title: Silenced B-cell receptor response to autoantigen in a poor-prognostic subset of chronic lymphocytic leukemia.
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.
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Bergh
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Chamilly
authors.initials: C
authors.lastname: Evaldsson
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Lone Bredo
authors.initials: LB
authors.lastname: Pedersen
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Geisler
authors.affiliation: Department of Hematology and HCT Unit G. Papanicolaou Hospital, Thessaloniki, Greece Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden Anders.Rosen@liu.se.
authors.forename: Anders
authors.initials: A
authors.lastname: Rosén
mesh_terms: D001324:Autoantigens / Q000276:immunology*; D051940:B7-2 Antigen / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle; D020868:Gene Silencing; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007144:Immunoglobulin J-Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008077:Lipoproteins, LDL / Q000378:metabolism; D011485:Protein Binding; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: D001324:Autoantigens; D051940:B7-2 Antigen; D007143:Immunoglobulin Heavy Chains; D007144:Immunoglobulin J-Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D008024:Ligands; D008077:Lipoproteins, LDL; D011947:Receptors, Antigen, B-Cell; D051217:Toll-Like Receptor 9; C099252:oxidized low density lipoprotein; D016753:Interleukin-10; D002118:Calcium
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