The Journal of Steroid Biochemistry and Molecular Biology
ReviewRegulatory T cells, inflammation and the allergic response—The role of glucocorticoids and Vitamin D☆
Section snippets
Allergy and asthma: disease prevalence
The prevalence of allergic and asthmatic disease has increased dramatically over the past few decades. The prevalence of asthma is currently estimated at 300 million people worldwide with countries including the United Kingdom, Australia and New Zealand reporting prevalence of up to 20% [1], [2]. This rise can be demonstrated across the spectrum of allergic disease, with an increase in diseases such as allergic rhinoconjunctivitis causing significant morbidity [3], [4]. Whilst there is a strong
Immune mechanisms of allergic disease
Allergic sensitization has historically been associated with the development of allergen-specific Th2 responses and IgE production. IgE binds to the high affinity IgE receptor (FCɛRI) present on mast cells. Subsequent challenge with allergen results in cross linking of IgE on the mast cell surface, activation and rapid degranulation of the mast cells, with the release of pre-formed mediators including cysteinyl leukotrienes and histamine [5], [6]. The late phase response is denoted by an influx
Regulatory T cells (TRegs)
A number of different regulatory T cell (TReg) populations have been described although the best understood to date are CD4+ TReg. A major CD4+ TReg population are those deriving from the thymus, which constitute a small percentage of the CD4+ T cell population in humans in the periphery [10]. They are often termed “naturally occurring TReg” and are characterized by the expression of the forkhead winged transcription factor FoxP3 (forkhead box P3), which is constitutively expressed by these
TReg function in allergy and asthma
Evidence that TReg function is impaired in allergic and asthmatic disease has been extensively reviewed elsewhere [43], [44]. This is however best highlighted by studies of a mutation of the FoxP3 gene in humans that leads to the loss of this naturally occurring TReg compartment, and a disorder known as immune dysregulation polyendocrinopathy X-linked (IPEX). IPEX is characterized not only by autoimmunity but also severe atopy, manifested as food allergies, atopic dermatitis, hyper-IgE and
Current therapies for asthma and allergic disease
At present the mainstay of therapy for allergic disease are anti-histamines and glucocorticoids. In asthma, glucocorticoid therapy is generally used in combination with other anti-inflammatory or reliever medications such as beta-agonists [55]. These treatments ameliorate disease but they are not curative. Allergen immunotherapy, the injection of patients with gradually increasing quantities of the allergen to which they are sensitized in order to induce tolerance, is done under carefully
Vitamin D physiology
The role of Vitamin D and its metabolites in bone and calcium metabolism is well established and there is increasing awareness of its importance in immune regulation [70], [71]. Bioavailability of Vitamin D in the body is greatly influenced by exposure of the skin to sunlight with maximum synthesis achieved when UVB reacts with 7-dihydrocholesterol in the skin at wavelengths of 295 nm. Very little Vitamin D is produced in areas at beyond a latitude of 35° from October to March. Synthesis is
Vitamin D epidemiology
The modern lifestyle, which involves working indoors or the use of protective clothing and sunscreen explains why more and more studies emerge reporting hypovitaminosis D in widespread areas of the world including temperate climates [71], [73], [74], [75], [76], [77], [78]. Serum levels of 25-hydroxyvitamin D3 as low as 25 nmol/L (10 ng/mL) will prevent rickets in children but it is now widely acknowledged that much higher levels, from 75 to 100 nmol/L (30–40 ng/mL) are required for multiple health
Immunological effects of Vitamin D
1α-Hydroxylation of 25-hydroxyvitamin D3 occurs at extrarenal sites such as the brain, breast, colon, prostate and cells of the immune system at sites of inflammation, allowing local synthesis of calcitriol (subject to availability of 25-hydroxyvitamin D3 substrate), which can modulate immune responses in a paracrine fashion [72]. Calcitriol binds to the nuclear Vitamin D receptor (VDR), which is found in many cell types including immune cells such as monocytes, macrophages, dendritic cells and
Summary and future perspectives
A number of studies, both epidemiological and immunological, are converging to suggest a role for Vitamin D in promoting peripheral tolerance through the inhibition of inflammation, and the induction or maintenance of regulatory T cell populations, both IL-10+ and/or Foxp3+. In the context of infection, in particular respiratory infections, studies have highlighted a role for the Vitamin D pathway in the induction of antimicrobial mechanisms. A model is therefore emerging whereby Vitamin D
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Article from the special issue on Steroids: modulators of inflammation and immunity.
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Joint first authorship.