Analyses of Recombinant Stereotypic <i>IGHV3-21</i>–Encoded Antibodies Expressed in Chronic Lymphocytic Leukemia

Ghia, Emanuela M.; Widhopf, George F.; Rassenti, Laura Z.; Kipps, Thomas J.

doi:10.4049/jimmunol.0902875

Cited by 5 publications

(3 citation statements)

References 48 publications

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“…These observations indicate no major structural constraints contributing to certain IGH-IG light chain pairing in the CLS-IG of a normal B-cell repertoire. This is in keeping with what has been reported about the possibility of CLL subset #2 IGHV rearrangement to pair with “non-native” (e.g., other than IGLV3.21 encoded IGλ light chain) IG light chains ( 38 ).…”

Section: Discussionsupporting

confidence: 90%

Characterizing Features of Human Circulating B Cells Carrying CLL-Like Stereotyped Immunoglobulin Rearrangements

et al. 2022

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Chronic Lymphocytic Leukemia (CLL) is characterized by the accumulation of monoclonal CD5+ B cells with low surface immunoglobulins (IG). About 40% of CLL clones utilize quasi-identical B cell receptors, defined as stereotyped BCR. CLL-like stereotyped-IG rearrangements are present in normal B cells as a part of the public IG repertoire. In this study, we collected details on the representation and features of CLL-like stereotyped-IG in the IGH repertoire of B-cell subpopulations purified from the peripheral blood of nine healthy donors. The B-cell subpopulations were also fractioned according to the expression of surface CD5 molecules and IG light chain, IGκ and IGλ. IG rearrangements, obtained by high throughput sequencing, were scanned for the presence of CLL-like stereotyped-IG. CLL-like stereotyped-IG did not accumulate preferentially in the CD5+ B cells, nor in specific B-cell subpopulations or the CD5+ cell fraction thereof, and their distribution was not restricted to a single IG light chain type. CLL-like stereotyped-IG shared with the corresponding CLL stereotype rearrangements the IGHV mutational status. Instead, for other features such as IGHV genes and frequency, CLL stereotyped-IGs presented a CLL-like subset specific behavior which could, or could not, be consistent with CLL stereotyped-IGs. Therefore, as opposed to the immuno-phenotype, the features of the CLL stereotyped-IG repertoire suggest a CLL stereotyped subset-specific ontogeny. Overall, these findings suggest that the immune-genotype can provide essential details in tracking and defining the CLL cell of origin.

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Section: Discussionsupporting

confidence: 90%

Characterizing Features of Human Circulating B Cells Carrying CLL-Like Stereotyped Immunoglobulin Rearrangements

et al. 2022

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“…Ficoll-Hypaque density-gradient centrifugation was used to obtain mononuclear cells. ZAP-70 status and immunoglobulin heavy chain variable (IGHV) mutation status were assessed by the Consortium Tissue Core as per established criteria (see Rassenti et al 12,13 for ZAP-70 and Ghia et al, 14 Widhopf et al, 15 Giudicelli et al, 16 and Lefranc et al 17 for IGHV). Sequences with ,98% homology to the corresponding germline IGHV gene were considered mutated.…”

Section: Correlative Studiesmentioning

confidence: 99%

Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity

Lampson

Kasar

Matos

et al. 2016

Blood

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270

262

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• Idelalisib as upfront therapy for CLL caused an early hepatotoxicity in a subset of primarily younger patients with IGHV-mutated disease.• Multiple lines of evidence suggest that this adverse effect is immune mediated, perhaps through inhibition of regulatory T cells.Idelalisib is a small-molecule inhibitor of PI3Kd with demonstrated efficacy for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as front-line therapy, we enrolled 24 subjects in a phase 2 study consisting of 2 months of idelalisib monotherapy followed by 6 months of combination therapy with idelalisib and the anti-CD20 antibody ofatumumab. After a median follow-up period of 14.7 months, hepatotoxicity was found to be a frequent and often severe adverse event. A total of 19 subjects (79%) experienced either grade ‡1 ALT or AST elevation during the study, and 13 subjects (54%) experienced grade ‡3 transaminitis. The median time to development of transaminitis was 28 days, occurring before ofatumumab introduction. Younger age and mutated immunoglobulin heavy chain status were significant risk factors for the development of hepatotoxicity. Multiple lines of evidence suggest that this hepatotoxicity was immune mediated. A lymphocytic infiltrate was seen on liver biopsy specimens taken from 2 subjects with transaminitis, and levels of the proinflammatory cytokines CCL-3 and CCL-4 were higher in subjects experiencing hepatotoxicity. All cases of transaminitis resolved either by holding the drug, initiating immunosuppressants, or both, and rates of recurrent toxicity were lower in patients taking steroids when idelalisib was reinitiated. A decrease in peripheral blood regulatory T cells was seen in patients experiencing toxicity on therapy, which is consistent with an immune-mediated mechanism. These results suggest that caution should be taken as drugs within this class are developed for CLL, particularly in younger patients who have not received prior disease-specific therapy. This study was registered at www.clinicaltrials.gov as #NCT02135133. (Blood. 2016;128(2):195-203)

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“…29,33,65,95,96 Of note, light-chain mediated binding to the bacterial protein L and to the actin-binding protein cofilin was described for subset #2 recombinant Igs, independent of the subset #2 heavy chain, suggesting that binding to these antigens cannot account for the non-stochastic pairing of subset #2 heavy and lambda light chain. 97 In the structural analysis by Minici et al the subset #2 BCR homotypic interactions are also largely mediated through the subset #2 IgL. Importantly, however, the subset #2 heavy chain with the characteristically short VH-CDR3{Agathangelidis, 2012 #13724;Agathangelidis, 2012 #13724} 28,29 facilitates the spatial proximity between the two BCRs, while establishing one direct hydrogen bond with the epitope on the light chain, 65 implying that BCR homotypic interactions may indeed account for the biased pairing of subset #2 heavy and lambda light Ig chain.…”

Section: Cll-bcr Stereotyped Subsetsmentioning

confidence: 99%

The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia

2018

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B cell receptor (BCR) signaling is a central pathway promoting the survival and proliferation of normal and malignant B cells. Chronic lymphocytic leukemia (CLL) arises from mature B cells, expressing functional BCRs, mainly of IgM and IgD isotypes. Importantly, 30% of CLL patients express quasi-identical BCRs, so-called "stereotyped" receptors, indicating the existence of common antigenic determinants, which may drive disease initiation and favor its progression. Although the antigenic specificity of IgM and IgD receptors is identical, there are distinct isotypespecific responses after IgM and IgD triggering. Here, we discuss the most important steps of normal B cell development, and highlight the importance of BCR signaling for CLL pathogenesis, with a focus on differences between IgM and IgD isotype signaling. We also highlight the main characteristics of CLL patient subsets, based on BCR stereotypy, and describe subset-specific BCR function and antigen binding characteristics. Finally, we outline the key biologic and clinical responses to kinase inhibitor therapy, targeting the BCR-associated Bruton tyrosine kinase (BTK), phosphoinositide-3-kinase (PI3K), and spleen tyrosine kinase (SYK) in patients with CLL. The B cell receptor (BCR) during B cell developmentB lymphocytes develop from hematopoietic stem cells through a continuum of developmental stages that originate within the primary lymphoid tissues (i.e. fetal liver and fetal/adult marrow), with later stages of maturation occurring in secondary lymphoid organs, including the lymph nodes and the spleen (Figure 1). 1 One of the first essential steps towards maturation of a normal B cell is the successful rearrangement of immunoglobulin (Ig) heavy chain (IGH) gene segments (V, D and J segments), during a process named VDJ recombination (Figure 2), which occurs in progenitor (pro)-B cells, and leads to precursor (pre)-B-cell development. 2 During this process, a highly diverse repertoire of antigen-

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Analyses of Recombinant Stereotypic IGHV3-21–Encoded Antibodies Expressed in Chronic Lymphocytic Leukemia

Cited by 5 publications

References 48 publications

Characterizing Features of Human Circulating B Cells Carrying CLL-Like Stereotyped Immunoglobulin Rearrangements

Characterizing Features of Human Circulating B Cells Carrying CLL-Like Stereotyped Immunoglobulin Rearrangements

Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity

The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia

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