Institute immunologists uncover new process important for antibody diversity

Key points:

• Institute Immunologists uncover the role of a mechanism important for antibody diversity.
• The research answers a long-standing question about how cells manage antibody quality control in developing B cells.
• The discovery may also be relevant to explaining the decreased antibody repertoire seen in older people.

Work just published by the Corcoran lab at the Institute has described a mechanism estimated to be responsible for shaping the generation of up to half of all antibodies produced by our immune system.

In order to provide protection against the huge range of infectious pathogens that exist in the world, our bodies are adept at making a similarly diverse range of antibodies. This diversity, what’s known as the antibody repertoire, is estimated to range from 10 million to over one trillion different antibodies although in practice, the number of different antibodies expressed in an individual at any one time is much smaller. With a normally functioning immune system, the breadth of this protection is taken for granted as our immune system runs efficiently behind the scenes: whatever you encounter, you have an antibody to recognise it.

This astonishing diversity is generated by a combination of processes: the shuffling and cut and pasting of gene segments in a process called VDJ recombination which generates the variable regions of antibodies that bind antigen (a fragment of the substance triggering the immune system response), added nucleotides at the joins of these gene segments and then somatic hypermutation during B cell maturation that improves the affinity of an antibody to an antigen.

As we age, the mechanisms working to achieve antibody diversity change, resulting in a reduced antibody repertoire and increased vulnerability to infectious disease. The Corcoran lab are experts in understanding these mechanisms and how ageing results in a reduced diversity of antibodies. Their latest research took an in-depth look at the selection of the heavy chains used in antibodies during the maturation of B cells. Antibodies are assembled from four protein chains: two longer heavy chains that form the body and arms of the ’Y’ shape, and two shorter light chains that pair with the arm portions of the heavy chains.

Dr Harry White, visiting researcher at the Institute and first author on the research publication, said “This is a surprising case where we thought that the factors affecting antibody diversity were well understood but our research has uncovered valuable new knowledge about antibody production and B cell development. Our findings extend what we know about how our bodies make the diversity of antibodies that we depend on for health and also support our research into how ageing affects the immune system.”

Using the Institute’s Genomics, Bioinformatics and Flow Cytometry facilities, the team analysed the VDJ selection in developing B cells, using a technique developed previously by the lab (VDJseq). Unexpectedly, they found a molecular process in play to detect and correct heavy chain combinations that are unable to pair with light chains.

In a step forward in our understanding, the researchers discovered that non-pairing chains are altered by a process called VH-replacement. VH-replacement acts to edit non-pairing heavy chains in order to facilitate their binding to light chain proteins and create a functional antibody. Connecting VH-replacement to the development of B cells has identified a physiological role for the process, making it of fundamental importance to the formation of up to half of all antibodies produced.

Dr Anne Corcoran, associate group leader in the Institute’s Immunology programme, concluded: “It’s a bit like the ‘waste not, want not’ maxim. In probing the complex quality control mechanisms that exist to ensure B cell development proceeds in cells capable of making a functional antibody, we’ve discovered influential selection mechanisms that distinguish between non-productive heavy chains that simply don’t make the correct protein, and non-pairing heavy chains that make the correct protein but can’t bind light chains. With some modification, non-pairing heavy chain sequences can be corrected and B cell development proceeds. The B cell development stage at which VH-replacement occurs is also known to be altered in ageing, raising the question of whether VH-replacement also plays a role in the altered antibody diversity seen with age.”

Notes

Publication reference: White et al. (2025). VH-replacement shapes the antibody repertoire by removing the genes of non-functional heavy-chains. EMBO J.

Press contact: Dr Louisa Wood, Head of Communications, louisa.wood@babraham.ac.uk

Image description: Computer illustration of antibodies, showing the heavy chain (red) and the light chain (blue).

Affiliated authors (in author order):

Harry White, former senior scientist, Corcoran lab, visiting scientist, Immunology research programme

Peter Chovanec, former PhD student and postdoctoral researcher, Corcoran lab

Laura Biggins, Bioinformatician, Bioinformatics facility

Elise French, former PhD student, Corcoran lab

Georgia Bullen, former PhD student, Corcoran lab

Simon Andrews, Head of Bioinformatics

Anne Corcoran, associate group leader, Immunology research programme

Research funding: This research was supported by strategic funding to the Institute from BBSRC.

Animal research statement

As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. This research used mice as a source of developing B cells from bone marrow. Cells were isolated from femurs and tibias after mice were humanely killed.

All mouse experimentation was approved by the Babraham Institute Animal Welfare and Ethical Review Body. Animal husbandry and experimentation complied with European Union and United Kingdom Home Office legislation.

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