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29 Oct 2020

Revealed: how the immune system stays alert to related pathogens

Garvan researchers have revealed how the body generates a subset of ‘early responder’ immune cells that recognise threats similar to those they’ve already seen.

Researchers at the Garvan Institute of Medical Research have uncovered how the immune system ensures it can target foreign antigens that have changed from their original version – a common strategy pathogens such as viruses use to evade immune detection.

In experimental models, a team led by Professor Rob Brink revealed that the molecule BAFF generates a subset of ‘early responder’ immune cells that, instead of specialising to produce more effective antibodies, remained dormant and able to recognise close relatives of the pathogen.

“Our findings reveal an immune strategy that underpins a faster, more effective immune response,” says senior author Professor Robert Brink, who heads the B Cell Biology Lab at Garvan.

“These non-specialised ‘early responder’ B cells are a crucial component of the immune system and able to target pathogens that undergo mutations, such as the seasonal strains of the influenza virus. But how they’re generated and preserved in the body has been a mystery, until now.”

The researchers publish the findings in the Journal of Experimental Medicine.

Immune system’s early responders

When immune cells called B cells, that make antibodies, detect a foreign antigen, many migrate to germinal centres – the body’s ‘antibody tuning centres’ located in lymphoid organs such as the lymph nodes, spleen and tonsils – where they mutate and tweak their antibodies to specifically bind to the foreign pathogen.

Meanwhile, a separate subset of B cells that have also recognised the antigen remain dormant in the lymphoid organs, staying alert for the next time a similar pathogen comes around. These cells are called germinal centre-independent memory B cells (GC-independent MBCs).

“GC-independent MBCs have a huge potential advantage in some instances. They can recognise a similar or mutated version of the same pathogen, which would otherwise escape immune detection,” explains first author Dr Angelica Lau. “We were interested in how these cells were generated and preserved in the body long-term.”

Key strategy revealed

In mice that had been gene edited to either lack BAFF or lack the receptor it docks to, the researchers discovered that GC-independent MBCs were not maintained. When the researchers instead artificially increased BAFF activity, they saw that the total numbers of GC-independent MBCs also increased.

In contrast, the absence of BAFF or its receptor had no effect on the generation of memory B cells that were fine-tuned in the germinal centre.

“Together, our findings show that BAFF signalling is crucial for generating GC-independent MBCs. Essentially, BAFF allows B cells from early in the immune response to survive and wait for a related antigen. This means that the immune system will have a head start when that antigen arrives,” explains Professor Brink.

Potential for broader immunity

Beyond explaining a fundamental mechanism of the immune system, the researchers say the findings carry potential implications for boosting the immune response for a better, broader response to pathogens.

Some viruses, including the seasonal influenza virus, mutate rapidly, which means that the immune system constantly has to generate new antibody-producing B cells to keep up its defence.

“While further research is needed in this field, augmenting the levels of BAFF while administering a vaccine may allow our immune system to cover a broader range of viruses,” says Professor Brink.

“An effective immune system is central to our health. The more we can uncover about how it tackles challenges, the better chances we’ll have of finding approaches to enhance it.”

This research was supported by the National Health and Medical Research Council (Program Grant 1016953) and Mr & Mrs John and Megan Wade.