Neuronal Cell Surface Antigens Research Articles

B-cell targeted therapies in autoimmune encephalitis: mechanisms, clinical applications, and therapeutic potential.

Autoimmune encephalitis (AE) broadly refers to inflammation of the brain parenchyma mediated by autoimmune mechanisms. In most patients with AE, autoantibodies against neuronal cell surface antigens are produced by B-cells and induce neuronal dysfunction through various mechanisms, ultimately leading to disease progression. In recent years, B-cell targeted therapies, including monoclonal antibody (mAb) therapy and chimeric antigen receptor T-cell (CAR-T) therapy, have been widely used in autoimmune diseases. These therapies decrease autoantibody levels in patients and have shown favorable results. This review summarizes the mechanisms underlying these two B-cell targeted therapies and discusses their clinical applications and therapeutic potential in AE. Our research provides clinicians with more treatment options for AE patients whose conventional treatments are not effective.

S100A6 participates in initiation of autoimmune encephalitis and is under epigenetic control.

Autoimmune encephalitis (AE) is caused by autoantibodies attacking neuronal cell surface antigens and/or synaptic antigens. We previously demonstrated that S100A6 was hypomethylated in patients with AE and that it promoted B lymphocyte infiltration through the simulated blood-brain barrier (BBB). In this study, we focused on the epigenetic regulation of S100A6, the process by which S100A6 affects B lymphocyte infiltration, and the therapeutic potential of S100A6 antibodies. We enrolled and collected serum from 10 patients with AE and 10 healthy control (HC) subjects. Promoter methylation and 5-azacytidine treatment assays were conducted to observe the methylation process of S100A6. The effect of S100A6 on B lymphocytes was analyzed using an adhesion assay and leukocyte transendothelial migration (LTEM) assay. A LTEM assay was also used to compare the effects of the serum of HCs, serum of AE patients, S100A6 recombinant protein, and S100A6 antibodies on B lymphocytes. The promoter methylation and 5-azacytidine treatment assays confirmed that S100A6 was regulated by DNA methylation. The adhesion study demonstrated that the addition of S100A6 enhanced adhesion between B lymphocytes and a BBB endothelial cell line in a concentration-dependent manner. The LTEM assay showed that the serum of AE patients, as well as S100A6, promoted B lymphocyte infiltration and that this effect could be attenuated by S100A6 antibodies. We clarified that S100A6 was under epigenetic regulation in patients with AE and that it helped B lymphocytes to adhere to and infiltrate the BBB endothelial layer, which could be counteracted by S100A6 antibodies. Therefore, the methylation profile of S100A6 could be a marker of the activity of AE, and countering the effect of S100A6 may be a potential treatment target for AE.

A critical review and update on autoimmune encephalitis: understanding the alphabet soup.

Autoimmune encephalitis (AE) comprises a group of diseases mediated by antibodies against neuronal cell surface or synaptic antigens, such as ion channels or neurotransmitter receptors. New clinical syndromes and their associated antibodies were and are still being characterized over the last two decades. The fact that their main clinical features are interdisciplinary, - encompassing neuropsychiatric symptoms, cognitive dysfunction, epileptic seizures, movement and sleep disorders - has led to a surge of interest in this field. Some of these diseases present with a well-defined syndrome, being recognizable on clinical grounds. Correct diagnosis is important since AE are potentially treatable diseases, despite their severity. On the other hand, an increasing number of neuronal antibodies being described casts doubt upon the way we should utilize antibody testing and interpret results. In this article we review, summarize and update the current knowledge on antibody mediated encephalitis.

Antibody response to herpes simplex virus-1 is increased in autoimmune encephalitis.

Antibody response to herpes simplex virus-1 is increased in autoimmune encephalitis.

Kv5.1 antibody in epilepsy patients with unknown etiology

BackgroundNeuronal autoantibodies and favorable response to immunosuppressive treatment have been described in patients with chronic epilepsy of unknown cause, suggesting autoimmune etiology. Our aim was to identify novel epilepsy-specific autoantibodies reactive with neuronal surface antigens. MethodsSera of 172 epilepsy patients with unknown cause and 30 healthy controls were screened with indirect immunofluorescence to identify IgG reacting with primary rat neuronal cultures. Putative target autoantigens were investigated with immunoprecipitation (IP) and liquid chromatography-mass/mass spectrometry (LC-MS/MS) studies using SH-SY5Y cells. Validation of LC-MS/MS results was carried out by IP and immunocytochemistry assays. ResultsAntibodies to neuronal cell surface antigens were detected in 18 epilepsy patients. LC-MS/MS analysis identified voltage-gated potassium channel modifier subfamily F member 1 (KCNF1, Kv5.1) as the single common cell surface antigen in 4 patients with Lennox-Gastaut syndrome (n = 2), focal epilepsy of unknown cause (n = 1) and mesial temporal lobe epilepsy with hippocampal sclerosis (n = 1). These patients had the common features of early seizure onset and treatment-resistance. IP assays and co-localization (serum IgG and commercial Kv5.1-antibody) studies done with non-fixed Kv5.1-transfected HEK293 cells and primary neuronal cultures confirmed the presence of Kv5.1-antibody in 4 epilepsy patients identified by LC-MS/MS. Similar findings were not obtained by sera of other patients with epilepsy, patients with autoimmune encephalitis and healthy controls. ConclusionThe herein described novel neuronal surface antibody to Kv5.1 appears to be associated with treatment-resistant epilepsy of unknown cause. Exact clinical and pathogenic significance of this antibody remains to be elucidated.

Study on the pro-inflammatory mechanism of the HuD antibody in promoting M1 polarization and paraneoplastic neurological syndrome occurrence

ABSTRACT Paraneoplastic neurological syndrome (PNS) is a nonmetastatic complication of malignant tumors that may lead to immune-mediated neuronal dysfunction or death. The occurrence of PNS results from the binding of anti-neuronal antibodies to neuronal cell surface antigens or intracellular antigens, which hinders the function of target proteins and promotes cell death. The aim of this study is to research the effect and immune mechanism of the neuronal ELAV-like protein (HuD antibody) on PNS-related syndrome. Neuronal cells were co-cultured with monocyte macrophages with or without HuD antibody. Next, we detected the apoptosis of neuronal cells by flow cytometry. Meantime, macrophage M1/M2 polarization factors and the secretion of inflammatory factors in the co-culture system were also detected by quantitative polymerase chain reaction (qPCR), Western blots and ELISA technologies. The results showed that after adding the HuD antibody in the co-culture system, the apoptosis level of the neuroma cells were significantly increased, and the apoptosis level were not significant changed when co-culture with monocytes without HuD antibody. In addition, the level of factors of M1 macrophages TNF-α, IL-12, TGF-β and IFN-γ increased, while the level of factors of M2 macrophages IL-10, IL-4, and Arg-1 decreased. The outcomes demonstrated that absorption of the HuD antibody by cerebellar neuronal cells could promote the proliferation of M1 macrophages and stimulates macrophages to secrete inflammatory factors, further damage the neuronal cells, eventually resulting in the occurrence of PNS. This finding provided a theoretical basis for the subsequent treatment and prevention of PNS.

Paraneoplastic and Other Autoimmune Encephalitides: Antineuronal Antibodies, T Lymphocytes, and Questions of Pathogenesis.

Autoimmune and paraneoplastic encephalitides represent an increasingly recognized cause of devastating human illness as well as an emerging area of neurological injury associated with immune checkpoint inhibitors. Two groups of antibodies have been detected in affected patients. Antibodies in the first group are directed against neuronal cell surface membrane proteins and are exemplified by antibodies directed against the N-methyl-D-aspartate receptor (anti-NMDAR), found in patients with autoimmune encephalitis, and antibodies directed against the leucine-rich glioma-inactivated 1 protein (anti-LGI1), associated with faciobrachial dystonic seizures and limbic encephalitis. Antibodies in this group produce non-lethal neuronal dysfunction, and their associated conditions often respond to treatment. Antibodies in the second group, as exemplified by anti-Yo antibody, found in patients with rapidly progressive cerebellar syndrome, and anti-Hu antibody, associated with encephalomyelitis, react with intracellular neuronal antigens. These antibodies are characteristically found in patients with underlying malignancy, and neurological impairment is the result of neuronal death. Within the last few years, major advances have been made in understanding the pathogenesis of neurological disorders associated with antibodies against neuronal cell surface antigens. In contrast, the events that lead to neuronal death in conditions associated with antibodies directed against intracellular antigens, such as anti-Yo and anti-Hu, remain poorly understood, and the respective roles of antibodies and T lymphocytes in causing neuronal injury have not been defined in an animal model. In this review, we discuss current knowledge of these two groups of antibodies in terms of their discovery, how they arise, the interaction of both types of antibodies with their molecular targets, and the attempts that have been made to reproduce human neuronal injury in tissue culture models and experimental animals. We then discuss the emerging area of autoimmune neuronal injury associated with immune checkpoint inhibitors and the implications of current research for the treatment of affected patients.

Autoimmune encephalitis: Antibodies to neurotransmitters, ion channels, tumor antigens. what next?

Autoimmune encephalitis (AE) is relatively rare and recently described group of diseases involving autoantibodies (AB) directed against synaptic and neuronal cell surface antigens. AE includes wide range of neurological symptoms. Sensitive and specific diagnostic tests, such as cellular analysis, are of paramount importance for detecting neuronal cell surface AB, in cerebrospinal fluid or serum of patients. Prognosis depends on how quickly t disease is detected, identified, and properly treated.

Autoimmune Encephalitis–Related Seizures and Epilepsy: Diagnostic and Therapeutic Approaches

Autoimmune Encephalitis–Related Seizures and Epilepsy: Diagnostic and Therapeutic Approaches

Psychiatric manifestations of autoimmune encephalitis

IntroductionAutoimmune encephalitis (AE) refers to a newly described, heterogeneous group of rare diseases characterized by brain inflammation and circulating autoantibodies. Various AE have been described and each of them is linked to the presence of specific autoantibodies directed against synaptic and neuronal cell surface antigens. The clinical picture includes a wide array of neuropsychiatric symptoms and is correlated with the associated antibody subtype. Since pronounced psychiatric symptoms are relatively common at the onset, patients can be misdiagnosed and initially driven to psychiatric institutions, thus delaying the adequate diagnosis and management of AE.ObjectivesWe aim to review and summarize the psychiatric manifestations of AE that might dominate the clinical picture. We also aim to describe the clinical signs that should alert the psychiatrist to the possibility of these diagnoses.MethodsWe performed an updated review in the PubMed database using the terms “autoimmune”, “encephalitis” and “psychiatric manifestations”. The included articles were selected by title and abstract. We also consulted a reference textbook.ResultsWe summarize the reported psychiatric manifestations of AE and also include two situations that can be helpful in AE diagnosis in the psychiatric setting: symptoms that should alert the physician for the possibility of AE and symptoms that should prompt an antibody detection test.ConclusionsAE are rare diseases that present very frequently with psychiatric symptoms as the first manifestation. Psychiatrists need to be aware of the most common psychiatric manifestations of AE since the early recognition and treatment of AE is fundamental for a good outcome.

F-18 Fluorodeoxyglucose Positron-Emission Tomography/Computed Tomography Showing Mammillary Body Involvement in a Case of Autoimmune Anti-N-Methyl D-Aspartate Antibody Encephalitis.

Autoimmune encephalitis with antibodies against neuronal cell surface antigens is a group of neuropsychiatric disorders, with anti-N-methyl D-aspartate (NMDAR) encephalitis being one of them. We report a case of a young male patient who presented with complaints of seizures associated with fever, rapidly progressing memory loss, and choreoathetoid movements for 1 month. His serum was strongly positive for anti-NMDAR receptor antibodies. F-18 fluorodeoxyglucose positron-emission tomography/computed tomography for the brain revealed hypermetabolism involving bilateral basal ganglia and bilateral mammillary bodies associated with hypometabolism in bilateral occipital lobes.

Anti NMDA encephalitis presenting with mixed psychiatric symptoms - case report

Anti NMDA receptor encephalitis is an autoimmune reaction against neuronal cell surface antigens. The prevalence of this condition is about 0.6 per lakh. Here, we present the case of an 18-year-old female, who presented with seizures along with both dissociative and psychotic symptoms. Later, she turned out to be a case of Anti-NMDA receptor encephalitis. Anti NMDA receptor encephalitis presents with behavioural, cognitive, psychiatric and neurological symptoms progressing to coma and death if untreated. The patient did not show improvement with first-line therapy like IVIG. Hence, the second-line agent, Rituximab, had to be used. She needed three anti-epileptic drugs for seizure control. There is evidence that delay in treatment can adversely affect the prognosis. There should be increased awareness among psychiatrists and other relevant medical professionals about this under-diagnosed disorder.

Treatment of Movement Disorder Emergencies in Autoimmune Encephalitis in the Neurosciences ICU.

Immune response against neuronal and glial cell surface and cytosolic antigens is an important cause of encephalitis. It may be triggered by activation of the immune system in response to an infection (para-infectious), cancer (paraneoplastic), or due to a patient's tendency toward autoimmunity. Antibodies directed toward neuronal cell surface antigens are directly pathogenic, whereas antibodies with intracellular targets may become pathogenic if the antigen is transiently exposed to the cell surface or via activation of cytotoxic T cells. Immune-mediated encephalitis is well recognized and may require intensive care due to status epilepticus, need for invasive ventilation, or dysautonomia. Patients with immune-mediated encephalitis may become critically ill and display clinically complex and challenging to treat movement disorders in over 80% of the cases (Zhang et al. in Neurocrit Care 29(2):264-272, 2018). Treatment options include immunotherapy and symptomatic agents affecting dopamine or acetylcholine neurotransmission. There has been no prior published guidance for management of these movement disorders for the intensivist. Herein, we discuss the immune-mediated encephalitis most likely to cause critical illness, clinical features and mechanisms of movement disorders and propose a management algorithm.

Presence of cerebrospinal fluid antibodies associated with autoimmune encephalitis of humans in dogs with neurologic disease.

BackgroundPresumed autoimmune diseases affecting the central nervous system (CNS) of dogs are common. In people, antibodies against neuronal cell surface antigens that are associated with a wide variety of neurological syndromes have been identified. The presence of cerebrospinal fluid (CSF) autoantibodies that target neuronal cell surface proteins has not been reported in dogs with neurologic disorders.ObjectivesAutoantibodies to neuronal cell surface antigens can be found in the CSF of dogs with inflammatory CNS disease. Our aim was to determine whether 6 neuronal cell surface autoantibodies were present in the CSF of dogs diagnosed with inflammatory and noninflammatory CNS disease.AnimalsClient‐owned dogs with CNS disease and complete diagnostic evaluation including magnetic resonance imaging and CSF analysis were included. One healthy dog was included as a negative control.MethodsCerebrospinal fluid was tested for 6 antigenic targets with a commercially available indirect immunofluorescence assay test kit.ResultsThere were 32 dogs with neurological disease, 19 diagnosed with inflammatory disease (encephalitis and meningitis), 10 with noninflammatory disease (neoplasia, intervertebral disk disease, degenerative myelopathy, and epilepsy), 2 with no diagnosis, and 1 with neoplasia and meningoencephalitis. Anti‐N‐methyl‐d‐aspartate receptor 1 (NMDAR1) antibodies were detected in 3 dogs (3/32; 9.38%). All 3 dogs responded to treatment of meningoencephalomyelitis of unknown etiology (MUE).Conclusions and Clinical ImportanceFurther evaluation of the prevalence and clinical relevance of CSF and serum antibodies to neuronal cell surface antigens is warranted. Defining antigenic targets associated with encephalitis in dogs might allow diagnostic categorization of MUE antemortem.

Neuronal Antibodies and Associated Syndromes.

Introduction Multiple well-recognized conditions, such as Lambert–Eaton myasthenic syndrome (LEMS) and myasthenia gravis (MG), have been associated with neuronal antibodies. Materials and Methods A search was performed using Embase, PubMed, and CINAHL. An initial search of each database was conducted using keywords and terms related to the aim of the current review. Additional articles were obtained by examining the reference lists and citations in the selected records. Results The studies identified through the search process used different designs and methods to explore neuronal antibodies and associated syndromes. Previous studies have shown that neurological and psychiatric disorders can be mediated and influenced by various antibodies. The identification of autoantibodies can help with the accurate diagnosis of conditions and commencement of early treatment. Discussion A review of selected studies identified in the literature implicated that classic anti-neuronal antibodies, such as anti-Ri and anti-Hu, play a role in the development of neurological diseases. More recent studies have indicated that other novel antibodies act on neuronal cell surface antigens to contribute to the development of neurological disorders. Conclusion Existing research provides evidence revealing a spectrum of antibodies linked to the development and progression of neurological diseases. However, further antibody testing and studies should be performed to validate the relationship between conditions and antibodies.

Autoantibody-associated schizophreniform psychoses: pathophysiology, diagnostics, and treatment

In the context of secondary, possibly organic schizophreniform psychoses, autoantibody(AB)-associated autoimmune encephalitis (AE) plays an increasingly important role. If this is suspected, clinical investigations, including laboratory, magnetic resonance imaging, electroencephalography and cerebrospinal fluid (CSF) analyses are recommended. The AB screening should include the most frequent ABs against neuronal cell surface antigens (NMDA receptor [R], CASPR2, LGI1, AMPA-R, GABAB-R), intracellular antigens (Hu, Ri, Yo, CV2/CRMP5, Ma2[Ta], amphiphysin, GAD65), thyroid tissue (TG, TPO, TRAK), and antinuclear antigens (ANAs). The ABs against cell surface antigens and GAD65 should be examined directly in serum and CSF. Less frequent ABs can be looked for in a second step. Furthermore, immunofluorescence tests on brain slices of rodents may identify previously unknown ABs. The detection of ABs in combination with further findings can lead to the diagnosis of AE which implies new therapeutic opportunities with immunomodulators.

Immune-mediated encephalitis for the infectious disease specialist.

Autoimmune encephalitis is increasingly recognized and must be distinguished from infectious forms of encephalitis. Moreover, physicians should be aware of infectious triggers of autoimmune encephalitis and of infectious complications associated with treatment. Recent epidemiological studies suggest that the incidence of autoimmune encephalitis may rival that of infectious encephalitis. Although distinguishing autoimmune from infectious forms of encephalitis on clinical grounds can be challenging, recently proposed diagnostic criteria can provide some assistance. There has been an explosion in our knowledge of autoimmune encephalitis associated with antibodies to neuronal cell surface antigens, and two of the most common forms, anti-NMDA receptor encephalitis and anti-LGI1 encephalitis, are typically associated with distinctive clinical features. Although tumors have long been known to trigger autoimmune encephalitis, it has been recently recognized that herpes simplex encephalitis may trigger the generation of antineuronal autoantibodies resulting in an autoimmune neurologic relapse. Both first and second-line therapies for autoimmune encephalitis are associated with infectious complications, whereas emerging treatments, including anakinra and tocilizumab, may also result in increased susceptibility to certain infections. The diagnosis and management of autoimmune encephalitis is complex, and awareness of diagnostic criteria and modalities, typical clinical syndromes, infectious triggers of disease, and infectious complications of therapies is critical in optimizing care for affected patients.

Serum and CSF neurofilament light chain levels in antibody-mediated encephalitis

Circulating and cerebrospinal fluid (CSF) neurofilament light chain (NfL) levels represent a reliable indicator of disease activity and axonal damage in different neuroinflammatory conditions. Recently, high CSF NfL levels have been detected in active autoimmune encephalitis, as opposed to significant lower levels after clinical improvement. The aim of the present study was to evaluate serum and CSF NfL concentration in patients with autoimmune encephalitis and to analyse the association between NfL levels and clinical, MRI, and CSF data. We retrospectively included 25 patients with neurological syndromes associated with autoantibodies to neuronal cell surface antigens and we collected clinical, MRI, CSF, and follow-up data. Using an ultrasensitive method (Simoa, Quanterix), we measured NfL levels in serum and CSF samples of all patients and in 25 sera of healthy controls. Serum NfL levels were higher in all cases, including 20 patients with inflammatory MRI/CSF features and 5 non-inflammatory cases (median 16.9pg/ml, range 4.5-90) than in controls (median 6.9pg/ml, range 2.7-12.8; p < 0.001). A correlation between serum and CSF NfL levels was found (r = 0.461, p = 0.023), whereas no significant association was observed between NfL levels and clinical, MRI/CSF inflammatory burden, and antibody type. In the 13 available follow-up samples, correlation between disease activity and NfL values was also observed. In conclusion, NfL levels are significantly increased in the serum of patients with antibody-mediated encephalitis, independently of the MRI/CSF inflammatory profile. These findings support the presence of ongoing axonal damage and suggest the co-occurrence of different mechanisms for neuronal/axonal involvement in antibody-associated CNS syndromes.

Recent progress in autoimmune encephalitis and its related disorders

After the discovery of a series of autoantibodies against neuronal cell surface antigens (NSAs) of the CNS in the past 10 years, the concept of encephalitis has changed dramatically. Accordingly, a practical, syndrome-based diagnostic approach to autoimmune encephalitis was proposed in 2016. These autoantibodies have also been identified in a subset of overlapping encephalitis and demyelinating syndrome, epilepsy, first episode psychosis, movement disorders, post-herpes simplex encephalitis, progressive dementia, postpartum psychosis, stiff-person spectrum disorders, or non-REM/REM sleep behavior disorder. Although not all neuronal antibody tests are available in Japan, we have entered a new era that we have to make a correct diagnosis and start appropriate immunotherapy based on initial neurological assessment and conventional tests, without being constrained by conventional fixed ideas or normal-appearing brain MRIs while waiting for neuronal antibody test results. Although many issues need to be resolved in Japan in terms of diagnosis and treatment in autoimmune encephalitis, this review focusses on recent progress in autoimmune encephalitis and its related disorders closely related to clinical practice, including Hashimoto encephalopathy and new-onset refractory status epilepticus (NORSE).

Systematic Review: Syndromes, Early Diagnosis, and Treatment in Autoimmune Encephalitis.

In recent years, new antibodies have been discovered which mediate autoimmune encephalitis. This immunological response can be triggered by an infection or a tumor. Classical onconeuronal antibodies are directed against intracellular neuronal agents but recently, a novel group of antibodies to neuronal cell-surface and synaptic antigens associated with different CNS-syndromes, has been discovered. Interestingly, the syndromes in this group can be successfully treated with immunotherapy and frequently do not have underlying tumors. The aim of this review is to describe the current state of knowledge about autoimmune encephalitis, in order to provide clinicians with a concise, up-to-date overview. Thus, a comprehensive literature search was performed in medical databases. The literature was carefully studied and new findings focusing on the symptoms, diagnosis and treatment were summarized and interpreted. Even though it might be challenging in some cases, the awareness of certain symptom constellations and demographic information, in combination with laboratory- and MRI-results, allows clinicians to make the diagnosis of probable autoimmune encephalitis at an early stage. Treatment can therefore be initiated faster, which significantly improves the outcome. Further investigations could define the underlying pathogenic mechanisms. Randomized controlled trials, paired with increasing clinical experience, will be necessary to improve the identification of affected patients, treatment strategies, and outcomes in the years to come.