Vitamin D and Innate and Adaptive Immunity

Abstract

In the last 5 years there has been renewed interest in the health benefits of vitamin D. A central feature of this revival has been new information concerning the nonclassical effects of vitamin D. In particular, studies of the interaction between vitamin D and the immune system have highlighted the importance of localized conversion of precursor 25-hydroxyvitamin D (25OHD) to active 1,25-dihydroxyvitamin D (1,25(OH)₂D) as a mechanism for maintaining antibacterial activity in humans. The clinical relevance of this has been endorsed by increasing evidence of suboptimal 25OHD status in populations across the globe. Collectively these observations support the hypothesis that vitamin D insufficiency may lead to dysregulation of human immune responses and may therefore be an underlying cause of infectious disease and immune disorders. The current review describes the key mechanisms associated with vitamin D metabolism and signaling for both innate immune (antimicrobial activity and antigen presentation) and adaptive immune (T and B lymphocyte function) responses. These include coordinated actions of the vitamin D-activating enzyme, 1α-hydroxylase (CYP27B1), and the vitamin D receptor (VDR) in mediating intracrine and paracrine actions of vitamin D. Finally, the review will consider the role of immunomodulatory vitamin D in human health, with specific emphasis on infectious and autoimmune disease.

Introduction

In the last 5 years vitamin D has undergone a renaissance. A simple search of Pubmed from 2000 to 2005 identifies approximately 8000 entries for the term “vitamin D.” This is almost identical to the number of entries for “thyroid hormone” over the same period. A similar search for “vitamin D” over the years 2005–2010 shows 11,200 entries, a 40% increase on the previous 5 years. This contrasts with 9000 entries for “thyroid hormone,” a 12% increase over the previous 5 years. Two key factors have contributed to this. The first concerns our current view of what constitutes adequate vitamin D status. Until recently, the vitamin D status of an individual was defined simply by presence or absence of the bone disease rickets (osteomalacia in adults). Rachitic bone disease associated with vitamin D deficiency is relatively rare but it is now clear that suboptimal vitamin D status can occur in the absence of rachitic bone disease. This new perspective on vitamin D status arose from the observation that serum levels of the main circulating form of vitamin D (25OHD) as high as 75 nM correlate inversely with serum parathyroid hormone (PTH) concentrations (Chapuy et al., 1997). As a result, new terminology for suboptimal vitamin D status has been introduced. Vitamin D “insufficiency” now refers to serum levels of 25OHD that are suboptimal (< 75 nM) but not necessarily rachitic (< 20 nM; Holick, 2007). Circulating levels of 25OHD are a direct reflection of vitamin D status, which for any given individual will depend on access to vitamin D either through exposure to ultraviolet (UV) light and epidermal synthesis of vitamin D or as a result of dietary intake. Consequently vitamin D status can vary significantly in populations depending on geographical, social, or economic factors. Moreover, recent studies of populations in the USA suggest that in the last 10 years alone, serum vitamin D levels have on average fallen by approximately 20% (Ginde et al., 2009).

The key question now being considered is what is the physiological and clinical impact of global vitamin D insufficiency beyond classical bone diseases such as rickets? Part of the answer to this has been provided by the second recent development in vitamin D research. A potential role for vitamin D as a modulator of the immune system has been postulated for many years. Until recently, this was considered to simply be a manifestation of granulomatous diseases such as sarcoidosis, where synthesis of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)₂D) from precursor 25OHD is known to be dysregulated. However, in the last 5 years a wealth of in vitro, in vivo and clinical association studies have provided new evidence to support a role for 25OHD and 1,25(OH)₂D in mediating normal function of both the innate and adaptive immune systems. These new developments and the studies that preceded them are discussed in more detail in the following review with specific emphasis on different facets of the immune system.