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The Drakesmith group finds that low blood serum iron levels can inhibit T-cell and B-cell immune responses to vaccines and infections.

Graphic illustration of a syringe with bacteria, virus particles and a cell.

The study, based at the MRC HIU, also suggests that increasing blood iron in situations where iron levels are low may boost immunity.

Iron deficiency is the most common micronutrient deficiency worldwide, affecting millions of children, pregnant women, the elderly, and hospitalized patients. However, the influence of iron deficiency on immunity, despite many previous studies, has remained unclear.

In new research published in Med, the Drakesmith Group investigated how iron influences adaptive immune responses to infections and to vaccines, and how the iron regulating hormone hepcidin is involved in this process. The researchers found that low amounts of iron in the blood inhibits immune responses to vaccines, because immune cells called T-lymphocytes need iron to support their metabolism.  T-lymphocytes are crucial for destroying infected cells, for helping the antibody response to infections, and for remembering infections (immune memory).

The team found that activated T-lymphocytes need large amounts of iron; and if iron is scarce, the mitochondria in T-lymphocytes generate less energy, making the T-cells less able to carry out their functions and fight infections.

The importance of hepcidin

Hepcidin is the hormone that controls the amount of iron in the bloodstream. Mice with high hepcidin and low serum iron made poorer immune responses to vaccines, and were worse at forming immune memory, a crucial aspect of how the immune system remains protective over many years. Mice with high hepcidin were also worse at making an immune response to influenza virus infection, and their lungs were more damaged by the infection. This situation may be important in Covid-19, where high hepcidin and low iron also occur.

People with a rare genetic mutation that results in high hepcidin and low serum iron levels had fewer antibodies against some infectious pathogens, which meant that their immune systems may be less able to fight off some infections.  

Low blood iron (hypoferremia) caused by hepcidin is a common physiological response to infection – it acts to deny microbes access to the iron they need to grow and spread, potentially slowing the progress of infection. However, the new work from the Drakesmith group suggests there may be a price to pay for this response: the T-cells and B-cells that make up the adaptive immune response to infection are also denied access to iron. If the inhibition of adaptive immunity by hepcidin is severe enough, then while the short-term ‘battle for iron’ may be won by the host’s fast hepcidin response, the ‘war’ might be lost because long-term immune protection is not achieved.

Improving vaccine efficacy

On the other side of the coin, the research team also found that if they increased iron levels in the bloodstream of animals with low iron, they could improve immune responses, paving the way for a potential therapeutic intervention.

The researcher found that supplementing with iron boosted vaccination-induced immunity in piglets: after birth, piglets normally develop low levels of iron, making them a natural model of iron deficiency. The finding that iron can improve response to a vaccine is important because vaccines can have different efficacies in different parts of the world, and some vaccines have lower efficacy in areas where iron deficiency is common.

Professor Hal Drakesmith said; "It's long been known that iron is important during infections because infectious organisms need iron to grow. We've shown the amount of iron in the bloodstream is critical for the T-cell and B-cell response to vaccines and to a 'flu virus infection. The hormone hepcidin regulates iron, so by targeting hepcidin it is possible to control immune responses."

'Understanding what influences the immune response to vaccines is very important, so by identifying iron as a key factor, our work may eventually help to improve efficacy of some vaccines in populations where iron deficiency is common. However, it also important to note that too much iron may be dangerous as it can sometimes make infections worse.'


Read the full paper