Iron and immunity

Iron is an important nutrient for maintaining our health, and yet around 2 billion people worldwide have iron deficiency. A well-known consequence of iron deficiency is anaemia, because red blood cells need iron to transport oxygen.
However, we have recently found that the white blood cells of our immune system are also very sensitive to iron deficiency, and immune responses can be disabled by iron insufficiency. This discovery means that we now need to study in more depth the interplay between iron and immunity. We are going to do this in three ways.
First, we will examine why iron is so important to immune cells, and whether the chemical reactions that normally occur in white blood cells are altered by a lack of iron, and how this affects different types of immune cells.
Second, we will try to suppress unwanted and dangerous immune responses, for example in autoimmunity and during rejection of transplanted organs, by withholding iron from immune cells.
Lastly, through studies in healthy humans and patients around the world, we will learn how iron deficiency and iron nutrition influence the development and function of the immune system, including responses to vaccines.

Our lab investigates the role and regulation of iron in health and disease, especially in the context of immunity and infection. In particular we have focussed on the iron regulatory hormone hepcidin. Hepcidin is transcriptionally regulated by a complex array of signals including circulating and stored iron, erythropoietic drive, and inflammation. In the past five years, we studied the underlying molecular mechanisms that govern mammalian iron homeostasis, how defects in control of hepcidin lead to iron-related pathology in haemochromatosis and thalassaemia, and helped develop new therapeutic approaches for these disorders. We investigated how invading microorganisms affect hepcidin regulation and how this influences the outcome of infection, consistent with the known critical role for iron in supporting growth and metabolism of both host and pathogen. Our recent work revealed an unexpected sensitivity of immunity to availability of extracellular iron, which is in turn tightly controlled by hepcidin. We found that adaptive immune responses to immunisation and viral infection are suppressed by low plasma iron concentrations (hypoferraemia) because activated lymphocytes are highly iron-demanding. We also found that hypoferraemia impairs the generation and function of neutrophils. These discoveries uncovered some important unknowns that form the focus of our future work. We are developing a method to measure iron content of immune cells at the single cell level, to define which immune cells are most sensitive to changes in iron status and to directly quantify iron deficiency. We will characterise how low iron influences immune cell metabolism, because metabolic processes support and direct proliferation, differentiation and effector functions of immune cells. In pre-clinical murine studies, we are testing how to regulate iron transport to suppress unwanted immune responses, for example to prevent graft rejection after transplantation, avoid graft-versus-host disease, and suppress immunopathological responses. A major implication of our findings is that hypoferraemia may alter immune development and impair response to vaccines in populations where iron deficiency is common. Using facilities in the HIU and with multi-disciplinary collaborators in the UK, Africa and Asia, we are leading and partnering in several clinical trials to analyse effects of iron on the the human immune system, vaccine responses and gastrointestinal health in infants, pre-menopausal women, pregnant women, mother-child pairs and ICU patients. Together the work will advance basic understanding of effects of iron on immunity, suggest new methods to therapeutically control immune responses, and potentially make a direct contribution to improving global health.