Mini Reviews in Medicinal Chemistry - Volume 15, Issue 11, 2015

During the last decades, vitamin D deficiency has re-emerged worldwide affecting not only population’s bone health, but also several other conditions including asthma and allergies. Increasing number of published epidemiological studies in the last seven years have examined the role of vitamin D deficiency in childhood in several outcomes including asthma diagnosis, asthma disease severity, allergic sensitization and atopy. This review presents evidence on this association from a systematic search in the literature of all available observational studies and their limitations. A total of 33 studies were identified: 3 prospective, 16 case-control and 14 cross-sectional studies. Overall, most of the case-control studies tend to report that asthmatics have lower vitamin D levels/status as compared to healthy children, although most of these studies are mainly descriptive in nature and tend to provide only crude, unadjusted comparisons. Studies that investigated the association of vitamin D with the prevalence, development and/or severity of asthma gave mixed findings, with the exception of studies that focused on vitamin D and severity of asthma which suggest a positive association of vitamin D levels with better asthma control, reduced use of asthma medication, fewer asthma exacerbations and lower utilisation of health care facilities for urgent treatment. Insufficient evidence also exists for the association of inadequate vitamin D status with higher risk of atopic sensitization. The lack of adequate number of prospective studies, the variable definitions for case ascertainment, the wide age range of the participants, and commonly the inadequate control for confounders make inferences difficult. Future studies are needed with a prospective design and repeated measurements of vitamin D to provide critical information on the timing and dosage of future vitamin D supplementation interventions.

Vitamin D has an indisputable immunodulatory role in both lung and immune system development, which is initiated during fetal life and is mainly accomplished in the first years of extrauterine life. Several published studies have shown that low levels of vitamin D may increase the risk of developing asthma and allergic diseases. Moreover, vitamin D deficiency epidemic reported over the last decades coincides with an increase in the prevalence of asthma and allergies in westernized societies. Since placental transfer of 25(OH)D is the major source of vitamin D in the developing fetus, important questions concerning the impact of maternal vitamin D status on the outcome of pregnancy have arisen. The aim of this review is to present the current evidence regarding the determinants of vitamin D status in pregnancy as well as its role in the development of asthma and allergies in early childhood.

Asthma and allergy are complex diseases influenced by poorly understood environmental and genetic factors. The innate and adaptive immune systems play an important role in the pathogenesis of these diseases. Many genes involved in inflammation and immunoregulation pathways have been related to asthma and allergy susceptibility. Among the diverse extra-skeletal actions of vitamin D, growing evidence indicates that vitamin D is an important modulator of the immune system response and may influence the development of asthma and allergy susceptibility through different mechanisms. The vitamin D pathway is under the control of a set of polymorphic genes that code for key enzymes which regulate the synthesis and metabolism of vitamin D (i.e. CYP27A1, GC, CYP27B1 and CYP24A1) and of genes that encode for downstream mediators of vitamin D signalling (i.e. VDR, RXR, PPAR, NCOA and SMAD). This metabolism gene pathway is of fundamental importance in regulating vitamin D availability and biological response. Unravelling the role of vitamin D metabolism genes on asthma and atopy susceptibility may help to understand the impact of vitamin D on the development of these disorders. This review article aims: 1) to describe the genetics of the vitamin D pathway, 2) to revise the potential mechanisms by which vitamin D pathway genes may affect the immune and respiratory systems predisposing to asthma and allergy disorders; and 3) to summarize the influence of genetic variation on vitamin D pathway genes on the development of asthma and allergy.

Atopic dermatitis is a chronic inflammatory skin disease that affects a high number of children worldwide. It is mainly caused by a disruption of the epidermal barrier and an abnormal immune response. Vitamin D might have some effects on the innate and adaptive immune system, generally in favour of decreasing allergenic mechanisms, as well as it might improve the skin barrier and decrease the risk of skin colonization. Thus, an increasing body of evidence links this vitamin to atopic dermatitis, although conclusions are not unanimous. Many observational studies have shown that low vitamin D serum levels are associated with a higher prevalence of this epidermal disease in childhood, but others have not. Differences in exposure time, vitamin D dose, age of participants, etc. could explain these conflicting results. Moreover, no study has been performed to date in order to determine whether variations in vitamin D levels at different ages differentially influence the risk of atopic dermatitis. A number of randomized controlled trials have tested the usefulness of systemic vitamin D as a treatment for this condition, but the results are also inconclusive. Nevertheless, topical vitamin D is not recommended because it can worsen skin lesions. Narrowband ultraviolet B is used to treat atopic dermatitis, although there is little evidence relating this type of phototherapy with variations of serum vitamin D levels or to what extent phototherapy benefits are mediated through vitamin D.

In recent years, low vitamin D status has been proposed as a putative risk factor for allergic diseases. A growing body of literature reports low vitamin D levels in atopic patients and supports an association between vitamin D deficiency and risk of adverse asthma and allergies outcomes. Therefore, it has been speculated that vitamin D supplementation may either prevent or reduce the risk of allergic diseases. Birth cohort studies addressing the role of vitamin D intake during pregnancy have shown conflicting results regarding allergy outcomes in offspring. Currently, only a few studies have tried to supplement vitamin D in asthmatic patients, often as an add-on therapy to standard asthma controller medications, and results are not all consistent. There is emerging data to show that vitamin D can enhance the antiinflammatory effects of glucocorticoids and potentially be used as adjuvant therapy in steroid-resistant asthma. Recent in vivo data suggest that vitamin D supplementation may also reduce the severity of atopic dermatitis. This review examines the existing relevant literature focusing on vitamin D supplementation in the treatment of allergic diseases.

Studies from several countries have reported an association between latitudes further from the equator and proxy markers of food allergy prevalence. As latitudes further from the equator are associated with lower sun exposure and vitamin D status (VDS), it has been proposed that low VDS may be a risk factor for food allergy. A range of basic science evidence supports the biological plausibility of this hypothesis; and recent work has identified a cross sectional association between low VDS and challenge proven food allergy in infants. Overall, however, the evidence regarding the relationship between VDS and food allergy remains controversial and the limited longitudinal data are discouraging. In this review we consider the evidence for and against low VDS as a risk factor for food allergy and discuss the possibility that other factors (including genetic variables) may contribute to the inconsistent nature of the available observational evidence. We then discuss whether genetic and/or environmental factors may modify the potential influence of VDS on food allergy risk. Finally, we argue that given the rising burden of food allergy, the balance of available evidence regarding the potential relevance of VDS to this phenomenon, and the inherent limitations of the existing observational data, there is a compelling case for conducting randomised clinical trials of vitamin D supplementation for the prevention of food allergy during early life.

More than thirty years ago functions of vitamin D other than its beneficial effects on calcium homeostasis and bone metabolism have been identified, mainly in relation to its antiproliferative effects on cancer cells. Notably, vitamin D deficiency has been associated with a number of pathological conditions, including infections, autoimmune and allergic diseases. Vitamin D, and its metabolites, are actively involved in the regulation of innate and adaptive immune responses. Vitamin D signals through the vitamin D receptor (VDR), a specific zinc-finger nuclear receptor. The functions of vitamin D are characterized as genomic, mediated through the VDR transcriptional effects inside the cell nucleus, and non-genomic, when the VDR induces rapid signaling, situated on the cell membrane and/or cytoplasm. Emerging evidence supports the notion that vitamin D enhances immunity, providing protection towards pathogens, while, concomitantly, it exerts immunosuppressive effects by preventing the detrimental effects of prolonged inflammatory responses to the host. Still, the precise molecular mechanisms involved in vitamin D’s genomic and non-genomic actions remain incompletely defined. Moreover, it is unclear whether vitamin D actions require the synergistic activation of other mediators, such as nuclear membrane receptors. Understanding the biology of vitamin D and the molecular pathways utilized will pave the way for the design of more effective therapeutic strategies. In this review, we present the recent genomic and non-genomic effects of vitamin D from an immunological perspective with a focus on immune-mediated diseases.