Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity

Abstract

Vitamin D has received increased attention recently for its pleiotropic actions on many chronic diseases. The importance of vitamin D on the regulation of cells of the immune system has gained increased appreciation over the past decade with the discovery of the vitamin D receptor (VDR) and key vitamin D metabolizing enzymes expressed by cells of the immune system. Animal studies, early epidemiologic and clinical studies have supported a potential role for vitamin D in maintaining immune system balance. The hormonal form of vitamin D up-regulates anti-microbial peptides, namely cathelicidin, to enhance clearance of bacteria at various barrier sites and in immune cells. Vitamin D modulates the adaptive immune system by direct effects on T cell activation and on the phenotype and function of antigen-presenting cells (APCs), particularly of DCs. The purpose of this manuscript is to review the molecular and clinical evidence for vitamin D as a modulator of the innate and adaptive immune system.

Fig. 1

Proposed mechanism for vitamin D’s action on the innate immune system. Vitamin D is produced in the skin upon exposure to UVB radiation from the sun or obtained from vitamin D containing foods. Vitamin D is converted to its major circulating form, 25-hydroxyvitamin D (25(OH)D), by the liver 25-hydroxylase and to 1,25-dihydroxyvitamin D (1,25(OH)₂D) by the kidney 1-alpha-hydroxylase for optimal intestinal absorption of calcium in the classic vitamin D pathway. In the non-classic pathway of the immune system, the circulating 25(OH)D is taken up by macrophages, neutrophils or epithelial cells at locations exposed to the external environment. The 25(OH)D is converted to 1,25 (OH)₂D in the target cell to act as an autocrine hormone. The locally produced 1,25(OH)₂D binds to its nuclear receptor (VDR) and binds to the promoter of genes containing the vitamin D response element (VDRE). In neutrophils, macrophages and epithelial cells, this results in increased production of uncleaved cathelicidin (hCAP18 in humans) which undergoes further cleavage to the active cathelicidin (LL37 in humans) which results in killing of microorganisms. Of note, invading microorganisms that trigger specific toll-like receptors (in this example, TLR 2/1) result in increased production of the VDR and 1-alpha-hydroxylase which allows for vitamin D to enhance the production of cathelicidin only in the presence of adequate 25(OH)D substrate (adapted from Ref. [8])

Fig. 2

Proposed mechanism for vitamin D’s influence on the development and progression of autoimmunity. 1,25(OH)₂D regulates DC maturation and the differentiation and activity of CD4+ T cells to prevent the loss of self-tolerance. In a genetically predisposed individual, it is more likely that autoantibodies will develop and proliferate in the setting of vitamin D deficiency. Ultimately, deficiency of vitamin D may act as an environmental trigger of clinical disease. Left untreated, the cycle of vitamin D deficiency will continue as many autoimmune diseases and several medications used to treat them lead to sun avoidance from photosensitivity. The role of vitamin D status in the natural history of autoimmunity warrants further investigation