Published: October 12, 2011
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Effective immune responses to tuberculosis infection are critically dependent on vitamin D availability, researchers said.
In a healthy response to Mycobacterium tuberculosis invasion, macrophages mount a frontal assault on the pathogens -- but this failed to happen in vitro when human macrophages were incubated in serum with low levels of vitamin D, according to Robert Modlin, PhD, of the University of California Los Angeles, and colleagues.
On the other hand, when the serum was supplemented with 25-hydroxyvitamin D3 (25-OH-D, the active metabolite of vitamin D), antimicrobial activity in the macrophages was restored, the researchers reported online in Science Translational Medicine.
"The present findings underscore the importance of adequate amounts of vitamin D in all human populations for sustaining both innate and acquired immunity against infection," Modlin and colleagues wrote.
Pathogens such as M. tuberculosis that take up lodging inside human host cells can only be fought off with T cell-mediated adaptive immune responses, the researchers explained.
Mounting this attack is a multi-step process: T cells that recognize infected host cells are generated, which then secrete interferon-gamma. This, in turn, mobilizes macrophages that carry out the dirty work of killing the infected cells and the pathogens within them.
This process has been understood for some time and has prompted investigations of interferon-gamma as a means of boosting the immune response in tuberculosis -- futilely, it turned out.
"Multiple studies of interferon-gamma treatment of human macrophages have consistently failed to demonstrate antimicrobial activity against intracellular M. tuberculosis," Modlin and colleagues wrote.
But subsequent research showed that innate immune responses, mediated by Toll-like receptors, could also stimulate macrophages to attack cells infected with M. tuberculosis as long as vitamin D was available.
These findings suggested to Modlin and colleagues that this process may also influence T-cell-mediated responses to tuberculosis infection.
In their key experiment, the researchers cultured human macrophages in serum from Caucasian donors who had mean 25-OH-D levels of 113 nM (SD 11) and from African American donors with mean levels of 56 nM (SD 2).
When then treated with interferon-gamma, the macrophages incubated in the white donors' serum produced cathelicidin and expressed other genes characteristic of antimicrobial activity. This activity was lacking in the cells incubated in the black donors' serum.
Moreover, when the serum from African Americans was supplemented with additional 25-OH-D, antimicrobial activity was then apparent in the macrophages.
In other experiments, Modlin and colleagues found similar results in monocytes, which also showed substantial antimicrobial peptide expression when incubated in the vitamin D-sufficient serum but not when grown in the deficient serum.
The researchers also infected human monocytes and macrophages with virulent M. tuberculosis and then dosed them with interferon-gamma in the two types of serum. The pathogen's growth was inhibited in the presence of the white donors' serum but not with the black donors' serum.
The difference between sera from whites and African Americans is clinically significant but not surprising. Dark skin reduces the ability to make vitamin D from sun exposure; furthermore, "dark-skinned populations ... are known to have increased susceptibility to tuberculosis and other infectious diseases," Modlin and colleagues wrote.
They noted as well that, in earlier studies, low vitamin D and African ancestry were both linked to impairments in the innate immune system.
"Vitamin D deficiency may compromise both the innate and the acquired antimicrobial host defense pathways against tuberculosis infection and likely other infections known to be greater in blacks," the researchers wrote.
In discussing their results, Modlin and colleagues stressed that the role of vitamin D in immune responsiveness must be investigated in human cells and tissues, not in mouse models.
"The interferon-gamma-induced antimicrobial pathway described here is vitamin D-dependent in humans but not in the mouse," they wrote. In humans, for example, several vitamin D response elements have been identified in the mechanisms leading to antimicrobial peptide expression that are lacking in mice.
"The evolution of distinct antimicrobial mechanisms makes sense teleologically as well because mice are nocturnal animals and humans are not, and the amount of vitamin D increases with sun exposure," they added
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