Review
Regulatory T cells, inflammation and the allergic response—The role of glucocorticoids and Vitamin D

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Abstract

Regulatory T cells (TRegs) play a central role in the maintenance of peripheral tolerance. They prevent inappropriate immune responses to ubiquitous allergens in healthy individuals, and contribute to the maintenance of immune homeostasis in the airways. Both Foxp3+ and IL-10+ TReg have been implicated in these functions. Glucocorticoids represent the mainstay of treatment for asthma and other allergic conditions, and evidence that steroids influence TReg function will be reviewed. Growing bodies of epidemiological and immunological data suggest a role for endogenous Vitamin D in immune regulation. This review will discuss the role of glucocorticoids and Vitamin D, and their potential interactions in promoting tolerance in the context of allergic disease and asthma.

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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