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Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity

Abstract

Knowledge about the ability of vitamin D to function outside its established role in skeletal homeostasis is not a new phenomenon. Nonclassical immunomodulatory and antiproliferative responses triggered by active 1,25-dihydroxyvitamin D were first reported more than a quarter of a century ago. It is only in recent years, however, that there has been a significant improvement in our understanding of how these nonclassical effects of vitamin D can influence the pathophysiology and possible prevention of human disease. Three particular strands of evidence have been prominent: firstly, population studies have revised our interpretation of normal vitamin D status in humans, suggesting, in turn, that vitamin D insufficiency is a clinical problem of global proportions; secondly, epidemiology has linked vitamin D status with disease susceptibility and/or mortality; and, thirdly, expression of the machinery required to synthesize 1,25-dihydroxyvitamin D in normal human tissue seems to be much more widespread than originally thought. Collectively, these observations suggest that nonclassical metabolism and response to vitamin D might have a significant role in human physiology beyond skeletal and calcium homeostasis. Specific examples of this will be detailed in the current Review, with particular emphasis on the immunomodulatory properties of vitamin D.

Key Points

  • Nonclassical effects of vitamin D have been recognized for many years, but it is only recently that these have been accepted as a potentially significant component of vitamin D physiology

  • Immune cells such as macrophages contain all of the machinery required to synthesize and respond to active vitamin D, 1,25-dihydroxyvitamin D, and these functions are enhanced by challenge to the immune system

  • 1,25-Dihydroxyvitamin D stimulates innate (macrophage) immunity by enhancing bacterial killing but it also modulates adaptive (lymphocyte) immunity to minimize inflammation and autoimmune disease

  • Vitamin D insufficiency is now a global health issue—even in developed countries

  • Vitamin D insufficiency is associated with compromised immunity, leading to increased infectious diseases such as tuberculosis, and increased susceptibility to autoimmune diseases such as type 1 diabetes

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Figure 1: Vitamin D and innate immunity.
Figure 2: Vitamin D, antigen presentation and adaptive immunity.

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Adams, J., Hewison, M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Rev Endocrinol 4, 80–90 (2008). https://doi.org/10.1038/ncpendmet0716

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