Bergh A.-C.,Linköping University |
Evaldsson C.,Linköping University |
Pedersen L.B.,Rigshospitalet |
Geisler C.,Rigshospitalet |
And 5 more authors.
Haematologica | Year: 2014
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. © 2014 Ferrata Storti Foundation.
Spanoudakis M.,University of Crete |
Koutala H.,University of Crete |
Ximeri M.,University of Crete |
Pyrovolaki K.,University of Crete |
And 3 more authors.
Clinical Immunology | Year: 2010
Chronic idiopathic neutropenia (CIN) is a bone marrow (BM) disorder characterized by presence of activated T-lymphocytes in peripheral blood (PB) and BM. We investigated the pattern of T-cell responses in CIN by analyzing the T-cell receptor β-chain variable (Vβ) gene repertoire. Compared to controls, CIN patients displayed different patterns of Vβ gene usage in PB CD3+, CD4+ and CD8+ cells. The frequency of Vβ skewing and the number of expanded Vβ families per subject were higher in patients compared to controls in all cell subpopulations. Skewing was more profound within the CD8+ cells. The number of Vβ expansions per patient was higher in BM compared to PB. The majority of patients displayed a skewed oligoclonal/monoclonal pattern within the PB and/or BM CD8+ cells and a polyclonal profile within the CD4+ cells. We concluded that aberrant T-cell expansions are invariably detected in CIN patients and may have a role in the disease pathogenesis. © 2010 Elsevier Inc.