Led by Consuelo Anzilotti, a clinical immunologist in Richard Cornall’s group in the Nuffield Department of Medicine and MRC Human Immunology Unit, the project published today in Nature Immunology brought together scientists and clinicians from Oxford, the University of Newcastle, Durham, Imperial College, the Netherlands and the USA.
Dietary zinc deficiency is recognised as a worldwide problem. It is associated with skin disease, increased susceptibility to infections and poor immune function. The World Health Organisation now recommends zinc supplementation to individuals with diarrhoea in resource-poor settings.
The remarkable importance of this nutrient is due to its important function in the structure of more than 3,000 proteins, facilitated by the remarkable stability of its Zn2+ ion. However, how partial zinc deficiency causes specific forms of human disease remains a mystery.
A role in immunity
Lack of zinc in the diet has been previously associated with defects in the immune system, particularly in the development of B cells. However, molecular mechanisms by which Zinc might influence the immune system in these situations remains unknown.
This new study makes the first clear link between Zinc and the human immune system. The team examined the DNA of patients from five unrelated families that were affected by unknown B cell defects. Symptoms included loss of B cells, low levels of antibodies and skin disease. They found that all patients were affected by mutations in the gene ZIP7, which encodes for a cell membrane transporter responsible for transporting Zinc (Zn2+) from the endoplasmic reticulum inside of the cells into the cytoplasm.
The researchers showed that low levels of cytoplasmic Zn2+ in ZIP7 deficient B cells were associated with reduced cell signalling during crucial stages in B cell development. The biochemical data suggests that the normal level of Zn2+ ions may be required to inhibit phosphatases which act as the ‘off-switch’ in cell signalling.
This project brought together scientists across the medical science division in immunology, cancer biology, cell biology, imaging and genetics to build and study models of the human disease. The tools developed open the field to studying how zinc regulates other cellular processes and how zinc operates more widely in health and disease.