Igs Expressed by Chronic Lymphocytic Leukemia B Cells Show Limited Binding-Site Structure Variability

Marcatili, Paolo; Ghiotto, Fabio; Tenca, Claudya; Chailyan, Anna; Mazzarello, Andrea Nicola; Yan, Xinfeng; Colombo, Monica; Albesiano, Emilia; Bagnara, Davide; Cutrona, Giovanna; Morabito, Fortunato; Bruno, Silvia; Ferrarini, Manlio; Chiorazzi, Nicholas; Tramontano, Anna; Fais, Franco

doi:10.4049/jimmunol.1300321

Cited by 23 publications

(24 citation statements)

References 50 publications

(55 reference statements)

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“…Taken together, the present findings offer a novel perspective to BcR antagonism40 as an attractive therapeutic strategy for CLL, targeting the BcR structure rather than the signalling initiated by BcR triggering. Homology models of CLL BcR IGs previously suggested that receptors from different subsets, as well as non-stereotyped cases, might be clustered according to the combining site similarity41. It will be of extreme interest to see if this insight can be confirmed with experimental structures, thus allowing to design bioactive antagonists that can simultaneously target different subsets of patients carrying stereotyped receptors rather than individual CLL cases.…”

Section: Discussionmentioning

confidence: 96%

Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia

Minici

Gounari

Übelhart³

et al. 2017

Nat Commun

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110

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Cell-autonomous B-cell receptor (BcR)-mediated signalling is a hallmark feature of the neoplastic B lymphocytes in chronic lymphocytic leukaemia (CLL). Here we elucidate the structural basis of autonomous activation of CLL B cells, showing that BcR immunoglobulins initiate intracellular signalling through homotypic interactions between epitopes that are specific for each subgroup of patients with homogeneous clinicobiological profiles. The molecular details of the BcR–BcR interactions apparently dictate the clinical course of disease, with stronger affinities and longer half-lives in indolent cases, and weaker, short-lived contacts mediating the aggressive ones. The diversity of homotypic BcR contacts leading to cell-autonomous signalling reconciles the existence of a shared pathogenic mechanism with the biological and clinical heterogeneity of CLL and offers opportunities for innovative treatment strategies.

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Section: Discussionmentioning

confidence: 96%

Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia

Minici

Gounari

Übelhart³

et al. 2017

Nat Commun

Self Cite

110

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“…It would be interesting to determine the affinity of these overlapping subclones in comparison to high-abundant non-overlapping clones. Marcatili and coworkers (62) used BCR repertoires from a large number of CLL patients to cluster the receptors into groups with similar sequence properties that potentially can be used for prognostics. Alternatively, one can compare repertoires across patients to identify consistent Ab sequence features (63).…”

Section: Discussionmentioning

confidence: 99%

Computational Model Reveals Limited Correlation between Germinal Center B-Cell Subclone Abundancy and Affinity: Implications for Repertoire Sequencing

et al. 2017

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Immunoglobulin repertoire sequencing has successfully been applied to identify expanded antigen-activated B-cell clones that play a role in the pathogenesis of immune disorders. One challenge is the selection of the Ag-specific B cells from the measured repertoire for downstream analyses. A general feature of an immune response is the expansion of specific clones resulting in a set of subclones with common ancestry varying in abundance and in the number of acquired somatic mutations. The expanded subclones are expected to have BCR affinities for the Ag higher than the affinities of the naive B cells in the background population. For these reasons, several groups successfully proceeded or suggested selecting highly abundant subclones from the repertoire to obtain the Ag-specific B cells. Given the nature of affinity maturation one would expect that abundant subclones are of high affinity but since repertoire sequencing only provides information about abundancies, this can only be verified with additional experiments, which are very labor intensive. Moreover, this would also require knowledge of the Ag, which is often not available for clinical samples. Consequently, in general we do not know if the selected highly abundant subclone(s) are also the high(est) affinity subclones. Such knowledge would likely improve the selection of relevant subclones for further characterization and Ag screening. Therefore, to gain insight in the relation between subclone abundancy and affinity, we developed a computational model that simulates affinity maturation in a single GC while tracking individual subclones in terms of abundancy and affinity. We show that the model correctly captures the overall GC dynamics, and that the amount of expansion is qualitatively comparable to expansion observed from B cells isolated from human lymph nodes. Analysis of the fraction of high- and low-affinity subclones among the unexpanded and expanded subclones reveals a limited correlation between abundancy and affinity and shows that the low abundant subclones are of highest affinity. Thus, our model suggests that selecting highly abundant subclones from repertoire sequencing experiments would not always lead to the high(est) affinity B cells. Consequently, additional or alternative selection approaches need to be applied.

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“…However, the use of RosettaAntibody for repertoire analysis requires, first and foremost, the availability of high-quality paired VH and VL sequence data for each antibody; second, significant computational resources for efficient execution of large-scale computational modeling of antibody repertoires; and, finally, an appropriate suite of informatic tools and statistical metrics suitable for repertoirelevel comparisons. Such a pipeline enables the study of the physicochemical properties of antibody repertoires important for disease and autoimmunity (9,18,28) on a 3D level at the site of antigen contact.…”

Section: Significancementioning

confidence: 99%

Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires

DeKosky

Lungu

Park

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

179

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Elucidating how antigen exposure and selection shape the human antibody repertoire is fundamental to our understanding of B-cell immunity. We sequenced the paired heavy-and light-chain variable regions (VH and VL, respectively) from large populations of single B cells combined with computational modeling of antibody structures to evaluate sequence and structural features of human antibody repertoires at unprecedented depth. Analysis of a dataset comprising 55,000 antibody clusters from CD19− IgM-naive B cells, >120,000 antibody clusters from CD19+ antigenexperienced B cells, and >2,000 RosettaAntibody-predicted structural models across three healthy donors led to a number of key findings: (i) VH and VL gene sequences pair in a combinatorial fashion without detectable pairing restrictions at the population level; (ii) certain VH:VL gene pairs were significantly enriched or depleted in the antigen-experienced repertoire relative to the naive repertoire; (iii) antigen selection increased antibody paratope net charge and solvent-accessible surface area; and (iv) public heavy-chain third complementarity-determining region (CDR-H3) antibodies in the antigen-experienced repertoire showed signs of convergent paired light-chain genetic signatures, including shared light-chain third complementarity-determining region (CDR-L3) amino acid sequences and/or Vκ,λ-Jκ,λ genes. The data reported here address several longstanding questions regarding antibody repertoire selection and development and provide a benchmark for future repertoire-scale analyses of antibody responses to vaccination and disease.antibody | B cell | immunology | high-throughput sequencing | computational modeling E ffective antigen recognition by the humoral immune system is predicated on the somatic generation of a large antibody repertoire that encompasses the sequence and conformational diversity to respond to a highly diversified set of antigens (1-3). Upon antigen challenge, naive B cells (NBCs) expressing unmutated antibodies capable of binding antigen with an affinity sufficient to initiate B-cell receptor (BCR) signaling may be stimulated to undergo somatic hypermutation (SHM) of the antibody genes. B cells expressing higher-affinity BCRs are better equipped to compete for antigen and thus receive signals that enable their preferential proliferation and further antibody sequence diversification in additional rounds of SHM. This process generates a repertoire of somatically mutated antibodies that, at the structural level, generally display decreased conformational flexibility (4, 5), slower antigen dissociation rates, and increased binding selectivity relative to the germline repertoire.Understanding the salient features of the human antibody repertoire is critical for immunology research (6, 7). Specifically, additional information is needed regarding how a history of pathogen and environmental exposure modulates the sequence and conformational properties of naive antibodies to yield a mature antibody repertoire that confers effective protection. Hi...

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Igs Expressed by Chronic Lymphocytic Leukemia B Cells Show Limited Binding-Site Structure Variability

Cited by 23 publications

References 50 publications

Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia

Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia

Computational Model Reveals Limited Correlation between Germinal Center B-Cell Subclone Abundancy and Affinity: Implications for Repertoire Sequencing

Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires

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