ReviewThe paradoxical effects of vitamin D on type 1 mediated immunity☆
Introduction
The classical role of vitamin D is in the regulation of calcium homeostasis. Recently it has become clear that vitamin D regulates immune function. In particular, poor vitamin D status has been linked to the development of a number of different type 1 (Th1) mediated autoimmune diseases including type 1 diabetes, multiple sclerosis (MS), and inflammatory bowel diseases (IBD) (Cantorna and Mahon, 2004). In addition the active form of vitamin D (1,25(OH)2D3) has been shown to completely block the development of experimental models of these autoimmune diseases (Cantorna et al., 1996, Cantorna et al., 2000, Zella et al., 2003). Th1 mediated immunity is critical for the ability of the host to mount a protective immune response to many different infections. Paradoxically, 1,25(OH)2D3 treatments did not compromise the ability of infected mice to fight a fungal infection that depends on Th1 mediated immunity (Cantorna et al., 1998a, Cantorna et al., 1998b, Kaposzta et al., 1998). Furthermore, vitamin D status and 1,25(OH)2D3 have been suggested to be protective against tuberculosis (TB) where host immunity depends on Th1 production of the cytokine IFN-γ. Clouding the picture further is the evidence that patients with Th1 driven diseases like IBD (Crohn’s disease), sarcoidosis and tuberculosis show hypercalcemia and calcification of granulomatous lesions and suggest that the local immune response may produce 1,25(OH)2D3 (Yang et al., 2000, Tuohy and Steinman, 2005, Volpicelli et al., 2005, Falk et al., 2007). How can 1,25(OH)2D3 selectively regulate the immune system to suppress autoimmune disease without compromising the host’s ability to fight infection? Furthermore, is the local production of 1,25(OH)2D3 in granulomatous lesions protective or pathogenic? The effects of vitamin D, 1,25(OH)2D3 and vitamin D metabolism on the susceptibility and resistance to Th1 driven immune responses will be discussed in order to clarify the seemingly paradoxical effects of vitamin D.
Section snippets
Vitamin D and the hygiene hypothesis
The incidence of immune mediated diseases like IBD, MS, allergies and asthma have all increased in developed countries over the last 50 years. This rapid increase in disease incidence cannot be explained genetically. In addition, the concordance rate between identical twins is only between 20% to 50% for IBD and MS (Cantorna, 2006). Therefore, environmental factors impact the development of autoimmunity. The prevailing theory about the environmental cause of the increase in immune mediated
Autoimmunity, IBD and Th1 driven immune responses
The etiology of autoimmune diseases and asthma are very different and cells that are pathogenic for one disease are beneficial for the other. For most forms of autoimmunity the immune response is characterized by overproduction of Th1 associated cytokines including interferon (IFN)-γ and tumor necrosis factor (TNF)-α (Fig. 1). Th1 mediated immune responses are induced when a combination of circumstances occur. Antigen specific T cells that are primed in the presence of interleukin (IL)-12 and
Vitamin D and the immune system
The identification of the vitamin D receptor (VDR) in peripheral blood mononuclear cells sparked the early interest in vitamin D as an immune system regulator (Bhalla et al., 1983, Provvedini et al., 1983). All cells of the immune system that have been evaluated express the VDR and at least in T cells activation induces the expression of additional VDR (Veldman et al., 2000, Mahon et al., 2003). 1,25(OH)2D3 is a potent in vivo suppressor of experimental autoimmune diseases such as arthritis,
Vitamin D and Th1 mediated host immunity to infection
Th1 mediated immune responses and especially the ability to produce IFN-γ is important for host immunity to a number of infectious diseases. In particular, immunity to intracellular pathogens including many viruses, bacteria such as Mycobacteria and Listeria species and parasites like Leishmania require IFN-γ as part of the host response for successful clearance. Regulatory cell induction and IL-10 production are associated with prolonged infections and chronicity with these same organisms (
Extra-renal production of the 1 alpha hydroxylase
Cyp27B1 is the gene encoding the 1 alpha hydroxylase that produces active 1,25(OH)2D3 and is expressed classically in the kidneys. Extra-renal production of Cyp27B1 has been implicated to occur in a number of inflammatory conditions including sarcoidosis, and Crohn’s disease and may explain hypercalcemia that occurs in these patients (Conron et al., 2000, Abreu et al., 2004). Other granulomatous diseases including TB are associated with disordered vitamin D metabolism and hypercalcemia (Yang et
Conclusions
The effects of vitamin D on immunity are beginning to be appreciated. Regardless of whether Th1 mediated autoimmunity or infectious immunity is being monitored, 1,25(OH)2D3 inhibits IL-12 and IFN-γ production. Induction of regulatory T cells by 1,25(OH)2D3 is an additional mode for inhibition of immune responsiveness. In addition, regulatory NKT cells depend on vitamin D for development and are upregulated by 1,25(OH)2D3. For L. monocytogenes and L. major 1,25(OH)2D3 suppression of the Th1
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Grant support: This work was supported by National Institutes of Health Grant #R01 DK070781 to MTC.