B‐cell receptors of EBV‐negative Burkitt lymphoma bind modified isoforms of autoantigens
Abstract Burkitt lymphoma (BL) represents the most aggressive B‐cell‐lymphoma. Beside the hallmark of IG‐MYC‐translocation, surface B‐cell receptor (BCR) is expressed, and mutations in the BCR pathway are frequent. Coincidental infections in endemic BL, and specific extra‐nodal sites suggest antigen...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-08-01
|
| Series: | eJHaem |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jha2.475 |
| _version_ | 1828716073266970624 |
|---|---|
| author | Theresa Bock Moritz Bewarder Onur Cetin Natalie Fadle Evi Regitz Eva C. Schwarz Jana Held Sophie Roth Stefan Lohse Thorsten Pfuhl Rabea Wagener Sigrun Smola Sören L. Becker Rainer Maria Bohle Lorenz Trümper Reiner Siebert Martin‐Leo Hansmann Michael Pfreundschuh Hans G. Drexler Markus Hoth Boris Kubuschok Klaus Roemer Klaus‐Dieter Preuss Sylvia Hartmann Lorenz Thurner |
| author_facet | Theresa Bock Moritz Bewarder Onur Cetin Natalie Fadle Evi Regitz Eva C. Schwarz Jana Held Sophie Roth Stefan Lohse Thorsten Pfuhl Rabea Wagener Sigrun Smola Sören L. Becker Rainer Maria Bohle Lorenz Trümper Reiner Siebert Martin‐Leo Hansmann Michael Pfreundschuh Hans G. Drexler Markus Hoth Boris Kubuschok Klaus Roemer Klaus‐Dieter Preuss Sylvia Hartmann Lorenz Thurner |
| author_sort | Theresa Bock |
| collection | DOAJ |
| description | Abstract Burkitt lymphoma (BL) represents the most aggressive B‐cell‐lymphoma. Beside the hallmark of IG‐MYC‐translocation, surface B‐cell receptor (BCR) is expressed, and mutations in the BCR pathway are frequent. Coincidental infections in endemic BL, and specific extra‐nodal sites suggest antigenic triggers. To explore this hypothesis, BCRs of BL cell lines and cases were screened for reactivities against a panel of bacterial lysates, lysates of Plasmodium falciparum, a custom‐made virome array and against self‐antigens, including post‐translationally modified antigens. An atypically modified, SUMOylated isoform of Bystin, that is, SUMO1‐BYSL was identified as the antigen of the BCR of cell line CA46. SUMO1‐BYSL was exclusively expressed in CA46 cells with K139 as site of the SUMOylation. Secondly, an atypically acetylated isoform of HSP40 was identified as the antigen of the BCR of cell line BL41. K104 and K179 were the sites of immunogenic acetylation, and the acetylated HSP40 isoform was solely present in BL41 cells. Functionally, addition of SUMO1‐BYSL and acetylated HSP40 induced BCR pathway activation in CA46 and BL41 cells, respectively. Accordingly, SUMO1‐BYSL‐ETA’ immunotoxin, produced by a two‐step intein‐based conjugation, led to the specific killing of CA46 cells. Autoantibodies directed against SUMO1‐BYSL were found in 3 of 14 (21.4%), and autoantibodies against acetylated HSP40 in 1/14(7.1%) patients with sporadic Burkitt‐lymphoma. No reactivities against antigens of the infectious agent spectrum could be observed. These results indicate a pathogenic role of autoreactivity evoked by immunogenic post‐translational modifications in a subgroup of sporadic BL including two EBV‐negative BL cell lines. |
| first_indexed | 2024-03-12T14:07:08Z |
| format | Article |
| id | doaj.art-dd8c74630d094db89e2da563ef835603 |
| institution | Directory Open Access Journal |
| issn | 2688-6146 |
| language | English |
| last_indexed | 2024-03-12T14:07:08Z |
| publishDate | 2022-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | eJHaem |
| spelling | doaj.art-dd8c74630d094db89e2da563ef8356032023-08-21T14:06:34ZengWileyeJHaem2688-61462022-08-013373974710.1002/jha2.475B‐cell receptors of EBV‐negative Burkitt lymphoma bind modified isoforms of autoantigensTheresa Bock0Moritz Bewarder1Onur Cetin2Natalie Fadle3Evi Regitz4Eva C. Schwarz5Jana Held6Sophie Roth7Stefan Lohse8Thorsten Pfuhl9Rabea Wagener10Sigrun Smola11Sören L. Becker12Rainer Maria Bohle13Lorenz Trümper14Reiner Siebert15Martin‐Leo Hansmann16Michael Pfreundschuh17Hans G. Drexler18Markus Hoth19Boris Kubuschok20Klaus Roemer21Klaus‐Dieter Preuss22Sylvia Hartmann23Lorenz Thurner24Department of Internal Medicine I and José Carreras Center for Immuno‐ and Gene Therapy Saarland University Medical School Homburg/Saar GermanyDepartment of Internal Medicine I and José Carreras Center for Immuno‐ and Gene Therapy Saarland University Medical School Homburg/Saar GermanyDepartment of Internal Medicine I and José Carreras Center for Immuno‐ and Gene Therapy Saarland University Medical School Homburg/Saar GermanyDepartment of Internal Medicine I and José Carreras Center for Immuno‐ and Gene Therapy Saarland University Medical School Homburg/Saar GermanyDepartment of Internal Medicine I and José Carreras Center for Immuno‐ and Gene Therapy Saarland University Medical School Homburg/Saar GermanyCenter for Integrative Physiology and Molecular Medicine (CIPMM) School of Medicine Homburg GermanyInstitute of Tropical Medicine Eberhard Karls Universität Tübingen Tübingen GermanyInstitute of Medical Microbiology and Hygiene Saarland University Homburg/Saar GermanyInstitute of Virology University of Saarland Homburg GermanyInstitute of Virology University of Saarland Homburg GermanyInstitute of Human Genetics Ulm University and Ulm University Medical Center Ulm GermanyInstitute of Virology University of Saarland Homburg GermanyInstitute of Medical Microbiology and Hygiene Saarland University Homburg/Saar GermanyInstitute of Pathology Saarland University Medical School Homburg/Saar GermanyDepartment of Hematology and Oncology Georg August University Göttingen Göttingen GermanyInstitute of Human Genetics Ulm University and Ulm University Medical Center Ulm GermanyDr. Senckenberg Institute of Pathology Goethe University Hospital of Frankfurt a. Main Frankfurt a. Main GermanyDepartment of Internal Medicine I and José Carreras Center for Immuno‐ and Gene Therapy Saarland University Medical School Homburg/Saar GermanyFaculty of Life sciences Technical University of Braunschweig Braunschweig GermanyCenter for Integrative Physiology and Molecular Medicine (CIPMM) School of Medicine Homburg GermanyDepartment of Internal Medicine II Augsburg University Medical Center Augsburg GermanyDepartment of Internal Medicine I and José Carreras Center for Immuno‐ and Gene Therapy Saarland University Medical School Homburg/Saar GermanyDepartment of Internal Medicine I and José Carreras Center for Immuno‐ and Gene Therapy Saarland University Medical School Homburg/Saar GermanyDr. Senckenberg Institute of Pathology Goethe University Hospital of Frankfurt a. Main Frankfurt a. Main GermanyDepartment of Internal Medicine I and José Carreras Center for Immuno‐ and Gene Therapy Saarland University Medical School Homburg/Saar GermanyAbstract Burkitt lymphoma (BL) represents the most aggressive B‐cell‐lymphoma. Beside the hallmark of IG‐MYC‐translocation, surface B‐cell receptor (BCR) is expressed, and mutations in the BCR pathway are frequent. Coincidental infections in endemic BL, and specific extra‐nodal sites suggest antigenic triggers. To explore this hypothesis, BCRs of BL cell lines and cases were screened for reactivities against a panel of bacterial lysates, lysates of Plasmodium falciparum, a custom‐made virome array and against self‐antigens, including post‐translationally modified antigens. An atypically modified, SUMOylated isoform of Bystin, that is, SUMO1‐BYSL was identified as the antigen of the BCR of cell line CA46. SUMO1‐BYSL was exclusively expressed in CA46 cells with K139 as site of the SUMOylation. Secondly, an atypically acetylated isoform of HSP40 was identified as the antigen of the BCR of cell line BL41. K104 and K179 were the sites of immunogenic acetylation, and the acetylated HSP40 isoform was solely present in BL41 cells. Functionally, addition of SUMO1‐BYSL and acetylated HSP40 induced BCR pathway activation in CA46 and BL41 cells, respectively. Accordingly, SUMO1‐BYSL‐ETA’ immunotoxin, produced by a two‐step intein‐based conjugation, led to the specific killing of CA46 cells. Autoantibodies directed against SUMO1‐BYSL were found in 3 of 14 (21.4%), and autoantibodies against acetylated HSP40 in 1/14(7.1%) patients with sporadic Burkitt‐lymphoma. No reactivities against antigens of the infectious agent spectrum could be observed. These results indicate a pathogenic role of autoreactivity evoked by immunogenic post‐translational modifications in a subgroup of sporadic BL including two EBV‐negative BL cell lines.https://doi.org/10.1002/jha2.475atypical post‐translationally modified isoformsautoantigensBCRBurkitt lymphomaimmunotoxinsneoantigens |
| spellingShingle | Theresa Bock Moritz Bewarder Onur Cetin Natalie Fadle Evi Regitz Eva C. Schwarz Jana Held Sophie Roth Stefan Lohse Thorsten Pfuhl Rabea Wagener Sigrun Smola Sören L. Becker Rainer Maria Bohle Lorenz Trümper Reiner Siebert Martin‐Leo Hansmann Michael Pfreundschuh Hans G. Drexler Markus Hoth Boris Kubuschok Klaus Roemer Klaus‐Dieter Preuss Sylvia Hartmann Lorenz Thurner B‐cell receptors of EBV‐negative Burkitt lymphoma bind modified isoforms of autoantigens eJHaem atypical post‐translationally modified isoforms autoantigens BCR Burkitt lymphoma immunotoxins neoantigens |
| title | B‐cell receptors of EBV‐negative Burkitt lymphoma bind modified isoforms of autoantigens |
| title_full | B‐cell receptors of EBV‐negative Burkitt lymphoma bind modified isoforms of autoantigens |
| title_fullStr | B‐cell receptors of EBV‐negative Burkitt lymphoma bind modified isoforms of autoantigens |
| title_full_unstemmed | B‐cell receptors of EBV‐negative Burkitt lymphoma bind modified isoforms of autoantigens |
| title_short | B‐cell receptors of EBV‐negative Burkitt lymphoma bind modified isoforms of autoantigens |
| title_sort | b cell receptors of ebv negative burkitt lymphoma bind modified isoforms of autoantigens |
| topic | atypical post‐translationally modified isoforms autoantigens BCR Burkitt lymphoma immunotoxins neoantigens |
| url | https://doi.org/10.1002/jha2.475 |
| work_keys_str_mv | AT theresabock bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT moritzbewarder bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT onurcetin bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT nataliefadle bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT eviregitz bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT evacschwarz bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT janaheld bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT sophieroth bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT stefanlohse bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT thorstenpfuhl bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT rabeawagener bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT sigrunsmola bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT sorenlbecker bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT rainermariabohle bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT lorenztrumper bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT reinersiebert bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT martinleohansmann bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT michaelpfreundschuh bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT hansgdrexler bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT markushoth bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT boriskubuschok bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT klausroemer bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT klausdieterpreuss bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT sylviahartmann bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens AT lorenzthurner bcellreceptorsofebvnegativeburkittlymphomabindmodifiedisoformsofautoantigens |