Understanding how age affects immunity

Dinis Calado.

As we age, our immune system becomes weaker and less able to fight off infections and disease. The reasons behind this are not fully understood, in part due to the highly complex nature of the immune system, with many cells and mechanisms involved. 

We spoke to Dinis Calado, Senior Group Leader at the Crick, who studies the role of plasma cells in the immune system about a new study to discover how these cells are affected by aging. 

What role do plasma cells play in the immune system?

Plasma cells are a special type of immune cell that develop from B cells. They are vital to immunity as they produce antibodies, the proteins that recognise and neutralise antigens on the surface of viruses and bacteria.

There are both long-lived and short-lived plasma cells and, as their name suggests, one group survives in the body for much longer than the other. In fact, the long-lived group resides in the bone marrow for many years, even decades or a whole life-time, producing antibodies against a disease we were previously exposed to via either infection or vaccination. 

One powerful example of this was described in the 2000s, in which scientists found antibodies in the blood of people aged 91 years old or older against the flu strain that caused the 1918 pandemic. These people had been exposed to the flu strain as children and 80 years later they still had plasma cells producing the relevant antibody. 

What plasma cells secrets is your lab hoping to uncover in the new project?

We’ve recently been awarded a grant of over £825,000 from the Biotechnology and Biological Sciences Research Council (BBSRC), following a pilot study supported by The Dunhill Medical Trust to explore how long-lived plasma cells differ in older people compared to younger generations. 

Data from previous human research suggests that long-lived plasma cells are generally less effectively formed or maintained in older individuals, but we don’t know why this is. And there are a lot of other unknowns. For example, we don’t fully understand how long-lived plasma cells develop from B cells; if long and short-lived plasma cells are formed separately from B cells or whether short-lived plasma cells then go on to become long-lived?

To answer these questions, we’ll be using a mouse model generated by An Qi Xu in the lab that allows us to genetically manipulate plasma cells in vivo in their niche without impacting B cells, the progenitor cells from which plasma cells develop. We use a fluorescent tag to mark the plasma cells at a specific time and then, many months later, look back at the mice to see if these fate-mapped plasma cells have survived. We can then extract the cells to examine properties of truly long-lived plasma cells. 

By comparing these cells in young and old mice, we hope to find differences which may explain why plasma cells in older people are less effectively formed or maintained. The work could also help us understand why cancer of plasma cells, multiple myeloma, is more common in people over the age of 65. 

How could this work be used clinically? 

Understanding how plasma cells are generated and survive could help inform new vaccination strategies that increase the length of time that vaccines protect us for. This could remove the need for people to receive multiple booster shots for particular diseases. 

Another way this work could be used is to help develop vaccines that are more efficient in certain age groups. This is not an entirely new concept as we already use two types of flu vaccine each year, one for those under 65 and one for people over 65 years old. But it would be new to adapt vaccinations to different age groups based on the properties impacting plasma cell quality. 

How does this project fit into the ongoing research in your lab?

My lab is interested in plasma cells, including how B cells become plasma cells and how plasma cells become diseased. One element of our work is studying how healthy cells become cancerous, if cancers can develop from both short and long-lived plasma cells, and if this origin affects the evolution of the tumour or how it responds to different treatments. 

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