In a set of experiments in mice, scientists at NYU Langone have rewritten the definition of vitamin A deficiency and upended long-held explanations for how too little of the vitamin works its damage.

Scientists have known for over a decade that malnourished people whose diets are seriously lacking the nutrient are very vulnerable to some forms of blindness, and their immune systems are less than stellar in fighting off infections from viruses and parasites. The conventional wisdom was that vitamin A deficiency led to a weakened immune response from too few attacking white blood cells, including those called macrophages.

But that conventional wisdom turns out to be only half true, according to a team of researchers led by NYU Langone parasitologist P'ng Loke, PhD.

Results of his latest study, published in the journal Nature Immunology online, show that certain macrophages, which are supposed to gobble up invading cells (to make them easier to expel from the body), actually increase in number in the absence of adequate vitamin A. And the researchers report that the massive buildup of these macrophages, immediately after infection and as part of a process of excessive inflammation, is what distorts the overall immune response to invading organisms.

"Our study changes previously held concepts about vitamin A deficiency and suggests that such deficiency doesn't so much weaken a necessary immune response as it disrupts the balance and regulation of that response," says Loke, an associate professor at NYU Langone. "A lack of vitamin A actually increases certain kinds of inflammatory cells, such as macrophages."

In their experiments, Loke's team found that vitamin A was essential for the conversion of one type of macrophage into another. Until now, Loke says, scientists thought the two types of macrophages were separate and distinct in mammals, including mice and humans. One set of macrophages originated from the bone marrow (where blood cells are produced), and another set of macrophages developed in the womb (from the growing fetus) and resided in the body's tissues, such as the liver.

According to Loke's new research, the blood-derived macrophages need vitamin A to turn into the tissue-resident kind after they have moved there.

During infection, his new research shows, vitamin A deficiency leads to a buildup of inflammatory macrophages of the blood-derived variety. Yet, they cannot develop into tissue-resident macrophages where they are needed to reduce inflammation. Consequently, 80 percent of mice lacking vitamin A died from a parasitic worm infection, whereas none of the mice on a healthy diet died from infection.

In blood and tissue samples from mice fed nutrient-rich diets, 82 percent of all macrophages were of the tissue-resident variety, and 9 percent were blood-derived.

By contrast, mice lacking vitamin A had only 0.5 percent tissue-resident macrophages, and 52 percent blood-derived.

Changing the mice's diet to replenish vitamin A levels, however, corrected both kinds of macrophage levels to those whose diet never lacked the nutrient.