An Update on Vitamin D and Human Immunity

Martin Hewison


Clin Endocrinol. 2012;76(3):315-325. 

In This Article

Abstract and Introduction


In the last 5 years, there has been a remarkable change in our understanding of the health benefits of vitamin D. The classical actions of vitamin D as a determinant of mineral metabolism and rachitic bone disease have been expanded to include a broader role in skeletal homoeostasis and prevalent bone disorders such as osteoporosis. However, it is the nonskeletal function of vitamin D that has attracted most attention. Although pluripotent responses to vitamin D have been recognized for many years, our new perspective on nonclassical vitamin D function stems from two more recent concepts. The first is that impaired, vitamin D status is common to many populations across the globe. This has prompted studies to explore the health impact of suboptimal circulating levels of vitamin D, with association studies linking vitamin D 'insufficiency' to several chronic health problems including autoimmune and cardiovascular disease, hypertension and common cancers. In support of a broader role for vitamin D in human health, studies in vitro and using animal models have highlighted immunomodulatory and anticancer effects of vitamin D that appear to depend on localized activation of vitamin D. The conclusion from these reports is that many nonclassical actions of vitamin D are independent of conventional vitamin D endocrinology and are therefore more sensitive to variations in vitamin D status. The current review summarizes these developments, with specific reference to the newly identified effects of vitamin D on the immune system, but also highlights the challenges in translating these observations to clinical practice.


At the end of 2010, the Institute of Medicine (IOM), an independent, nonprofit, nongovernment organization, based in the USA published the findings of a lengthy study to define the references values that best represent the levels of vitamin D and calcium that are optimal for human health.[1] The select panel of scientists and clinicians that made up this IOM committee was faced with several challenges, not the least because the physiology and nutrition of vitamin D and calcium has for many years been intertwined. An additional challenge to any appraisal of vitamin D nutrition is the terminology that defines the various metabolites contributing to vitamin D physiology. The term 'vitamin D' specifically refers to the parental vitamin D produced endogenously by the action of sunlight on 7-dehydrocholesterol in skin (also known as vitamin D3, or cholecalciferol), or obtained from dietary foodstuffs as either vitamin D3 or vegetable vitamin D2 (also known as ergocalciferol). Vitamin D derived from sunlight or diet undergoes metabolism, firstly to 25-hydroxyvitamin D (25OHD) that is the main circulating form of vitamin D used to define 'vitamin D status'. At physiological concentrations, 25OHD appears to be inactive as a signalling molecule. Consequently, the target cell function of vitamin D is determined by conversion of 25OHD to active 1,25-dihydroxyvitamin D [1,25(OH)2D], which is catalysed by the vitamin D-activating enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1). The 1,25(OH)2D produced in this manner then functions as a steroid hormone by binding to the nuclear vitamin D receptor (VDR) and acting as a regulator of gene transcription.[2]

In the section of the IOM report that focuses specifically on vitamin D, the committee addressed four principal issues: (i) the health outcomes that are associated with vitamin D and its principal metabolites – pro-hormone 25OHD and active 1,25(OH)2D; (ii) the circulating level of vitamin D (or more precisely the serum concentration of 25OHD) that is optimal for these health outcomes; (iii) the daily intake of vitamin D required to achieve and maintain optimal vitamin D (25OHD) status; (iv) the likelihood of adverse side-effects from vitamin D supplementation. The report concluded that classical effects on skeletal homoeostasis remained the most clinically robust health outcome associated with vitamin D.[1] Based on this, the IOM suggested that a serum level of 50 nM (20 ng/ml) 25OHD was sufficient to optimize bone mineral density (BMD) as a marker of skeletal health for most populations in the United States and Canada. However, the IOM did acknowledge that people with darker skin pigmentation (for whom UV-light induction of epidermal vitamin D production is less efficient) and those living at more Northerly latitudes may find it harder to meet this target level. This may be particularly relevant to populations in Northern Europe, where several countries are further North than many Canadian cities. To achieve the 50 nM target level of circulating 25OHD, the IOM recommended a modest increase in the recommended daily allowance for supplemental vitamin D to 600 IU/day. They also stated that although no adverse side-effects had been reported for doses of supplemental vitamin D up to 10 000 IU/day, a safe upper limit of 4000 IU/day was preferable. The IOM also pointed out that although clinical trials data did not currently support nonskeletal actions of vitamin D as a robust health outcome, there was nevertheless sufficient evidence to support more detailed studies in future.

The report was endorsed by many organizations such as the American Society for Bone and Mineral Research, and the cautious recommendations of the IOM have been supported in other reports.[3,4] However, the support for the IOM proposals was not universal, and the report received a more hostile reception from many researchers in the world of vitamin D.[5–8] A key underlying cause of this dichotomy of opinion was the remarkable increase of data highlighting nonclassical effects of 25OHD and 1,25(OH)2D, and the health consequences this may have in humans with impaired vitamin D status. The remainder of this review will consider some of the reports that have contributed to this new perspective on vitamin D and physiology, how this relates to the IOM's report, and the future challenges that need to be addressed to better define the role of vitamin D in human health. This now includes a role for vitamin D in prevention and treatment of common cancers,[9,10] hypertension and cardiovascular disease[11,12] and brain development.[13] As the function of vitamin D in each of these areas of human health is a subject in its own right, the current review will focus specifically on another prominent nonclassical action of vitamin D – namely its role as an immunomodulator.


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