Neuronal Na
            <sup>+</sup>
            /K
            <sup>+</sup>
            ATPase is an autoantibody target in paraneoplastic neurologic syndrome

Scharf, Madeleine; Miske, Ramona; Heidenreich, Fedor; Giess, Ralf; Landwehr, P.; Blöcker, Inga-Madeleine; Begemann, Nora; Denno, Yvonne; Tiede, Stephan; Dähnrich, Cornelia; Schlumberger, Wolfgang; Unger, Mandy; Teegen, Bianca; Stöcker, W.; Probst, Christian; Komorowski, Lars

doi:10.1212/wnl.0000000000001493

Cited by 12 publications

(6 citation statements)

References 20 publications

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“…Following the successful identification of target autoantigens based on index samples, cohort studies including patients with similar neurological symptoms and disease as well as healthy controls must validate whether the discovered autoantibodies appear rarely or are common markers for specific phenotypes like autoantibody-mediated brain disorders or paraneoplastic neurological syndromes. For autoantibodies against ATP1A3, ITPR1, NCDN, and ROCK2 an association to autoimmune cerebellar syndromes has already been demonstrated by the authors ( 20 , 31 , 33 , 36 ). Moreover, anti-Flotillin1/2 autoantibodies were found to be present in multiple sclerosis patients ( 24 ).…”

Section: Discussionmentioning

confidence: 63%

“…Not all of the antigens we identified are exclusively expressed in neural tissues. For some antigens like ATP1A3, ITPR1, or ROCK2 an expression in tumor samples of the respective index patient was observed, pointing to a paraneoplastic autoimmune background ( 20 , 31 , 36 ). Antigens like Flotillin1/2, GRIPAP1, or CLIP1 are also expressed in non-neural tissues without a tumor association ( 21 , 24 , 26 ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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BackgroundA plurality of neurological syndromes is associated with autoantibodies against neural antigens relevant for diagnosis and therapy. Identification of these antigens is crucial to understand the pathogenesis and to develop specific immunoassays. Using an indirect immunofluorescence assay (IFA)-based approach and applying different immunoprecipitation (IP), chromatographic and mass spectrometric protocols was possible to isolate and identify a spectrum of autoantigens from brain tissue.MethodsSera and CSF of 320 patients suspected of suffering from an autoimmune neurological syndrome were comprehensively investigated for the presence of anti-neural IgG autoantibodies by IFA using mosaics of biochips with brain tissue cryosections and established cell-based recombinant antigen substrates as well as immunoblots. Samples containing unknown brain tissue-specific autoantibodies were subjected to IP with cryosections of cerebellum and hippocampus (rat, pig, and monkey) immobilized to glass slides or with lysates produced from homogenized tissue, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, tryptic digestion, and matrix-assisted laser desorption/ionization–time of flight mass spectrometry analysis. Identifications were confirmed by IFA with recombinant HEK293 cells and by neutralizing the patients’ autoantibodies with the respective recombinantly expressed antigens in the tissue-based immunofluorescence test.ResultsMost samples used in this study produced speckled, granular, or homogenous stainings of the hippocampal and cerebellar molecular and/or granular layers. Others exclusively stained the Purkinje cells. Up to now, more than 20 different autoantigens could be identified by this approach, among them ATP1A3, CPT1C, Flotillin1/2, ITPR1, NBCe1, NCDN, RGS8, ROCK2, and Syntaxin-1B as novel autoantigens.DiscussionThe presented antigen identification strategy offers an opportunity for identifying up to now unknown neural autoantigens. Recombinant cell substrates containing the newly identified antigens can be used in serology and the clinical relevance of the autoantibodies can be rapidly evaluated in cohort studies.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…IFA was conducted using slides with a biochip array of brain tissue cryosections (hippocampus of rat, cerebellum of rat and monkey) combined with recombinant HEK293 cells separately expressing 27 different brain antigens (EUROIMMUN AG, Luebeck, Germany) as described previously [28]. Additionally, a standard biochip mosaic containing frozen sections of 30 different human, monkey and rat organs and tissues (EUROIMMUN AG, Luebeck, Germany) was applied to determine an autoantibody profile.…”

Section: Methodsmentioning

confidence: 99%

Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis

Popkirov

Ayzenberg

Hahn

et al. 2017

acta neuropathol commun

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Onconeural antibodies are associated with cancer and paraneoplastic encephalitis. While their pathogenic role is still largely unknown, their high diagnostic value is undisputed. In this study we describe the discovery of a novel target of autoimmunity in an index case of paraneoplastic encephalitis associated with urogenital cancer.A 75-year-old man with a history of invasive bladder carcinoma 6 years ago with multiple recurrences and a newly discovered renal cell carcinoma presented with seizures and progressive cognitive decline followed by super-refractory status epilepticus. Clinical and ancillary findings including brain biopsy suggested paraneoplastic encephalitis. Immunohistochemistry of the brain biopsy was used to characterize the inflammatory response. Indirect immunofluorescence assay (IFA) was used for autoantibody screening. The autoantigen was identified by histo-immunoprecipitation and mass spectrometry and was validated by expressing the recombinant antigen in HEK293 cells and neutralization tests. Sera from 125 control patients were screened using IFA to test for the novel autoantibodies.IFA analysis of serum revealed a novel autoantibody against brain tissue. An intracellular enzyme, Rho-associated protein kinase 2 (ROCK2), was identified as target-antigen. ROCK2 was expressed in affected brain tissue and archival bladder tumor samples of this patient. Brain histopathology revealed appositions of cytotoxic CD8+ T cells on ROCK2-positive neurons. ROCK2 antibodies were not found in the sera of 20 patients with bladder cancer and 17 with renal cancer, both without neurological symptoms, 49 healthy controls, and 39 patients with other antineuronal autoantibodies. In conclusion, novel onconeural antibodies targeting ROCK2 are associated with paraneoplastic encephalitis and should be screened for when paraneoplastic neurological syndromes, especially in patients with urogenital cancers, occur.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0447-3) contains supplementary material, which is available to authorized users.

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“…Winfried Sto¨cker (Germany) described the combination of the novel technique of histo-immunoprecipitation and mass spectrometric analysis of purified proteins as a potent strategy for identification of hitherto unknown antigens targeted by AABs that are associated with various neurological AIDs. 35 By this strategy, the panel of diagnostic markers for various neuroimmunological conditions, predominantly autoimmune encephalitis, can be expanded significantly, supporting rapid diagnosis and initiation of often lifesaving therapies (examples in Table 1). Peter Schulz-Knappe (Germany) presented SeroTag, a new screening pipeline for discovery of novel AABs in AIDs.…”

Section: Novel Aabs and Novel Aspects Of Aab Testingmentioning

confidence: 99%

From autoantibody research to standardized diagnostic assays in the management of human diseases – report of the 12th Dresden Symposium on Autoantibodies

Conrad

Andrade

Chan

et al. 2016

Lupus

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Testing for autoantibodies (AABs) is becoming more and more relevant, not only for diagnosing autoimmune diseases (AIDs) but also for the differentiation of defined AID subtypes with different clinical manifestations, course and prognosis as well as the very early diagnosis for adequate management in the context of personalized medicine. A major challenge to improve diagnostic accuracy is to harmonize or even standardize AAB analyses. This review presents the results of the 12th Dresden Symposium on Autoantibodies that focused on several aspects of improving autoimmune diagnostics. Topics that are addressed include the International Consensus on ANA Patterns (ICAP) and the International Autoantibody Standardization (IAS) initiatives, the optimization of diagnostic algorithms, the description and evaluation of novel disease-specific AABs as well as the development and introduction of novel assays into routine diagnostics. This review also highlights important developments of recent years, most notably the improvement in diagnosing and predicting the course of rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, and of autoimmune neurological, gastrointestinal and liver diseases; the potential diagnostic role of anti-DFS70 antibodies and tumor-associated AABs. Furthermore, some hot topics in autoimmunity regarding disease pathogenesis and management are described.

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Neuronal Na ⁺ /K ⁺ ATPase is an autoantibody target in paraneoplastic neurologic syndrome

Cited by 12 publications

References 20 publications

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

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

Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis

From autoantibody research to standardized diagnostic assays in the management of human diseases – report of the 12th Dresden Symposium on Autoantibodies

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Neuronal Na + /K + ATPase is an autoantibody target in paraneoplastic neurologic syndrome

Cited by 12 publications

References 20 publications

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

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

Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis

From autoantibody research to standardized diagnostic assays in the management of human diseases – report of the 12th Dresden Symposium on Autoantibodies

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Neuronal Na ⁺ /K ⁺ ATPase is an autoantibody target in paraneoplastic neurologic syndrome