B-cell receptor reactivity against <i>Rothia mucilaginosa</i> in nodular lymphocyte-predominant Hodgkin lymphoma
Lorenz Thurner,
Natalie Fadle,
Evi Regitz,
Sophie Roth,
Onur Cetin,
Igor Age Kos,
Simon Mauro Hess,
Julia Bein,
Rainer Maria Bohle,
Martine Vornanen,
Christer Sundström,
Laurence de Leval,
Enrico Tiacci,
Peter Borchmann,
Andreas Engert,
Viola Poeschel,
Gerhard Held,
Eva C. Schwarz,
Frank Neumann,
Klaus-Dieter Preuss,
Markus Hoth,
Ralf Küppers,
Karola Lehman,
Martin-Leo Hansmann,
Sören L. Becker,
Moritz Bewarder,
Sylvia Hartmann
Affiliations
Lorenz Thurner
José Carreras Center for Immuno-and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar
Natalie Fadle
José Carreras Center for Immuno-and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar
Evi Regitz
José Carreras Center for Immuno-and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar
Sophie Roth
Institute of Medical Microbiology and Hygiene, Saarland University, Homburg
Onur Cetin
José Carreras Center for Immuno-and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar
Igor Age Kos
José Carreras Center for Immuno-and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar
Simon Mauro Hess
José Carreras Center for Immuno-and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar
Julia Bein
Dr. Senckenberg Institute of Pathology, Goethe University Hospital of Frankfurt am Main, Theodor-Stern-Kai
Rainer Maria Bohle
Saarland University Medical School, Institute of Pathology, Homburg/Saar
Martine Vornanen
Department of Pathology, Tampere University Hospital and University of Tampere, Tampere 33520, Finland
Christer Sundström
Department of Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden
Laurence de Leval
D-60590 Frankfurt a. Main
Enrico Tiacci
Institute of Hematology, Ospedale S. Maria della Misericordia, and the Department of Medicine, University of Perugia
Peter Borchmann
University of Cologne, First Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Cologne
Andreas Engert
University of Cologne, First Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Cologne
Viola Poeschel
José Carreras Center for Immuno-and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar
Gerhard Held
Department of Internal Medicine 1, Westpfalz-Klinikum, Kaiserslautern
Eva C. Schwarz
Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, Medical Faculty, Saarland University, Homburg
Frank Neumann
José Carreras Center for Immuno-and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar
Klaus-Dieter Preuss
José Carreras Center for Immuno-and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar
Markus Hoth
Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, Medical Faculty, Saarland University, Homburg
Ralf Küppers
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Essen, Germany; and Deutsches Konsortium für translationale Krebsforschung (DKTK)
Karola Lehman
Proteome Factory AG, Berlin
Martin-Leo Hansmann
Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany; Institute of Pathology and Molecular Pathology, Helios University Hospital Wuppertal
Sören L. Becker
Institute of Medical Microbiology and Hygiene, Saarland University, Homburg
Moritz Bewarder
José Carreras Center for Immuno-and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar
Sylvia Hartmann
Dr. Senckenberg Institute of Pathology, Goethe University Hospital of Frankfurt am Main, Theodor-Stern-Kai
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a Hodgkin lymphoma expressing functional B-cell receptors (BCR). Recently, we described a dual stimulation model of IgD+ lymphocyte-predominant cells by Moraxella catarrhalis antigen RpoC and its superantigen MID/hag, associated with extralong CDR3 and HLA-DRB1*04 or HLADRB1* 07 haplotype. The aim of the present study was to extend the antigen screening to further bacteria and viruses. The fragment antibody-binding (Fab) regions of seven new and 15 previously reported cases were analyzed. The reactivity of non-Moraxella spp.-reactive Fab regions against lysates of Rothia mucilaginosa was observed in 5/22 (22.7%) cases. Galactofuranosyl transferase (Gltf) and 2,3-butanediol dehydrogenase (Bdh) of R. mucilaginosa were identified by comparative silver- and immuno-staining in two-dimensional gels, with subsequent mass spectrometry and validation by western blots and enzyme-linked immunosorbent assay. Both R. mucilaginosa Gltf and Bdh induced BCR pathway activation and proliferation in vitro. Apoptosis was induced by recombinant Gltf/ETA’-immunotoxin conjugates in DEV cells expressing recombinant R. mucilaginosa-reactive BCR. Reactivity against M. catarrhalis RpoC was confirmed in 3/7 newly expressed BCR (total 10/22 reactive to Moraxella spp.), resulting in 15/22 (68.2%) cases with BCR reactivity against defined bacterial antigens. These findings strengthen the hypothesis of bacterial trigger contributing to subsets of NLPHL.
