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 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<sup>+</sup> 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.
Authors
- Rosa Catera
- Charles C. Chu (ORCID: https://orcid.org/0000-0002-9353-0806)
- Anastasia Iatrou (ORCID: https://orcid.org/0000-0002-8995-4454)
- Dzmitry Padhorny (ORCID: https://orcid.org/0000-0002-7840-8677)
- Stan Xiaogang Li
- Nicholas Chiorazzi (ORCID: https://orcid.org/0000-0003-1023-6650)
- Κώστας Σταματόπουλος (ORCID: https://orcid.org/0000-0001-8529-640X)
- Dima Kozakov (ORCID: https://orcid.org/0000-0003-0464-4500)
- Massimo Degano (ORCID: https://orcid.org/0000-0002-0787-1883)
- Jonathan E. Kolitz (ORCID: https://orcid.org/0000-0003-2700-4784)
- Andrea Nicola Mazzarello (ORCID: https://orcid.org/0000-0003-2167-8817)
- Florian Krammer (ORCID: https://orcid.org/0000-0003-4121-776X)
- Hassan Jumaa (ORCID: https://orcid.org/0000-0003-3383-141X)
- P. Ghia
- Steven L. Allen (ORCID: https://orcid.org/0000-0002-3482-3182)
- Antonella Nicolò (ORCID: https://orcid.org/0000-0003-3105-7571)
- R. Kanti (ORCID: https://orcid.org/0000-0002-5804-2823)
- Yan Liu (ORCID: https://orcid.org/0000-0002-2566-6867)
- Xiao‐Jie Yan (ORCID: https://orcid.org/0009-0008-6370-6138)
- Noemi Destefani
Institutions
- Semmelweis University (HU)
- Northwell Health (US)
- Feinstein Institute for Medical Research (US)
- Vita-Salute San Raffaele University (IT)
- Universität Ulm (DE)
- IRCCS Ospedale San Raffaele (IT)
- Centre for Research and Technology Hellas (GR)
- North Shore Diabetes and Endocrine Associates (US)
- Stony Brook University (US)
- Medical University of Vienna (AT)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Frontiers in Immunology
- Published
- 2025-08-21
- DOI
- https://doi.org/10.3389/fimmu.2025.1607189
- Citations
- 1
- Primary Topic
- Chronic Lymphocytic Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 1.63
Funders
- National Science Foundation
- Northwell Health
- Associazione Italiana per la Ricerca sul Cancro
- National Institutes of Health