Biology subjects

Bullen, G.

Publications and source records attributed to Bullen, G..

2 recordsLinked to original sources

bioRxiv2025

VH-replacement shapes the antibody repertoire by targeting non-pairing heavy-chains

The diversity of antibodies underpins robust immune responses. During the formation of the antibody repertoire in early bone marrow B-cells, random antibody heavy-chain proteins are generated from recombined V, D and J gene-segments. Many are non- functional and are negatively selected. Critically, this phase of development is impacted by ageing and inflammation. To understand this process in normal mice we have undertaken the first in-depth analysis of heavy-chain selection at this pre-B cell transition. We find independent selection acting on three regions of the CDR3 antigen binding site, with particularly heavy counter-selection of certain productive VH/JH combinations. This led us to hypothesise that VH-replacement is targeting productive VDJ rearrangements that cannot pair with the surrogate light-chain (SLC). We detect VH-replacement recombination products that closely follow the pattern of counter- selection of productive VDJ. This reveals a physiological role for VH-replacement: the developmental release of B-cells that are stalled, with a productive but not SLC-pairing VDJ, leading to re-modelling of the early VDJ repertoire toward locus-distal VH that we show are more tolerant of CDR3 composition.

immunology↗

bioRxiv2020

Deep mining of early antibody response in COVID-19 patients yields potent neutralisers and reveals high level of convergence

Passive immunisation using monoclonal antibodies will play a vital role in the fight against COVID-19. Until now, the majority of anti-SARS-CoV-2 antibody discovery efforts have relied on screening B cells of patients in the convalescent phase. Here, we describe deep-mining of the antibody repertoires of hospitalised COVID-19 patients using a combination of phage display technology and B cell receptor (BCR) repertoire sequencing to isolate neutralising antibodies and gain insights into the early antibody response. This comprehensive discovery approach has yielded potent neutralising antibodies with distinct mechanisms of action, including the identification of a novel non-ACE2 receptor blocking antibody that is not expected to be affected by any of the major viral variants reported. The study highlighted the presence of potent neutralising antibodies with near germline sequences within both the IgG and IgM pools at early stages of infection. Furthermore, we highlight a highly convergent antibody response with the same sequences occurring both within this study group and also within the responses described in previously published anti-SARS-CoV-2 studies.

immunology↗