A Spectrum of Neural Autoantigens, Newly Identified by Histo-Immunoprecipitation, Mass Spectrometry, and Recombinant Cell-Based Indirect Immunofluorescence

Scharf, Madeleine; Miske, Ramona; Kade, Stephanie; Hahn, Stefanie; Denno, Yvonne; Begemann, Nora; Rochow, Nadine; Radzimski, Christiane; Brakopp, S.; Probst, Christian; Teegen, Bianca; Stöcker, W.; Komorowski, Lars

doi:10.3389/fimmu.2018.01447

Cited by 27 publications

(15 citation statements)

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“…It is questionable if these novel autoantibodies are pathogenetic. Contrary to previous descriptions [ 31 ], recent evidence reported by Lang et al led to the assumption that Kv1 subunit-associated autoantibodies were more likely directed to the intracellular epitope, as they did identified no detectable binding to the hippocampal cell culture system. Furthermore, they detected no specific autoimmune phenotype, and the response of most patients to immunotherapy was generally poor, with exception of one young male with Kv1.2 antibody-associated limbic encephalitis.…”

Section: Discussioncontrasting

confidence: 72%

“…Overall, the pathological and clinical relevance of double negative VGCK antibodies is controversial, as they comprise a wide range of only partially known targets, heterogeneous clinical phenotypes, and reveal a variable response to standard immunotherapy [ 30 ]. KCNA2 autoantibodies were recently discovered to target the plasma membrane-associated Kv1.2 subunit in the VGKC complex of patients with suspected autoimmune neurological syndromes [ 31 ]. It is questionable if these novel autoantibodies are pathogenetic.…”

Section: Discussionmentioning

confidence: 99%

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KCNA2 Autoimmunity in Progressive Cognitive Impairment: Case Series and Literature Review

et al. 2021

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Autoimmune dementia is a novel and expanding field which subsumes neuropsychiatric disorders with predominant cognitive impairments due to an underlying autoimmune etiology. Progressive dementias with atypical clinical presentation should trigger a thorough diagnostic approach including testing for neural surface and intracellular antibodies to avoid a delay in accurate diagnosis and initiating appropriate therapy. Here, we present two emerging cases of progressive dementia with co-existing serum autoantibodies against the KCNA2 (potassium voltage-gated channel subfamily A member 2) subunit. We found various cognitive deficits with dominant impairments in the memory domain, particularly in delayed recall. One patient presented a subacute onset of then-persisting cognitive deficits, while the other patient’s cognitive impairments progressed more chronically and fluctuated. Cognitive impairments coincided with additional neuropsychiatric symptoms. Both had a potential paraneoplastic background according to their medical history and diagnostic results. We discuss the potential role of KCNA2 autoantibodies in these patients and in general by reviewing the literature. The pathogenetic role of KCNA2 antibodies in cognitive impairment is not well delineated; clinical presentations are heterogeneous, and thus a causal link between antibodies remains questionable. Current evidence indicates an intracellular rather than extracellular epitope. We strongly suggest additional prospective studies to explore KCNA2 antibodies in specifically-defined cohorts of cognitively impaired patients via a systematic assessment of clinical, neuropsychological, neuroimaging, as well as laboratory and CSF (cerebrospinal fluid) parameters, and antibody studies to (1) determine the epitope’s location (intracellular vs. extracellular), (2) the mode of action, and (3) seek co-existing, novel pathogenetic autoantibodies in sera and CSF.

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Section: Discussioncontrasting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

KCNA2 Autoimmunity in Progressive Cognitive Impairment: Case Series and Literature Review

et al. 2021

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“…This method was described in detail in Scharf et al 10 2018. Briefly, protein bands were excised from Coomassie Brilliant Blue G-250 stained gels, destained, and tryptic digested.…”

Section: Methodsmentioning

confidence: 99%

Autoantibodies Against the Purkinje Cell Protein RGS8 in Paraneoplastic Cerebellar Syndrome

Miske

Scharf

Stark

et al. 2021

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo describe the identification of regulator of G-protein signaling 8 (RGS8) as an autoantibody target in patients with cerebellar syndrome associated with lymphoma.MethodsSera of 4 patients with a very similar unclassified reactivity against cerebellar Purkinje cells were used in antigen identification experiments. Immunoprecipitations with cerebellar lysates followed by mass spectrometry identified the autoantigen, which was verified by recombinant immunofluorescence assay, immunoblot, and ELISA with the recombinant protein.ResultsThe sera and CSF of 4 patients stained the Purkinje cells and molecular layer of the cerebellum. RGS8 was identified as the target antigen in all 4 sera. In a neutralization experiment, recombinant human RGS8 was able to neutralize the autoantibodies' tissue reaction. Patient sera and CSF showed a specific reactivity against recombinant RGS8 in ELISA and immunoblot, whereas no such reactivity was detectable in the controls. Clinical data were available for 2 of the 4 patients, remarkably both presented with cerebellar syndrome accompanied by B-cell lymphoma of the stomach (patient 1, 53 years) or Hodgkin lymphoma (patient 2, 74 years).ConclusionOur results indicate that autoantibodies against the intracellular Purkinje cell protein RGS8 represent new markers for paraneoplastic cerebellar syndrome associated with lymphoma.Classification of EvidenceThis study provided Class IV evidence that autoantibodies against the intracellular Purkinje cell protein RGS8 are associated with paraneoplastic cerebellar syndrome in lymphoma.

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“…Immunoprecipitation (IP) was conducted as recently described . Briefly, 1g of freshly dissected rat brain tissue was homogenized in 5ml buffer (100mmol/l Tris[hydroxymethyl]‐aminomethane–HCl, pH 6.5, 150mmol/l sodium chloride, 1 mmol/l ethylenediaminetetraacetic acid, 1% [wt/vol] sodium deoxycholate, 1% [wt/vol] Triton X‐100, 1% [wt/vol] N‐octyl‐beta‐D‐glucopyranoside) containing protease inhibitors.…”

Section: Methodsmentioning

confidence: 99%

Drebrin Autoantibodies in Patients with Seizures and Suspected Encephalitis

Pitsch

Kamalizade

Braun

et al. 2020

Annals of Neurology

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Objective: Assess occurrence of the dendritic spine scaffolding protein Drebrin as a pathophysiologically relevant autoantibody target in patients with recurrent seizures and suspected encephalitis as leading symptoms. Methods: Sera of 4 patients with adult onset epilepsy and suspected encephalitis of unresolved etiology and equivalent results in autoantibody screening were subjected to epitope identification. We combined a wide array of approaches, ranging from immunoblotting, immunoprecipitation, mass spectrometry, subcellular binding pattern analyses in primary neuronal cultures, and immunohistochemistry in brains of wild-type and Drebrin knockout mice to in vitro analyses of impaired synapse formation, morphology, and aberrant neuronal excitability by antibody exposure. Results: In the serum of a patient with adult onset epilepsy and suspected encephalitis, a strong signal at $70kDa was detected by immunoblotting, for which mass spectrometry revealed Drebrin as the putative antigen. Three other patients whose sera also showed strong immunoreactivity around 70kDa on Western blotting were also anti-Drebrin-positive. Seizures, memory impairment, and increased protein content in cerebrospinal fluid occurred in anti-Drebrin-seropositive patients. Alterations in cerebral magnetic resonance imaging comprised amygdalohippocampal T2-signal increase and hippocampal sclerosis. Diagnostic biopsy revealed T-lymphocytic encephalitis in an anti-Drebrin-seropositive patient. Exposure of primary hippocampal neurons to anti-Drebrin autoantibodies resulted in aberrant synapse composition and Drebrin distribution as well as increased spike rates and the emergence of burst discharges reflecting network hyperexcitability. Interpretation: Anti-Drebrin autoantibodies define a chronic syndrome of recurrent seizures and neuropsychiatric impairment as well as inflammation of limbic and occasionally cortical structures. Immunosuppressant therapies should be considered in this disorder.

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A Spectrum of Neural Autoantigens, Newly Identified by Histo-Immunoprecipitation, Mass Spectrometry, and Recombinant Cell-Based Indirect Immunofluorescence

Cited by 27 publications

References 38 publications

KCNA2 Autoimmunity in Progressive Cognitive Impairment: Case Series and Literature Review

KCNA2 Autoimmunity in Progressive Cognitive Impairment: Case Series and Literature Review

Autoantibodies Against the Purkinje Cell Protein RGS8 in Paraneoplastic Cerebellar Syndrome

Drebrin Autoantibodies in Patients with Seizures and Suspected Encephalitis

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