Immunomodulation by vitamin D: implications for TB

Abstract

TB remains a major cause of mortality throughout the world. Low vitamin D status has been linked to increased risk of TB and other immune disorders. These observations suggest a role for vitamin D as a modulator of normal human immune function. This article will detail the cellular and molecular mechanisms by which vitamin D regulates the immune system and how vitamin D insufficiency may lead to immune dysregulation. The importance of vitamin D bioavailability as a mechanism for defining the immunomodulatory actions of vitamin D and its impact on TB will also be discussed. The overall aim will be to provide a fresh perspective on the potential benefits of vitamin D supplementation in the prevention and treatment of TB.

Keywords: CYP24A1; CYP27B1; TB; Toll-like receptor; cathelicidin; defensins; monocyte; neutrophil; vitamin D; vitamin D receptor.

Figure 1. Vitamin D, immune function and TB

Vitamin D is generated in the skin by UVB exposure through photoconversion of 7-DHC, produced from cholesterol by the action of DHCR7. Vitamin D can also be obtained by dietary supplementation. Vitamin D is converted into 25D by CYP2R1 in the liver. Total 25D levels (vitamin D status) in the blood is primarily determined by the 25D bound to DBP, although some 25D is bound to other serum proteins, such as albumin, or present as ‘free’ 25D. Glycosylation of DBP generates a MAF (DBP-MAF). Free 25D can enter into immune cells by simple diffusion and can then be activated via the enzyme CYP27B1. 1,25D generated in this way can then act in an intracrine fashion within the same cell if the VDR is expressed. Alternatively, 1,25D produced by immune cells may act in a paracrine fashion on neighboring cells expressing VDR. The enzyme CYP24A1 attenuates both intracrine and paracrine responses to vitamin D by catabolizing both 25D and 1,25D. Interaction between 1,25D and VDR acts to promote the transcriptional regulation of vitamin D target genes. These include genes associated with innate and adaptive immunity. Thus, sufficient vitamin D (bioavailability) may be a pivotal factor in appropriate and adequate immune responses to pathogens such as Mycobacterium tuberculosis, enabling protection against or by providing treatment for TB. 7-DHC: 7-dehydrocholesterol; 25D: 25-hydroxyvitamin D; 1,25D: 1,25-dihydroxyvitamin D; CYP2R1: Vitamin D-25-hydroxylase; CYP27B1: 25-hydroxyvitamin D-1a-hydroxylase; CYP24A1: Vitamin D-24-hydroxylase DHCR7: 7-dehydrocholesterol reductase; DBP: Vitamin D-binding protein; MAF: Macrophage-activating factor; NO: Nitric oxide; ROS: Reactive oxygen species; Treg: Regulatory T cell; UVB: Ultraviolet B; VDR: Vitamin D receptor.