Conventional and non-conventional antigen-binding sites promote the development and function of chronic lymphocytic leukemia stereotyped subset #4 clones
Immunoglobulins (IGs) made by chronic lymphocytic leukemia (CLL) B cells are unique in that they bind themselves (homo-dimerize). This interaction leads to signal transduction with functional consequences that depend on the affinity of homo-dimerization. We have studied the antigen-binding propertie...
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2025-08-01
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| author | Yun Liu Yun Liu Dzmitry Padhorny Dzmitry Padhorny Rosa Catera Rosa Catera Antonella Nicolo Xiao-Jie Yan Xiao-Jie Yan Stan Xiaogang Li Stan Xiaogang Li Anastasia Iatrou Andrea N. Mazzarello Andrea N. Mazzarello Noemi Destefani Noemi Destefani Steven L. Allen Steven L. Allen Jonathan E. Kolitz Jonathan E. Kolitz Kanti R. Rai Kanti R. Rai Massimo Degano Massimo Degano Paolo P. Ghia Paolo P. Ghia Charles C. Chu Charles C. Chu Florian Krammer Florian Krammer Hassan Jumaa Kostas Stamatopoulos Dima Kozakov Dima Kozakov Nicholas Chiorazzi Nicholas Chiorazzi |
| author_facet | Yun Liu Yun Liu Dzmitry Padhorny Dzmitry Padhorny Rosa Catera Rosa Catera Antonella Nicolo Xiao-Jie Yan Xiao-Jie Yan Stan Xiaogang Li Stan Xiaogang Li Anastasia Iatrou Andrea N. Mazzarello Andrea N. Mazzarello Noemi Destefani Noemi Destefani Steven L. Allen Steven L. Allen Jonathan E. Kolitz Jonathan E. Kolitz Kanti R. Rai Kanti R. Rai Massimo Degano Massimo Degano Paolo P. Ghia Paolo P. Ghia Charles C. Chu Charles C. Chu Florian Krammer Florian Krammer Hassan Jumaa Kostas Stamatopoulos Dima Kozakov Dima Kozakov Nicholas Chiorazzi Nicholas Chiorazzi |
| author_sort | Yun Liu |
| collection | DOAJ |
| description | Immunoglobulins (IGs) made by chronic lymphocytic leukemia (CLL) B cells are unique in that they bind themselves (homo-dimerize). This interaction leads to signal transduction with functional consequences that depend on the affinity of homo-dimerization. We have studied the antigen-binding properties of the IGs from a subset of patients with CLL (Subset #4) that homo-dimerize at high affinity. Previously, we had found that subset #4 IGs bound viable lymphocytes. Our new studies, probing an array of >8,000 antigens, indicate that these IGs also bind influenza virus. Because of the IGs high-affinity homo-dimerization, we asked if the defined foreign- and self-antigenic interactions were mediated by conventional B-cell receptor (BCR) domains or a non-conventional receptor created by homo-dimerization. The studies indicated the latter since abrogation of homo-dimerization eliminated binding to influenza virus and its hemagglutinin and to viable lymphocytes. Using these findings, we modeled a developmental path whereby a naive IgM+ B cell with subset #4 heavy and light chain variable domains used the conventional BCR to interact with auto- and foreign antigens and acquire homo-dimerization capacity to create the non-conventional antigen-receptor when transitioning to a leukemic cell. Future studies will determine if this process is an idiosyncratic occurrence or a physiologic principle. |
| format | Article |
| id | doaj-art-bd3f856440584bcabcc127a3d974425a |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-bd3f856440584bcabcc127a3d974425a2025-08-21T05:27:38ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-08-011610.3389/fimmu.2025.16071891607189Conventional and non-conventional antigen-binding sites promote the development and function of chronic lymphocytic leukemia stereotyped subset #4 clonesYun Liu0Yun Liu1Dzmitry Padhorny2Dzmitry Padhorny3Rosa Catera4Rosa Catera5Antonella Nicolo6Xiao-Jie Yan7Xiao-Jie Yan8Stan Xiaogang Li9Stan Xiaogang Li10Anastasia Iatrou11Andrea N. Mazzarello12Andrea N. Mazzarello13Noemi Destefani14Noemi Destefani15Steven L. Allen16Steven L. Allen17Jonathan E. Kolitz18Jonathan E. Kolitz19Kanti R. Rai20Kanti R. Rai21Massimo Degano22Massimo Degano23Paolo P. Ghia24Paolo P. Ghia25Charles C. Chu26Charles C. Chu27Florian Krammer28Florian Krammer29Hassan Jumaa30Kostas Stamatopoulos31Dima Kozakov32Dima Kozakov33Nicholas Chiorazzi34Nicholas Chiorazzi35Northwell, New Hyde Park, NY, United StatesInstitute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY, United StatesDepartment of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, United StatesLaufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY, United StatesNorthwell, New Hyde Park, NY, United StatesInstitute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY, United StatesInstitute of Immunology, Ulm University Medical Center, Ulm, GermanyNorthwell, New Hyde Park, NY, United StatesInstitute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY, United StatesDepartment of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, United StatesLaufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY, United StatesInstitute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, GreeceNorthwell, New Hyde Park, NY, United StatesInstitute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY, United StatesDepartment of Biochemistry, Università Vita-Salute San Raffaele, Milano, ItalyDivision of Immunology, Transplantation, and Infectious Diseases, IRCCS Scientific Institute San Raffaele, Milano, ItalyNorthwell, New Hyde Park, NY, United StatesInstitute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY, United StatesNorthwell, New Hyde Park, NY, United StatesInstitute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY, United StatesNorthwell, New Hyde Park, NY, United StatesInstitute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY, United StatesDepartment of Biochemistry, Università Vita-Salute San Raffaele, Milano, ItalyDivision of Immunology, Transplantation, and Infectious Diseases, IRCCS Scientific Institute San Raffaele, Milano, ItalyMedical School, Università Vita-Salute San Raffaele, Milano, Italy0B Cell Neoplasia Unit and Strategic Research Program on CLL, IRCCS Ospedale San Raffaele, Milano, ItalyNorthwell, New Hyde Park, NY, United StatesInstitute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY, United States1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States2Ignaz Semmelweis Institute, Interuniversity Institute for Infection Research, Medical University of Vienna, Vienna, AustriaInstitute of Immunology, Ulm University Medical Center, Ulm, GermanyInstitute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, GreeceDepartment of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, United StatesLaufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY, United StatesNorthwell, New Hyde Park, NY, United StatesInstitute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY, United StatesImmunoglobulins (IGs) made by chronic lymphocytic leukemia (CLL) B cells are unique in that they bind themselves (homo-dimerize). This interaction leads to signal transduction with functional consequences that depend on the affinity of homo-dimerization. We have studied the antigen-binding properties of the IGs from a subset of patients with CLL (Subset #4) that homo-dimerize at high affinity. Previously, we had found that subset #4 IGs bound viable lymphocytes. Our new studies, probing an array of >8,000 antigens, indicate that these IGs also bind influenza virus. Because of the IGs high-affinity homo-dimerization, we asked if the defined foreign- and self-antigenic interactions were mediated by conventional B-cell receptor (BCR) domains or a non-conventional receptor created by homo-dimerization. The studies indicated the latter since abrogation of homo-dimerization eliminated binding to influenza virus and its hemagglutinin and to viable lymphocytes. Using these findings, we modeled a developmental path whereby a naive IgM+ B cell with subset #4 heavy and light chain variable domains used the conventional BCR to interact with auto- and foreign antigens and acquire homo-dimerization capacity to create the non-conventional antigen-receptor when transitioning to a leukemic cell. Future studies will determine if this process is an idiosyncratic occurrence or a physiologic principle.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1607189/fullchronic lymphocytic leukemiaB cell receptorantigenantigen bindingautoreactivity |
| spellingShingle | Yun Liu Yun Liu Dzmitry Padhorny Dzmitry Padhorny Rosa Catera Rosa Catera Antonella Nicolo Xiao-Jie Yan Xiao-Jie Yan Stan Xiaogang Li Stan Xiaogang Li Anastasia Iatrou Andrea N. Mazzarello Andrea N. Mazzarello Noemi Destefani Noemi Destefani Steven L. Allen Steven L. Allen Jonathan E. Kolitz Jonathan E. Kolitz Kanti R. Rai Kanti R. Rai Massimo Degano Massimo Degano Paolo P. Ghia Paolo P. Ghia Charles C. Chu Charles C. Chu Florian Krammer Florian Krammer Hassan Jumaa Kostas Stamatopoulos Dima Kozakov Dima Kozakov Nicholas Chiorazzi Nicholas Chiorazzi Conventional and non-conventional antigen-binding sites promote the development and function of chronic lymphocytic leukemia stereotyped subset #4 clones Frontiers in Immunology chronic lymphocytic leukemia B cell receptor antigen antigen binding autoreactivity |
| title | Conventional and non-conventional antigen-binding sites promote the development and function of chronic lymphocytic leukemia stereotyped subset #4 clones |
| title_full | Conventional and non-conventional antigen-binding sites promote the development and function of chronic lymphocytic leukemia stereotyped subset #4 clones |
| title_fullStr | Conventional and non-conventional antigen-binding sites promote the development and function of chronic lymphocytic leukemia stereotyped subset #4 clones |
| title_full_unstemmed | Conventional and non-conventional antigen-binding sites promote the development and function of chronic lymphocytic leukemia stereotyped subset #4 clones |
| title_short | Conventional and non-conventional antigen-binding sites promote the development and function of chronic lymphocytic leukemia stereotyped subset #4 clones |
| title_sort | conventional and non conventional antigen binding sites promote the development and function of chronic lymphocytic leukemia stereotyped subset 4 clones |
| topic | chronic lymphocytic leukemia B cell receptor antigen antigen binding autoreactivity |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1607189/full |
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