Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia

Haematologica. 2014 Nov;99(11):1722-30. doi: 10.3324/haematol.2014.106054. Epub 2014 Aug 1.

Abstract

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 Ca(2+) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantigens / immunology*
  • B7-2 Antigen / metabolism
  • Calcium / metabolism
  • Cell Cycle
  • Gene Silencing*
  • Humans
  • Immunoglobulin Heavy Chains / genetics*
  • Immunoglobulin J-Chains / genetics
  • Immunoglobulin M / biosynthesis
  • Immunoglobulin M / immunology
  • Immunoglobulin Variable Region / genetics
  • Interleukin-10 / biosynthesis
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Interleukin-6 / biosynthesis
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology*
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Ligands
  • Lipoproteins, LDL / metabolism
  • Protein Binding
  • Receptors, Antigen, B-Cell / genetics*
  • Receptors, Antigen, B-Cell / metabolism
  • Toll-Like Receptor 9 / metabolism

Substances

  • Autoantigens
  • B7-2 Antigen
  • Immunoglobulin Heavy Chains
  • Immunoglobulin J-Chains
  • Immunoglobulin M
  • Immunoglobulin Variable Region
  • Interleukin-2 Receptor alpha Subunit
  • Interleukin-6
  • Ligands
  • Lipoproteins, LDL
  • Receptors, Antigen, B-Cell
  • Toll-Like Receptor 9
  • oxidized low density lipoprotein
  • Interleukin-10
  • Calcium