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Littérature scientifique sur le sujet « Antibody functional repertoire »

Auteur : Grafiati

Publié le 14 mars 2023

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Articles de revues sur le sujet "Antibody functional repertoire"

Raybould, Matthew I. J., Claire Marks, Aleksandr Kovaltsuk, Alan P. Lewis, Jiye Shi et Charlotte M. Deane. « Public Baseline and shared response structures support the theory of antibody repertoire functional commonality ». PLOS Computational Biology 17, n^o 3 (1 mars 2021) : e1008781. http://dx.doi.org/10.1371/journal.pcbi.1008781.

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The naïve antibody/B-cell receptor (BCR) repertoires of different individuals ought to exhibit significant functional commonality, given that most pathogens trigger an effective antibody response to immunodominant epitopes. Sequence-based repertoire analysis has so far offered little evidence for this phenomenon. For example, a recent study estimated the number of shared (‘public’) antibody clonotypes in circulating baseline repertoires to be around 0.02% across ten unrelated individuals. However, to engage the same epitope, antibodies only require a similar binding site structure and the presence of key paratope interactions, which can occur even when their sequences are dissimilar. Here, we search for evidence of geometric similarity/convergence across human antibody repertoires. We first structurally profile naïve (‘baseline’) antibody diversity using snapshots from 41 unrelated individuals, predicting all modellable distinct structures within each repertoire. This analysis uncovers a high (much greater than random) degree of structural commonality. For instance, around 3% of distinct structures are common to the ten most diverse individual samples (‘Public Baseline’ structures). Our approach is the first computational method to find levels of BCR commonality commensurate with epitope immunodominance and could therefore be harnessed to find more genetically distant antibodies with same-epitope complementarity. We then apply the same structural profiling approach to repertoire snapshots from three individuals before and after flu vaccination, detecting a convergent structural drift indicative of recognising similar epitopes (‘Public Response’ structures). We show that Antibody Model Libraries derived from Public Baseline and Public Response structures represent a powerful geometric basis set of low-immunogenicity candidates exploitable for general or target-focused therapeutic antibody screening.

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Collins, Andrew M., Yan Wang, Krishna M. Roskin, Christopher P. Marquis et Katherine J. L. Jackson. « The mouse antibody heavy chain repertoire is germline-focused and highly variable between inbred strains ». Philosophical Transactions of the Royal Society B : Biological Sciences 370, n^o 1676 (5 septembre 2015) : 20140236. http://dx.doi.org/10.1098/rstb.2014.0236.

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The human and mouse antibody repertoires are formed by identical processes, but like all small animals, mice only have sufficient lymphocytes to express a small part of the potential antibody repertoire. In this study, we determined how the heavy chain repertoires of two mouse strains are generated. Analysis of IgM- and IgG-associated VDJ rearrangements generated by high-throughput sequencing confirmed the presence of 99 functional immunoglobulin heavy chain variable (IGHV) genes in the C57BL/6 genome, and inferred the presence of 164 IGHV genes in the BALB/c genome. Remarkably, only five IGHV sequences were common to both strains. Compared with humans, little N nucleotide addition was seen in the junctions of mouse VDJ genes. Germline human IgG-associated IGHV genes are rare, but many murine IgG-associated IGHV genes were unmutated. Together these results suggest that the expressed mouse repertoire is more germline-focused than the human repertoire. The apparently divergent germline repertoires of the mouse strains are discussed with reference to reports that inbred mouse strains carry blocks of genes derived from each of the three subspecies of the house mouse. We hypothesize that the germline genes of BALB/c and C57BL/6 mice may originally have evolved to generate distinct germline-focused antibody repertoires in the different mouse subspecies.

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Robinson, William H. « Sequencing the functional antibody repertoire—diagnostic and therapeutic discovery ». Nature Reviews Rheumatology 11, n^o 3 (23 décembre 2014) : 171–82. http://dx.doi.org/10.1038/nrrheum.2014.220.

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Zheng, Tianqing, Jia Xie, Zhuo Yang, Pingdong Tao, Bingbing Shi, Lacey Douthit, Peng Wu et Richard A. Lerner. « Antibody selection using clonal cocultivation of Escherichia coli and eukaryotic cells in miniecosystems ». Proceedings of the National Academy of Sciences 115, n^o 27 (18 juin 2018) : E6145—E6151. http://dx.doi.org/10.1073/pnas.1806718115.

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We describe a method for the rapid selection of functional antibodies. The method depends on the cocultivation of Escherichia coli that produce phage with target eukaryotic cells in very small volumes. The antibodies on phage induce selectable phenotypes in the target cells, and the nature of the antibody is determined by gene sequencing of the phage genome. To select functional antibodies from the diverse antibody repertoire, we devised a selection platform that contains millions of picoliter-sized droplet ecosystems. In each miniecosystem, the bacteria produce phage displaying unique members of the antibody repertoire. These phage interact only with eukaryotic cells in the same miniecosystem, making phage available directly for activity-based antibody selection in biological systems.

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de Bourcy, Charles F. A., Cesar J. Lopez Angel, Christopher Vollmers, Cornelia L. Dekker, Mark M. Davis et Stephen R. Quake. « Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging ». Proceedings of the National Academy of Sciences 114, n^o 5 (17 janvier 2017) : 1105–10. http://dx.doi.org/10.1073/pnas.1617959114.

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The elderly have reduced humoral immunity, as manifested by increased susceptibility to infections and impaired vaccine responses. To investigate the effects of aging on B-cell receptor (BCR) repertoire evolution during an immunological challenge, we used a phylogenetic distance metric to analyze Ig heavy-chain transcript sequences in both young and elderly individuals before and after influenza vaccination. We determined that BCR repertoires become increasingly specialized over a span of decades, but less plastic. In 50% of the elderly individuals, a large space in the repertoire was occupied by a small number of recall lineages that did not decline during vaccine response and contained hypermutated IgD+B cells. Relative to their younger counterparts, older subjects demonstrated a contracted naive repertoire and diminished intralineage diversification, signifying a reduced substrate for mounting novel responses and decreased fine-tuning of BCR specificities by somatic hypermutation. Furthermore, a larger proportion of the repertoire exhibited premature stop codons in some elderly subjects, indicating that aging may negatively affect the ability of B cells to discriminate between functional and nonfunctional receptors. Finally, we observed a decreased incidence of radical mutations compared with conservative mutations in elderly subjects’ vaccine responses, which suggests that accumulating original antigenic sin may be limiting the accessible space for paratope evolution. Our findings shed light on the complex interplay of environmental and gerontological factors affecting immune senescence, and provide direct molecular characterization of the effects of senescence on the immune repertoire.

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Schwimmer, Lauren J., Betty Huang, Hoa Giang, Robyn L. Cotter, David S. Chemla-Vogel, Francis V. Dy, Eric M. Tam et al. « Discovery of diverse and functional antibodies from large human repertoire antibody libraries ». Journal of Immunological Methods 391, n^o 1-2 (mai 2013) : 60–71. http://dx.doi.org/10.1016/j.jim.2013.02.010.

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Nobrega, Alberto, Alf Grandien, Matthias Haury, Laura Hecker, Evelyne Malanchère et Antonio Coutinho. « Functional diversity and clonal frequencies of reactivity in the available antibody repertoire ». European Journal of Immunology 28, n^o 4 (avril 1998) : 1204–15. http://dx.doi.org/10.1002/(sici)1521-4141(199804)28:04<1204 ::aid-immu1204>3.0.co;2-g.

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Kodangattil, Sreekumar, Christine Huard, Cindy Ross, Jian Li, Huilan Gao, Alessandro Mascioni, Santosh Hodawadekar et al. « The functional repertoire of rabbit antibodies and antibody discovery via next-generation sequencing ». mAbs 6, n^o 3 (30 janvier 2014) : 628–36. http://dx.doi.org/10.4161/mabs.28059.

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Maleckar, J. R., et L. A. Sherman. « The composition of the T cell receptor repertoire in nude mice. » Journal of Immunology 138, n^o 11 (1 juin 1987) : 3873–76. http://dx.doi.org/10.4049/jimmunol.138.11.3873.

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Abstract Previous results from several laboratories have demonstrated the presence of functional T lymphocytes in congenitally athymic (nude) mice. The present study represents an analysis of the T cell receptor repertoire exhibited by such cells. Clones of H-2Kb-specific cytotoxic T lymphocytes (CTL) were generated under primary limiting dilution conditions by using spleen cells from nude mice. These clones were analyzed on a panel of Kb mutant target cells to assess the receptor specificity of each clone. Unlike thymic bearing mice the CTL repertoires of which are exceedingly diverse, it was found that in most cases the vast majority of clones from each individual exhibited the same reactivity pattern. The particular pattern varied from individual to individual. Clones from three animals that exhibited this phenomenon were additionally analyzed by using a monoclonal antibody that can detect the utilization of the gene products of the V beta 8 family. In one animal all clones were V beta 8 positive, whereas in the others, all clones were negative. We conclude that the T cell receptor repertoire in nude mice is extremely limited and represents in vivo expansion of a relatively small number of functional precursors.

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Kirchenbaum, Greg A., Giuseppe A. Sautto, Rodrigo B. Abreu, Paul V. Lehmann et Ted M. Ross. « Assessment of Antibody Functional Affinity using FluoroSpot ». Journal of Immunology 204, n^o 1_Supplement (1 mai 2020) : 86.11. http://dx.doi.org/10.4049/jimmunol.204.supp.86.11.

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Abstract Studies of B cell immunity often rely upon serologic methodologies that primarily assess antibody specificity. However, functional affinity of the antigen-specific antibody repertoire is a key determinant of protective efficacy. Presently, detailed assessment of single B cell/antibody functional affinity is labor-intensive and low-throughput. Therefore, we sought to evaluate whether B cell FluoroSpot assays would enable distinction between B cells with differential functional affinity since fluorescent intensity is directly proportional to antibody abundance in this assay. To test our prediction, murine B cell hybridomas (P65C6-2, 36–65 and 36–71) secreting monoclonal antibodies (mAb) with differential affinity for the p-azophenylarsonate (Ars) hapten were utilized as model antibody-secreting cells (ASC). Additionally, usage of an anti-idiotypic mAb (17–63) specific for the high-affinity anti-Ars mAb (36–71) confirmed unambiguous segregation of Ars-specific ASC. Moreover, we also evaluated the capacity of a multiplexed FluoroSpot assay to simultaneously distinguish antibody functional affinity among influenza hemagglutinin-reactive murine B cell hybridomas, or in vivo differentiated ASC from immunized mice, secreting various IgG subclasses (IgG1/IgG2a/IgG2b) in parallel. Collectively, our data support the notion that FluoroSpot assays can be used to assess the functional affinity of antigen-specific B cells, and that this approach is well-suited for detailed assessment of humoral immunity.

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Thèses sur le sujet "Antibody functional repertoire"

ANDREANO, EMANUELE. « A NOVEL APPROACH TO UNRAVEL THE RESPIRATORY SYNCYTIAL VIRUS (RSV) PREFUSION F-PROTEIN FUNCTIONAL ANTIBODY REPERTOIRE IN ADULT HEALTHY DONORS ». Doctoral thesis, Università di Siena, 2019. http://hdl.handle.net/11365/1071780.

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Respiratory syncytial virus (RSV) is the chief cause of low respiratory tract infection deaths in infants under 5 years of age. Since no vaccine is currently available, novel approaches are needed to support the development of new candidates. Herein, elements of the “Reverse Vaccinology 2.0” approach were used to unravel functional, genetic and structural features that characterize the effective adult human antibody response to RSV infection. The data presented in this thesis show that the majority of identified neutralizing antibodies (nAbs) recognize both RSV F-protein conformations (cross-binders) even if a preferential binding towards the prefusion (preF) was observed. Furthermore, the IGHV1 gene family was identified as predominant in the functional antibody response, despite different heavy chain gene rearrangements seem to better recognize specific epitope regions on the preF. Moreover, predominant gene derived-nAbs, showing high neutralization potency, were found to specifically recognize a defined epitope region placed between Site Ø, Site II and Site V on the preF surface. Finally, the co-crystal structure of preF bound to Pl2_E08, a predominant gene derived nAb belonging to the IGHV1-69 gene family, was determined. Structural data confirm what was previously observed in a competition assay and reveal an important epitope region that could play a pivotal role in eliciting nAbs against different RSV A strains and even human metapneumovirus (MPV). These findings identify a specific site of pathogen vulnerability and highlight the possibility to design novel strategies to target and expand predominant gene derived-nAbs. This approach could result in high protection against RSV and consequent reduction of the high burden brought by this pathogen.

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