Elucidating the mechanisms of plasma cell and memory B-cell differentiation in the germinal centre reaction

This project aims to better understand how the immune system protects us against bacterial or viral infections. This understanding will help form the scientific basis for uncovering new ways to make vaccinations more effective and to control the abnormal behaviour of immune system cells in autoimmunity and blood cancer. 

Background

The generation of highly specific antibodies by B cells and plasma cells after infections, and upon vaccination, is fundamental to our body’s protection against invading microbes. But the problem is that not all microbes or vaccines induce long-lasting, “durable” antibody responses, leaving the body exposed to future infections.

Also, the same cells that are critically involved in the immune response can sometimes be abnormally activated in lupus and arthritis, or can grow in an uncontrolled fashion in blood cancers.  

Rationale

There is a need to better understand how such plasma cells are generated, because this will help inform the invention of novel ways to enhance the durability of the antibody response to vaccination and to inhibit abnormally activated or cancerous B cells or plasma cells. 

Plan of work

Historically, the study of the immune system of mice has given us a better understanding of how our body fights infectious agents. We plan to use genetically modified mice to identify the central immune cell populations which ultimately become microbe-destroying plasma cells – and to understand precisely how they do this. 

We will immunise mice with well-established antigens to elicit an immune response which is similar to that in vaccinated humans. This response will be studied in detail by harvesting the immune system tissues from humanly killed mice and analysing the function of those “central” cells, which is impossible to do in humans. 

Replacement

So far, it has been impossible to reproduce, in vitro, the specific tissue in which the plasma cells that secrete antibodies with high affinity to the invading microbe are generated using human B-cell culture systems. This is due to the fragile nature of these cells – they do not survive in cell culture.

Reduction

The numbers of mice to be used will be kept at an optimal minimum to ensure acquisition of reliable experimental data. We determined group size based on the reports from the vast range of immunological studies with mice, in addition to implementing the NC3Rs Experimental-Design Assistant (https://www.nc3rs.org.uk/our-portfolio/experimental-design-assistant-eda).

Refinement

Immunisations with well-established antigens in adjuvant – an ingredient that can help create a stronger immune response – are currently the most refined methods to study the immune response in mice (mild severity). In a small fraction of mice (<5%), abdominal immunisation induces inflammation, due to an exaggerated response against the adjuvant (moderate severity). Thus, all immunised mice will be monitored daily for signs of ill health and, where necessary, humanely killed.  

Non-technical summary

Read elucidating the mechanisms of plasma cell and memory B-cell differentiation in the germinal centre reactions non-technical summary (PDF).

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