Vitamin D in early childhood and the effect on immunity to Mycobacterium tuberculosis

Abstract

A potential role for vitamin D as a therapeutic immunomodulator in tuberculosis (TB) has been recognised for over 150 years, but has only recently returned to the centre of the research arena due to the increasing awareness of the global vitamin D deficiency epidemic. As early as birth a child is often deficient in vitamin D, which may not only affect their bone metabolism but also modulate their immune function, contributing to the increased susceptibility to many infections seen early in life. Recent studies have begun to explain the mechanisms by which vitamin D affects immunity. Antimicrobial peptides are induced in conjunction with stimulation of innate pattern recognition receptors enhancing immunity to particular infections. In contrast the role of vitamin D within the adaptive immune response appears to be more regulatory in function, perhaps as a mechanism to reduce unwanted inflammation. In this paper we focus on the effect of vitamin D on immunity to TB. Where much of the attention has been paid by past reviews to the role of vitamin D in adult TB patients, this paper, where possible, focuses on research in paediatric populations.

Figure 1

Mechanism of vitamin-D-induced immunity to Mycobacterium tuberculosis (modified from [16]). Stimulation of monocyte Toll-like receptors (TLR1/2) by Mycobacterium tuberculosis (MTB) results in transcriptional induction of the vitamin D receptor (VDR) and 1α-hydroxylase (CYP27B1). Circulating 25-hydroxyvitamin D (25[OH]D) enters the cell and is converted to 1,25-dihydroxyvitamin D (1,25[OH]2D) by the CYP27B1 enzyme. VDR-bound 1,25(OH)2D then induces expression of cathelicidin and β-defensin 2 (DEFB4). In addition 1,25(OH)2D induces autophagy and downregulating metalloproteinases (MMPs), all of which help in the formation of phagolysosomes and the killing of Mtb. 1,25(OH)2D also affects the adaptive immune system and leads to an upregulation of regulatory responses and a skewing towards a Th2 response. IFNγ is thought to induce the expression of the CYP27B1 enzyme suggesting a feedback mechanism between the innate and adaptive response to vitamin D.