Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis
Abstract 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 enc...
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| Format: | Article |
| Language: | English |
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BMC
2017-05-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-017-0447-3 |
| _version_ | 1818274684027797504 |
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| author | Stoyan Popkirov Ilya Ayzenberg Stefanie Hahn Jan Bauer Yvonne Denno Nicole Rieckhoff Christiane Radzimski Volkmar H. Hans Sebastian Berg Florian Roghmann Joachim Noldus Christian G. Bien Sabine Skodda Jörg Wellmer Winfried Stöcker Christos Krogias Ralf Gold Uwe Schlegel Christian Probst Lars Komorowski Ramona Miske Ingo Kleiter |
| author_facet | Stoyan Popkirov Ilya Ayzenberg Stefanie Hahn Jan Bauer Yvonne Denno Nicole Rieckhoff Christiane Radzimski Volkmar H. Hans Sebastian Berg Florian Roghmann Joachim Noldus Christian G. Bien Sabine Skodda Jörg Wellmer Winfried Stöcker Christos Krogias Ralf Gold Uwe Schlegel Christian Probst Lars Komorowski Ramona Miske Ingo Kleiter |
| author_sort | Stoyan Popkirov |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-12T22:17:46Z |
| format | Article |
| id | doaj.art-27a524edfff64c67aa9cd7fb6f7d00e4 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-12T22:17:46Z |
| publishDate | 2017-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-27a524edfff64c67aa9cd7fb6f7d00e42022-12-22T00:10:01ZengBMCActa Neuropathologica Communications2051-59602017-05-015111010.1186/s40478-017-0447-3Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitisStoyan Popkirov0Ilya Ayzenberg1Stefanie Hahn2Jan Bauer3Yvonne Denno4Nicole Rieckhoff5Christiane Radzimski6Volkmar H. Hans7Sebastian Berg8Florian Roghmann9Joachim Noldus10Christian G. Bien11Sabine Skodda12Jörg Wellmer13Winfried Stöcker14Christos Krogias15Ralf Gold16Uwe Schlegel17Christian Probst18Lars Komorowski19Ramona Miske20Ingo Kleiter21Department of Neurology, Ruhr-Epileptology, Universitätsklinikum Knappschaftskrankenhaus Bochum, Ruhr University BochumDepartment of Neurology, St. Josef Hospital Bochum, Ruhr University BochumInstitute of Experimental Immunology, Euroimmun AGDepartment of Neuroimmunology, Center for Brain Research, Medical University ViennaInstitute of Experimental Immunology, Euroimmun AGInstitute of Experimental Immunology, Euroimmun AGInstitute of Experimental Immunology, Euroimmun AGInstitute of Pathology, Ruhr University BochumDepartment of Urology, Marien Hospital Herne, Ruhr University BochumDepartment of Urology, Marien Hospital Herne, Ruhr University BochumDepartment of Urology, Marien Hospital Herne, Ruhr University BochumEpilepsy Centre Bethel, Krankenhaus MaraDepartment of Neurology, Knappschaftskrankenhaus Bochum, Ruhr University BochumDepartment of Neurology, Ruhr-Epileptology, Universitätsklinikum Knappschaftskrankenhaus Bochum, Ruhr University BochumInstitute of Experimental Immunology, Euroimmun AGDepartment of Neurology, St. Josef Hospital Bochum, Ruhr University BochumDepartment of Neurology, St. Josef Hospital Bochum, Ruhr University BochumDepartment of Neurology, Knappschaftskrankenhaus Bochum, Ruhr University BochumInstitute of Experimental Immunology, Euroimmun AGInstitute of Experimental Immunology, Euroimmun AGInstitute of Experimental Immunology, Euroimmun AGDepartment of Neurology, St. Josef Hospital Bochum, Ruhr University BochumAbstract 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.http://link.springer.com/article/10.1186/s40478-017-0447-3Paraneoplastic encephalitisStatus epilepticusAutoantibodyRho-associated protein kinase 2Urogential cancer |
| spellingShingle | Stoyan Popkirov Ilya Ayzenberg Stefanie Hahn Jan Bauer Yvonne Denno Nicole Rieckhoff Christiane Radzimski Volkmar H. Hans Sebastian Berg Florian Roghmann Joachim Noldus Christian G. Bien Sabine Skodda Jörg Wellmer Winfried Stöcker Christos Krogias Ralf Gold Uwe Schlegel Christian Probst Lars Komorowski Ramona Miske Ingo Kleiter Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis Acta Neuropathologica Communications Paraneoplastic encephalitis Status epilepticus Autoantibody Rho-associated protein kinase 2 Urogential cancer |
| title | Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis |
| title_full | Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis |
| title_fullStr | Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis |
| title_full_unstemmed | Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis |
| title_short | Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis |
| title_sort | rho associated protein kinase 2 rock2 a new target of autoimmunity in paraneoplastic encephalitis |
| topic | Paraneoplastic encephalitis Status epilepticus Autoantibody Rho-associated protein kinase 2 Urogential cancer |
| url | http://link.springer.com/article/10.1186/s40478-017-0447-3 |
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