The objective of the immune system is to protect the parent organism from infection. The immune system is comprised of both the innate component and the adaptive component; see Figure 1. The innate immune system provides an immediate, but nonspecific, response against perceived invaders. Innate immune systems are found in all animals and plants. In vertebrates, if pathogens successfully evade the innate response, the adaptive immune system, which is the second line of protection, becomes activated by the innate response; see the bottom portion of Figure 1. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then biochemically “remembered” after the pathogen has been eliminated. In the event of a second invasion by the same pathogen, the existence of biochemical memory allows the initiation of a more rapid response.
Fig1. Schematic organization of the innate and adaptive immune systems and summary of the consequences of the presence of 1α,25(OH)2D3. The top portion lays out the components and responses of the innate immune system in a dendritic cell (DC), and the bottom portion illustrates the complexity of the adaptive immune system in a T-cell. The right-hand column (white boxes) illustrates the biological responses that are stimulated or repressed (green and red arrows) by the actions of 1α,25(OH)2D3 that is produced from 25(OH)D3. The presence of infective pathogens are shown by brown circles. The actions of the toll-like receptors are summarized in Figure 2. TLR, toll-like receptor (black box); DC, dendritic cell; T-cell, T lymphocytes, Mø, macrophage, Treg, regulatory T cell; cyto T-cell, cytotoxic T-cell; Th1, T helper cells. Modified from M. Hewison, Rheum. Dis. Clin. North Am. 38:125 (2012).
Fig2. Activation of a monocyte’s or macrophage’s toll-like signaling receptors by infection by a pathogen like Mycobacterium tuberculosis; involvement of circulating 25(OH)D3, and local 1α,25(OH)2D3 and local VDR. For the innate immune system’s dendritic cells, the key players are toll-like receptors that are single, membrane-spanning receptors that recognize and bind as a ligand structurally conserved molecules only derived from invading microbes. This initiates signal transduction pathways that lead to the suppression or induction of genes that orchestrate the inflammatory response against the invading pathogen. In this figure, a genomic increase in the production of the mitochondrial 25(OH) D3-1α-hydroxylase results in an increased production of 1α,25(OH)2D3. This newly synthesized 1α,25(OH)2D3 binds to the VDR and stimulates the production of cathelicidins that are essential for killing the Mycobacterium tuberculosis pathogen cells. Grey circles, individual invading M. tuberculosis microbes; small grey circles, killed M. tuberculosis microbes; pink triangles, newly synthesized cathelicidin molecules; green circles, 25(OH)D3; red circles, 1α,25(OH)2D3; blue half-moon, 25-hydroxyvitamin D3-1α-hydroxylase; purple icon, the vitamin D receptor (VDR) for 1α,25(OH)2D3. Modified from M. Hewison, Rheum. Dis. Clin. North Am. 38 125 (2012).
It has become clear that 1α,25(OH)2D3 can function as an immune modulator by binding to the VDR that is expressed by several immune cells, including monocytes, macrophages, dendritic cells (DC), as well as B-lymphocytes and T-lymphocytes. Thus, 1α,25(OH)2D3 has been shown to be function ally active in both the innate and adaptive immune responses. Some immune cells express vitamin D-metabolizing enzymes, allowing local conversion of inactive vitamin D3 into inactive 25(OH)D3 and then into functionally active 1α,25(OH)2D3. Taken together, these data indicate that 1α,25(OH)2D3 plays a selective role, depending on the presence or absence of the VDR, in the maintenance of immune homeostasis.
