Lee Soon-Tae,Park Kyung-Il,Jung Keun-Hwa,Jung Ki-Young,Lee Sang Kun,Chu Kon
Therapeutic advances in neurological disorders
Autoimmune encephalitis is one of the most rapidly growing research topics in neurology. Along with discoveries of novel antibodies associated with the disease, clinical experience and outcomes with diverse immunotherapeutic agents in the treatment of autoimmune encephalitis are accumulating. Retrospective observations indicate that early aggressive treatment is associated with better functional outcomes and fewer relapses. Immune response to first-line immunotherapeutic agents (corticosteroids, intravenous immunoglobulin, plasma exchange, and immunoadsorption) is fair, but approximately half or more of patients are administered second-line immunotherapy (rituximab and cyclophosphamide). A small but significant proportion of patients are refractory to all first- and second-line therapies and require further treatment. Although several investigations have shown promising alternatives, the low absolute number of patients involved necessitates more evidence to establish further treatment strategies. In this review, the agents used for first- and second-line immunotherapy are discussed and recent attempts at finding new treatment options are introduced.
Neurobiology of autoimmune encephalitis.
Fukata Masaki,Yokoi Norihiko,Fukata Yuko
Current opinion in neurobiology
Autoimmune encephalitis presenting with amnesia, seizures, and psychosis is highly topical in basic and clinical neuroscience. Recent studies have identified numerous associated autoantibodies, targeting cell-surface synaptic proteins including neurotransmitter receptors (e.g. NMDA receptors (NMDARs)) and a secreted protein, LGI1. In vitro and in vivo analyses of the influence of the autoantibodies have begun to clarify their causal roles. Of particular interest is the generation of recombinant monoclonal antibodies from patients' B cells with anti-NMDAR encephalitis. Patient monoclonal antibodies could be useful to reveal their direct, detailed pathogenicity. Such identification and characterization of autoantibodies could create new categories of neurological diseases and promote the understanding of patho-physiologic roles of target proteins in human brain function.
Management of Autoimmune Encephalitis: An Observational Monocentric Study of 38 Patients.
Macher Stefan,Zimprich Friedrich,De Simoni Desiree,Höftberger Romana,Rommer Paulus S
Frontiers in immunology
Over the last years the clinical picture of autoimmune encephalitis has gained importance in neurology. The broad field of symptoms and syndromes poses a great challenge in diagnosis for clinicians. Early diagnosis and the initiation of the appropriate treatment is the most relevant step in the management of the patients. Over the last years advances in neuroimmunology have elucidated pathophysiological basis and improved treatment concepts. In this monocentric study we compare demographics, diagnostics, treatment options and outcomes with knowledge from literature. We present 38 patients suffering from autoimmune encephalitis. Antibodies were detected against NMDAR and LGI1 in seven patients, against GAD in 6 patients) one patient had coexisting antibodies against GABA and GABA), against CASPR2, IGLON5, YO, Glycine in 3 patients, against Ma-2 in 2 patients, against CV2 and AMPAR in 1 patient; two patients were diagnosed with hashimoto encephalitis with antibodies against TPO/TG. First, we compare baseline data of patients who were consecutively diagnosed with autoimmune encephalitis from a retrospective view. Further, we discuss when to stop immunosuppressive therapy since how long treatment should be performed after clinical stabilization or an acute relapse is still a matter of debate. Our experiences are comparable with data from literature. However, in contrary to other experts in the field we stop treatment and monitor patients very closely after tumor removal and after rehabilitation from first attack.