Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia
2014 (English)In: Haematologica (online), 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 that is 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 for analysis of downstream B-cell receptor-signal transduction events, since it is more faithful to B-cell physiology than anti-IgM. 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 kinase 1/2 basal levels were high and could not be elevated further by oxidized low-density lipoprotein. Interestingly, B-cell receptor responsiveness was recovered after 48-h 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
2014. Vol. 99, no 11, 1722-1730 p.
IdentifiersURN: urn:nbn:se:uu:diva-243070DOI: 10.3324/haematol.2014.106054ISI: 000347016300013PubMedID: 25085355OAI: oai:DiVA.org:uu-243070DiVA: diva2:787206