Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia
2014 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no 11, 1722-1730 p.Article in journal (Refereed) Published
Chronic lymphocytic leukemia B-cells express auto/xeno-antigen-reactive antibodies that bind to self-epitopes and resemble natural IgM antibodies in their repertoire. One of the antigenic structures recognized is oxidation-induced malonedialdehyde present on low-density lipoprotein, apoptotic blebs, and on certain microbes. The poor-prognostic stereotyped subset #1 (Clan I IGHV genes-IGKV1(D)-39) express IgM B-cell receptors that bind oxidized low-density lipoprotein. In this study, we have used for the first time this authentic cognate antigen, since it is more faithful to B-cell physiology than anti-IgM, for analysis of downstream B-cell receptor-signal transduction events. Multivalent oxidized low-density lipoprotein showed specific binding to subset #1 IgM/IgD B-cell receptors, whereas native low-density lipoprotein did not. The antigen-binding induced prompt receptor-clustering, followed by internalization. However, the receptor-signal transduction was silenced, revealing no Ca2+ mobilization or cell-cycle entry, while phosphorylated extracellular-regulated kinase1/2 basal levels were high and could not be elevated further by oxidized low-density lipoprotein. Interestingly, B-cell receptor responsiveness was recovered after 48 hours culture in the absence of antigen in half of the cases. Toll-like receptor 9-ligand was found to breach the B-cell receptor-signaling incompetence in 5 of 12 cases pointing to intra-subset heterogeneity. Altogether, this study supports B-cell receptor-unresponsiveness to cognate self-antigen on its own in poor-prognostic subset #1 chronic lymphocytic leukemia indicating that these cells proliferate by other mechanisms that may override B-cell receptor-silencing brought about in a context of self-tolerance/anergy. These novel findings have implications for the understanding of chronic lymphocytic leukemia pathobiology and therapy.
Place, publisher, year, edition, pages
Ferrata Storti Foundation , 2014. Vol. 99, no 11, 1722-1730 p.
Anergy; B-cell Receptor Signaling; Chronic Lymphocytic Leukemia; Oxidized LDL; Stereotyped subsets
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-109020DOI: 10.3324/haematol.2014.106054ISI: 000347016300013PubMedID: 25085355OAI: oai:DiVA.org:liu-109020DiVA: diva2:735454