Chronic lymphocytic leukemic (CLL) cells secrete multispecific autoantibodies

Bröker, Barbara M.; Klajman, A; Youinou, Pierre; Jouquan, Jean; Worman, C. P.; Murphy, John J.; Mackenzie, Lorna; Quartey‐Papafio, Ruby; Blaschek, M; Collins, P. R.; Lal, Shangara; Lydyard, Peter M.

doi:10.1016/0896-8411(88)90068-6

Cited by 156 publications

(87 citation statements)

References 33 publications

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“…In a previous analysis of IGK locus rearrangements in λ-expressing chronic B cell leukemias (including CLL, prolymphocytic leukemia, hairy cell leukemia), IGKV-J junctions were detected in only 7 of 60 cases (12%) (32). The discrepant results between that study and our series as regards the percentage of IGKV-J-bearing cases could probably be attributed to differences in methodology (Southern blotting versus PCR), sample size, and homogeneity of patient groups.…”

Section: Discussioncontrasting

confidence: 55%

“…CLL Ig heavy and light chains have unique and often "autoimmune-like" features (23,24); also, subsets of CLL cases have remarkably similar immunoglobulins ("stereotyped B-cell receptors"), suggesting recognition of individual, discrete antigens or classes of structurally similar epitopes (24)(25)(26)(27)(28)(29)(30)(31). Furthermore, CLL cells frequently produce "natural" or polyreactive IgM autoantibodies (32)(33)(34)(35)(36)(37). Altogether, the similarity between B cells producing natural autoantibodies and CLL malignant B cells could mean that the process of positive selection of natural autoreactive B cells may carry a risk for malignant transformation (38).…”

Section: Introductionmentioning

confidence: 99%

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Analysis of Expressed and Non-Expressed IGK Locus Rearrangements in Chronic Lymphocytic Leukemia

Belessi

Stamatopoulos

Hadzidimitriou

et al. 2005

Mol Med

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Immunoglobulin κ (IGK) locus rearrangements were analyzed in parallel on cDNA/genomic DNA in 188 κ-and 103 λ-chronic lymphocytic leukemia (CLL) cases. IGKV-KDE and IGKJ-C-intron-KDE rearrangements were also analyzed on genomic DNA. In κ-CLL, only 3 of 188 cases carried double in-frame IGKV-J transcripts: in such cases, the possibility that leukemic cells expressed more than one κ chain cannot be excluded. Twenty-eight κ-CLL cases also carried nonexpressed (nontranscribed and/or outof-frame) IGKV-J rearrangements. Taking IGKV-J, IGKV-KDE, and IGKJ-C-intron-KDE rearrangements together, 38% of κ-CLL cases carried biallelic IGK locus rearrangements. In λ-CLL, 69 IGKV-J rearrangements were detected in 64 of 103 cases (62%); 24 rearrangements (38.2%) were in-frame. Four cases carried in-frame IGKV-J transcripts but retained monotypic light-chain expression, suggesting posttranscriptional regulation of allelic exclusion. In all, taking IGKV-J, IGKV-KDE, and IGKJ-C-intron-KDE rearrangements together, 97% of λ-CLL cases had at least 1 rearranged IGK allele, in keeping with normal cells. IG repertoire comparisons in κ-versus λ-CLL revealed that CLL precursor cells tried many rearrangements on the same IGK allele before they became λ producers. Thirteen of 28 and 26 of 69 non-expressed sequences in, respectively, κ-or λ-CLL had < 100% homology to germline. This finding might be considered as evidence for secondary rearrangements occurring after the onset of somatic hypermutation, at least in some cases. The inactivation of potentially functional IGKV-J joints by secondary rearrangements indicates active receptor editing in CLL and provides further evidence for the role of antigen in CLL immunopathogenesis.

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Section: Discussioncontrasting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Analysis of Expressed and Non-Expressed IGK Locus Rearrangements in Chronic Lymphocytic Leukemia

Belessi

Stamatopoulos

Hadzidimitriou

et al. 2005

Mol Med

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“…Because CLL cells likely derive from autoreactive B cells (15)(16)(17)(18), we explored if apoptosis-associated autoantigens were relevant to the selection and expansion of leukemic cells in this disease. Our data indicate that smIgs, particularly from patients with poor outcome U-CLL, recognize autoantigens made available during apoptosis and/or created by this catabolic process.…”

Section: Introductionmentioning

confidence: 99%

Chronic Lymphocytic Leukemia Cells Recognize Conserved Epitopes Associated with Apoptosis and Oxidation

Catera

Silverman

Hatzi

et al. 2008

Mol Med

180

101

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“…Likewise, CD5 expression prevents B lymphocytes from uncontrolled self reactivity increasing the BCR signalling threshold 51 , and is associated with reexpresion of RAG, receptor edition/revision, and lack of responsiveness to BAFF in some cells outside bone marrow and germinal centres (Lee et al 2009;Hippen et al 2000, Hillion et al 2005. Along this line, the fact that anergic autoreactive B cells may express CD5+ and that immunoglobulin secreted by unmutated B-CLL cells is often autoreactive and react with a variety of autoantigens (including Fc portion of IgG, DNA, histones, cardiolipin, cytoskeletal proteins and insulin) support the notion that unmutated self-reactive B CLL cells are under check to avoid pathogenic autoimmunity (Broker et al 1988;Caligaris-Cappio et al 1996;Morbach et al 2006). We speculate that the expression of ZAP-70 and CD38 could …”

Section: Are Unmutated Cll B Cells Insensitive To Cd5 Action?mentioning

confidence: 70%