Landscape of Non-canonical Cysteines in Human VH Repertoire Revealed by Immunogenetic Analysis

Prabakaran, Ponraj; Chowdhury, Partha S.

doi:10.1016/j.celrep.2020.107831

Cited by 23 publications

(25 citation statements)

References 59 publications

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“…Previously, we discovered CDR-H3 length-dependent usage of human IGHD germline genes [ 28 ]. Such CDR-H3 length-dependent usage of non-canonical cysteines was extensively characterized in human VH repertoires [ 30 ] and in other animals such as chicken [ 31 ], bovine [ 32 ], shark and camelid [ 33 ]. Intrigued by the roles of human IGHD gene segments in shaping human antibody CDR-H3 diversity, we analyzed the human IGHD germline gene usage of natural antibodies derived from 8 healthy donors and 44 DENV acutely infected patients—the same dataset we used in section Antibody heavy chain CDR3-dependent usage of human IGHJ4 and IGHJ6.…”

Section: Resultsmentioning

confidence: 99%

Antibody heavy chain CDR3 length-dependent usage of human IGHJ4 and IGHJ6 germline genes

Wang

Yan

Yang

et al. 2021

Antibody Therapeutics

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Background Therapeutic antibody discovery using synthetic diversity has been proved productive, especially for target proteins not suitable for traditional animal immunization-based antibody discovery approaches. In recent years, many lines of evidences suggest that the quality of synthetic diversity design limits the development success of synthetic antibody hits. The aim of our study is to understand the quality limitation and to properly address the challenges with a better design. Methods Using VH3–23 as a model framework, we analyzed the naturally and productively rearranged CDR-H3 diversity in human immune repertoire. With homology modeling, we further built VH3–23-based structural models to understand the spatial paratope and its influencing parameters. Results We observed and quantitatively mapped CDR-H3 loop length-dependent usage of human IGHJ4 and IGHJ6 germline genes in the natural human immune repertoire. Skewed usage of DH2-JH6 and DH3-JH6 rearrangements was quantitatively determined in a CDR-H3 length-dependent manner in natural human antibodies with long CDR-H3 loops. Such CDR-H3 length dependent usage of human germline genes was not impacted by the choices of VH in the V(D)J recombination, ethnic background and health conditions. Structural modeling suggests choices of JH help to stabilize antibody CDR-H3 loop and JH only partially contributes to the paratope. Conclusions We quantitatively determined the CDR-H3 length-dependent usage of human germline genes, which makes it possible to design synthetic diversity fully mimicking that of natural immune repertoire. Our observations shed light on the design of next generation synthetic diversity with improved probability of success.

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Section: Resultsmentioning

confidence: 99%

Antibody heavy chain CDR3 length-dependent usage of human IGHJ4 and IGHJ6 germline genes

Wang

Yan

Yang

et al. 2021

Antibody Therapeutics

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“…This suggests a possible implication for data mining in the NGS repositories for discovering therapeutic antibody candidates in future. Also, large-scale NGS analysis of individual antibodyome will lead to improved insights into overall diversity of the human antibody repertoire and B cell immunogenetics ( 15 – 17 ).…”

mentioning

confidence: 99%

Editorial: Next-Generation Sequencing of Human Antibody Repertoires for Exploring B-cell Landscape, Antibody Discovery and Vaccine Development

Prabakaran¹,

Glanville²,

Ippolito

2020

Front. Immunol.

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“…Interestingly, we found that 20% of receptors in these rare shared, expanding lineages contain multiple cysteines in their HCDR3s, in contrast to only 10% of the receptors in the whole repertoire. Such sequence patterns with cysteine pairs in the HCDR3 have been associated with stabilization of the HCDR3 loop by forming disulfide bonds with particular patterns and spacings of the cysteines (Lee et al, 2014; Prabakaran and Chowdhury, 2020). Disulfide bonds in the HCDR3 can decrease the conformational flexibility of the loop, thus decreasing the entropic cost of binding to improve the affinity of the receptor (Almagro et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, three distinct SARS-CoV-2-specific mAbs were found to be close in sequence to HCDR3s in our data, with only one amino acid difference, and one of these mAbs also had a matching V gene (Table 1). Among these, we found a class of antibodies containing multiple cysteines in their HCDR3s, with the potential to form disulfide bonds to enhance their affinity to antigens and paratope diversity (Almagro et al, 2012; Lee et al, 2014; Prabakaran and Chowdhury, 2020).…”

Section: Resultsmentioning

confidence: 99%

Dynamics of B-cell repertoires and emergence of cross-reactive responses in COVID-19 patients with different disease severity

Montague

Otwinowski

et al. 2020

Preprint

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COVID-19 patients show varying severity of the disease ranging from asymptomatic to requiring intensive care. Although a number of monoclonal antibodies against SARS-CoV-2 have been identified, we still lack an understanding of the overall landscape of B-cell receptor (BCR) repertoires in COVID-19 patients. Here, we used high-throughput sequencing of BCR repertoires collected over multiple time points during an infection to characterize statistical and dynamical signatures of the B-cell response to SARS-CoV-2 in 19 patients with different disease severities. Based on principled statistical approaches, we determined differential sequence features of BCRs associated with different disease severity. We identified 34 significantly expanded rare clonal lineages shared among patients as candidates for a specific response to SARS-CoV-2. Moreover, we identified natural emergence of a BCR with cross-reactivity to SARS-CoV and SARS-CoV-2 in a number of patients. Overall, our results provide important insights for development of rational therapies and vaccines against COVID-19.

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Landscape of Non-canonical Cysteines in Human VH Repertoire Revealed by Immunogenetic Analysis

Abstract: Highlights d NGS-based non-canonical cysteine landscape in human V H s d 1 to 8 non-canonical cysteines and up to 30% in long CDR-H3s d An array of potential disulfide motifs adds paratope diversity d Non-canonical cysteines in human V H s are reminiscent of lower animals

Cited by 23 publications

References 59 publications

Antibody heavy chain CDR3 length-dependent usage of human IGHJ4 and IGHJ6 germline genes

Antibody heavy chain CDR3 length-dependent usage of human IGHJ4 and IGHJ6 germline genes

Editorial: Next-Generation Sequencing of Human Antibody Repertoires for Exploring B-cell Landscape, Antibody Discovery and Vaccine Development

Dynamics of B-cell repertoires and emergence of cross-reactive responses in COVID-19 patients with different disease severity

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