Conventional and non-conventional antigen-binding sites promote the development and function of chronic lymphocytic leukemia stereotyped subset #4 clones

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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Main Authors: Yun Liu, Dzmitry Padhorny, Rosa Catera, Antonella Nicolo, Xiao-Jie Yan, Stan Xiaogang Li, Anastasia Iatrou, Andrea N. Mazzarello, Noemi Destefani, Steven L. Allen, Jonathan E. Kolitz, Kanti R. Rai, Massimo Degano, Paolo P. Ghia, Charles C. Chu, Florian Krammer, Hassan Jumaa, Kostas Stamatopoulos, Dima Kozakov, Nicholas Chiorazzi
Format: Article
Language:English
Published: Frontiers Media S.A. 2025-08-01
Series:Frontiers in Immunology
Subjects:
chronic lymphocytic leukemia
B cell receptor
antigen
antigen binding
autoreactivity
Online Access:https://www.frontiersin.org/articles/10.3389/fimmu.2025.1607189/full
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Summary: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.
ISSN:1664-3224

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