A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies

Myhrinder, Anna Lanemo; Hellqvist, Eva; Sidorova, E. V.; Söderberg, Anita; Baxendale, Helen; Dahle, Charlotte; Willander, Kerstin; Tobin, Gerard; Bäckman, E.; Söderberg, Ola; Rosenquist, Richard; Hörkkö, Sohvi; Rosén, Anders

doi:10.1182/blood-2007-11-125450

Cited by 239 publications

(256 citation statements)

References 59 publications

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“…25,26 Furthermore, recent in vitro studies demonstrated that recombinant mAbs from patients with CLL can react with antigenic epitopes on the surface of common bacteria and, most importantly, that mAbs encoded by different immunoglobulin genes reacted with different classes of antigenic epitopes. 27,28 Along these lines, it could not be unreasonable to speculate that persistent or intermittent infections by common pathogens could stimulate CLL precursors, and possibly CLL cells themselves, and somehow contribute to malignant transformation, at least for subsets of CLL cases.…”

Section: Introductionmentioning

confidence: 99%

Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

et al. 2009

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The chronic lymphocytic leukemia (CLL) immunoglobulin repertoire is uniquely characterized by the presence of stereotyped B-cell receptors (BCRs). A major BCR stereotype in CLL is shared by immunoglobulin G-switched cases utilizing the immunoglobulin heavy-chain variable 4-34 (IGHV4-34) gene. Increased titers of IGHV4-34 antibodies are detected in selective clinical conditions, including infection by B-cell lymphotropic viruses, particularly Epstein-Barr virus (EBV) and cytomegalovirus (CMV). In this context, we sought evidence for persistent activation by EBV and CMV in CLL cases expressing the IGHV4-34 gene. The study group included 93 CLL cases with an intentional bias for the IGHV4-34 gene. On the basis of real-time PCR results for CMV/EBV DNA, cases were assigned to three groups: (1) double-negative (59/93); (2) single-positive (CMV-or EBV-positive; 25/93); (3) double-positive (9/93). The doublenegative group was characterized by heterogeneous IGHV gene repertoire. In contrast, a bias for the IGHV4-34 gene was observed in the single-positive group (9/25 cases; 36%). Remarkably, all nine double-positive cases utilized the IGHV4-34 gene; seven of nine cases expressed the major BCR stereotype as described above. In conclusion, our findings indicate that the interactions of CLL progenitor cells expressing distinctive IGHV4-34 BCRs with viral antigens/superantigens might facilitate clonal expansion and, eventually, leukemic transformation. The exact type, timing and location of these interactions remain to be determined.

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Section: Introductionmentioning

confidence: 99%

Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

et al. 2009

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“…Most of the CLL clusters were also characterized by specific Ig light kappa (κ) or lambda (λ) chain gene usage (Widhopf et al, 2008;Hadzidimitriou et al, 2009). Together with a biased repertoire of Ig genes (Chiorazzi and Ferrarini, 2003), a similarity of CLL Ig sequences and antibodies against autoantigens and microbial/viral antigens (Lanemo Myhrinder et al, 2008) and some epidemiological data (Landgren et al, 2006(Landgren et al, , 2007 has led to the hypothesis that there is a possible role of viral/microbial antigens in the development of this (and other non-somatic) disease(s).…”

Section: Cll Cells Display Homology Of Their Ig Receptors With Antivimentioning

confidence: 99%

Persistent infections and their relationship with selected oncologic and non-tumor pathologies

Чумак

Abramenko

et al. 2010

Journal of Immunotoxicology

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“…Elucidation of the antigenic specificity of the clonogenic BcRs in CLL has previously been hindered by technical difficulties; however, more recent procedures utilizing cell lines derived from the neoplastic CLL clone established that these cells can produce BcRs/monoclonal antibodies (mAbs) that bind autoantigens and molecular structures present on apoptotic cells and bacteria such as IgG, vimentin, filamin B, cardiolipin and DNA (23)(24)(25). In addition, by using recombinant DNA technologies, the role of antigenic reactivity and the impact of somatic hypermutation (SHM) on CLL mAb specificity have been investigated and revealed that CLL cells likely derive from B cells producing polyreactive, natural antibodies encoded by germline IG genes which either retain or lose polyreactivity due to SHM (26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Temporal Dynamics of Clonal Evolution in Chronic Lymphocytic Leukemia with Stereotyped IGHV4-34/IGKV2-30 Antigen Receptors: Longitudinal Immunogenetic Evidence

Sutton

Kostareli²,

Stalika

et al. 2013

Mol Med

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Chronic lymphocytic leukemia (CLL) patients assigned to stereotyped subset #4 possess distinctive patterns of intraclonal diversification (ID) within their immunoglobulin (IG) genes. Though highly indicative of an ongoing response to antigen(s), the critical question concerning the precise timing of antigen involvement is unresolved. Hence, we conducted a large-scale longitudinal study of 8 subset #4 cases totaling 511 and 398 subcloned IG heavy and kappa sequences. Importantly, we could establish a hierarchical pattern of subclonal evolution, thus revealing which somatic hypermutations were negatively or positively selected. In addition, distinct clusters of subcloned sequences with cluster-specific mutational profiles were observed initially, however at later time-points the minor cluster had often disappeared and hence been selected against. Despite the high intensity of ID, it was remarkable that certain residues remained essentially unaltered. These novel findings strongly support a role for persistent antigen stimulation in the clonal evolution of CLL subset #4.

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A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies

Cited by 239 publications

References 59 publications

Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

Persistent infections and their relationship with selected oncologic and non-tumor pathologies

Temporal Dynamics of Clonal Evolution in Chronic Lymphocytic Leukemia with Stereotyped IGHV4-34/IGKV2-30 Antigen Receptors: Longitudinal Immunogenetic Evidence

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