vitamin d is a hormone with multiple physiological actions , many effects of which have been found to occur outside its classical role in calcium homeostasis .
we now know that vitamin d receptors ( vdrs ) are expressed in many cell types , including various immune cells , suggesting the role of vitamin d on immune system .
these recent findings have increased interest in vitamin d status and its link to several nonskeletal diseases .
the main source of vitamin d in humans is solar uv - b ( 290315  nm wavelengths ) radiation , which influences the formation of previtamin d in the skin ( cholecalciferol ) .
cholecalciferol from the skin or derived from nutrition is metabolized in the liver to 25-hydroxyvitamin d ( 25-oh - d ) .
this is the major circulating form ; thus it is usually used to measure serum vitamin d levels .
25-oh - d is then transported to the kidneys where it is metabolized to its active form calcitriol ( 1,25(oh)d,1,25-dihydroxyvitamin d ) ( figure 1 ) [ 2 , 3 ] . although thresholds of serum 25(oh)d are still debated , guidelines from the institute of medicine ( iom ) for bone health define  vitamin d deficiency  as serum 25(oh)d levels below 30  nmol / l ( < 12  ng / ml ) , while sufficient vitamin d levels should be considered serum levels of at least 50  nmol / l ( 20  ng / ml ) . due to evidence of vitamin d insufficiency on allergic disease prevalence , many researchers categorized vitamin d sufficiency as > 75  nmol / l ( 30  ng / ml ) . since 1999 , when wjst and dold were the first scientists to hypothesize a link between vitamin d and allergic diseases , two conflicting hypotheses are raised .
the first hypothesis tries to correlate high serum vitamin d levels with the rise in prevalence of allergies and asthma .
the authors suggest that the geographic trend of higher disease prevalence in more developed countries runs in parallel with vitamin d exposure .
the first study that investigated this possible connection was a birth cohort study conducted in finland .
the authors found that higher risk for atopy , allergic rhinitis , and asthma was associated with increase in vitamin d supplementation for newborns in order to prevent infantile rickets .
a second hypothesis developed later suggested that vitamin d deficiency may contribute to the recent increase in allergies in western countries [ 7 , 8 ] .
there is an increasing body of evidence to support the hypothesis that this widespread vitamin d deficiency correlates with atopy , asthma , and food allergy [ 812 ] .
prevalence of hypovitaminosis d varies among different countries and among different population groups within a given country and for each population over time . in many industrialized countries , up to 50% of the population
has insufficient vitamin d . based on one study , vitamin d insufficiency in the united states increased from 55% to 77% between data collection ranges of 19881994 to 20012004 .
there is a combination of different factors which determine 25(oh)d serum levels and vitamin d deficiency like skin pigmentation , low sun exposure , more time spent indoors , obesity , higher latitudes , and winter season [ 13 , 14 ] .
other secondary causes that could affect vitamin d serum levels are diseases including rheumatoid arthritis , cystic fibrosis , ulcerative colitis , crohn 's disease , celiac disease , rickets , and medications . in this review , we outline the basic metabolism of vitamin d and its effects on the immune system . in addition
, we discuss recent findings regarding vitamin d status and its relation to allergy , specifically throughout europe and mediterranean countries .
we also considered the effects of vitamin d supplementation in allergic disease , highlighting the recent recommendations .
there is plenty of evidence to show that vitamin d has significant effects on both of them .
its immunomodulatory role has been recognized recently with the discovery of vitamin d receptor ( vdr ) and the hydroxylation of 25(oh)d on distinct cell types .
vdrs have been identified in many tissues and cells in the human body , including nearly all cells of the immune system ( t cells , b cells , neutrophils , macrophages , and dendritic cells ) .
vitamin d inhibits the expression of tlr ( toll - like receptor ) on monocytes , inhibits proinflammatory cytokine production , and induces antimicrobial peptide synthesis [ 17 , 18 ] .
vitamin d also impacts the adaptive immune system , specially affecting t - cell activation and antigen - presenting cells function . in recent studies ,
vitamin d is associated with reduction of th1 cytokine secretion and inhibition of t cells proliferation .
the association of vitamin d and th2 cells is less clear and contradictory , with report of both increased and decreased expression of the th-2 cytokines il-4 , il-5 , and il-10 in adult peripheral blood cell cultures [ 19 , 20 ] . in conclusion , it seems that vitamin d has a key role in th1-th2 balance , which could be relevant in allergic disease .
vitamin d deficiency has been blamed as a cause of increased incidence of asthma and allergy symptoms . in a study conducted by hollams et al . in australia ,
this study showed that vitamin d levels at ages 6 and 14 years were predictive of allergy / asthma outcomes at both ages , but more importantly , vitamin d levels at age 6 years were predictive of subsequent atopy and asthma - associated phenotypes at age 14 years .
this is the first study which demonstrates the association between vitamin d and asthma in older children , comparing with the early - life birth cohort studies .
in addition to the relationship between vitamin d status and asthma , there is considerable interest in assessing whether this vitamin protects against or reduces asthma morbidity .
it is now well known that there is a significant association between vitamin d deficiency and infections .
 a recent clinical trial showed that vitamin d supplementation ( 500  iu / day ) given as adjuvant therapy to inhaled corticosteroids in children with asthma reduced the risk of asthma exacerbation triggered by respiratory tract infections .
other researchers in costa rica studied vitamin d levels in children with asthma and demonstrated that lower vitamin d levels were associated with increased airway responsiveness , higher eosinophilic counts and total ige levels , and increased risk of severe asthma exacerbations .
this finding suggests that sufficient vitamin d levels may help to control infections and reduce inflammatory responses , resulting in viral infections causing less severe symptoms .
the same authors conducted a longitudinal study based on childhood asthma management program and showed that the group with the lower risk of exacerbations was the group with 25(oh)d  30  ng / ml and who were receiving inhaled corticosteroids .
the hypothesis that vitamin d supplementation might potentiate the anti - inflammatory function of corticosteroids is intriguing because glucocorticoid resistance is an important obstacle to effective treatment in some patients with asthma . searing et al . in their study of asthmatic children demonstrated a significant association between lower vitamin d levels and greater use of inhaled or oral corticosteroids and total steroid dose .
demonstrated the same association in vitro by using cell cultures obtained from steroid sensitive and steroid - resistant asthmatic subjects .
adding vitamin d to cd4 + t - cell cultures from steroid - resistant patients enhances the response to dexamethasone by inducing the production of il-10 .
furthermore , they showed that oral administration of vitamin d in severe asthmatics inverted steroid resistance through induction of il-10-secreting tregs ( regulatory t - cells ) .
these observations , together with clinical and experimental studies , justify the use of vitamin d in the treatment of severe asthma , particularly to enhance action of steroids .
another aspect involved in the relationship between vitamin d deficiency and asthma relates to lung function impairment .
consistent with the role of vitamin d on enhancing steroid responsiveness , several studies of children and adults have shown that a low vitamin d level is associated with impaired lung function .
children with insufficient vitamin d levels were found to have a slightly lower mean fev1 than children with sufficient vitamin levels .
other studies in adults show a strong relationship between serum concentrations of vitamin d , forced expiratory volume in 1 second ( fev1 ) , and forced vital capacity , where decreasing pulmonary function is associated with vitamin d deficiency [ 26 , 28 ] .
it has been found that different gene polymorphisms of the vitamin d receptor ( vdr ) and vitamin d binding protein ( vdbp ) have variable associations with asthma .
together with different serum levels of vitamin d , also vdr and vdbp variants seem to represent a risk factor for asthma .
the vitamin d receptor is present in bronchial smooth muscle cells which are associated with active protein synthesis .
it has been demonstrated that vitamin d inhibits bronchial smooth muscle proliferation induced by platelet - derived growth factor and it also influences the microarray gene expression signature in bronchial smooth muscle cells [ 3032 ] .
this finding suggests a role of vitamin d in cell growth and survival and morphogenesis and airway remodeling , which may be important in asthma pathophysiology and treatment .
of the different allergic disorders , perhaps asthma has been the most closely examined in the context of vitamin d. although the underlying mechanisms of how vitamin d modulates the pathogenesis of asthma have not been completely understood , the available data suggest an association between vitamin d deficiency and asthma . on the other hand , there is insufficient and weak evidence for an association between vitamin d status and atopic disease other than asthma . in a cross - sectional study ,
hyppnen et al . showed a u - shaped relation between serum vitamin d and total ige in adults , at 45 years of age .
thus , ige concentrations were higher for participants with low ( < 25  nmol / l ) and with very high vitamin d serum levels ( > 135  nmol / l ) compared with a reference group ( 100125 
nmol / l ) . correcting serum concentrations of 25(oh)d to physiological levels reduced the ige level significantly , further supporting an allergy - protective role for vitamin d in adults . following patients with chronic rhinosinusitis ( crs ) ,
current clinical studies have shown that crs patients had serum vitamin d levels 4050% lower than the serum levels in the control group [ 34 , 35 ] . in a study performed in iran ,
vitamin d levels were assessed in 50 patients with allergic rhinitis and the study results were compared with vitamin d status in normal population .
the prevalence of severe vitamin d deficiency was higher in patients with allergic rhinitis than in normal population , 30% and 5.1% , respectively .
the relationship between vitamin d status and asthma has been the subject of several studies in the last decade . as mentioned in the introduction
according to isaac phase three ( 19992004 ) prevalence of asthma symptoms in children aged 6 - 7 years and 13 - 14 years was , respectively , from < 5% to 14.5% and < 5% to 11.2% for the east europe and for west europe 5.4%20.9% and 4.1%27.8% , respectively . on the other hand , the prevalence of allergic rhinoconjunctivitis symptoms in children aged 6 - 7 years and 13 - 14 years was < 5%7.1% and 5%19.3% for each group , respectively , at east europe and 6.2%11.1% and 7.1%22.2% at west europe .
in addition , a similar north - south gradient has been observed in europe for atopic diseases , with countries like albania and greece presenting the lowest prevalence .
this remarkable variation suggests that environmental factors play an important role in the pathogenesis of allergic diseases .
factors like geographical latitude and mediterranean diet with fresh fruits , vegetables , and nuts are protective factors which may determine the beneficial role of vitamin d in our region .
there has been growing interest in the influence of maternal vitamin d intake during pregnancy on the development of allergic diseases in children .
as the insufficiency of this vitamin is high in pregnant woman several studies tried to examine the associations between a mother 's vitamin d intake and the allergy risk in her child .
et al . conducted a birth cohort study and in early 2006 they published results of their 2- and 3-year follow - ups .
the authors reported that higher maternal intake of vitamin d was associated with a lower incidence of wheeze in the child .
for each 2.5  g / day ( 100  iu ) incremental increase in vitamin d intake the authors found a 10% decrease in risk of wheeze [ 8 , 37 ] .
a similar inverse association was also reported by other cohort studies [ 38 , 39 ] .
in addition erkkola et al . found similar association between maternal intake of vitamin d and risk of developing asthma and allergic rhinitis in 5-year- old children .
all of these studies did not measure vitamin d directly but looked at maternal vitamin d intake , mostly from supplements . during pregnancy the fetus is exposed to vitamin d through cord blood supply and the ability of 25(oh)d to cross the placenta . in a recent study camargo jr .
et al . measured cord blood 25(oh)d and found an inverse association with the risk of respiratory infections and childhood wheezing , but not with incident asthma .
vitamin d deficiency is very common in pregnant women globally , but until now very little information is available on the impact of this deficiency on neonatal immune function and future risk of allergic disease .
the prevalence of vitamin d deficiency among pregnant women was found to be 21.2% in uk , 44.6% in belgium , and 83.6% in china [ 4042 ] . on a molecular level , maternal vitamin d intake during pregnancy increases the mrna levels of the immunoglobulin - like transcripts ilt3 and ilt4 in umbilical cord blood . as these receptors are critical for the generation of t suppressor cells , this finding may point towards an early induction of immunological tolerance by maternal vitamin d intake in the developing child
. future studies with longitudinal cohorts are needed to light on the vitamin d hypothesis in fetal life . a randomized trial supported by the us nih
has already started on vitamin d supplementation in pregnant women ( 4000  iu / day ) and onset of asthma in their children ; the results will be available by june 2014 .
still , high vitamin d intake during pregnancy might also be harmful with respect to allergic disease development : children whose mothers had a 25(oh)d concentration during pregnancy greater than 75  nmol / l had an increased risk of atopic eczema on examination at 9 months and asthma at the age of 9 years compared with children whose mothers had a concentration of < 30  nmol / l .
future research should differentiate oral intake from endogenous contributions to 25(oh)d status in order to explain the immunological effects of each .
while the incidence of asthma appears to have reached a plateau in some developed nations , many of these regions are now facing a  second wave  of the allergy epidemic , which , according to jones et al . , appears to be the rising incidence of food allergy . based on epidemiological data , the recent increase in food allergen
factors like obesity and race , which are risk factors for vitamin d deficiency , are associated with food allergy .
although the precise biological mechanism for these epidemiologic associations is not yet known , there are hypotheses that this hormonal deficiency contributes to food allergy risk .
several studies have described higher rates of food allergy among children born in seasons of low uv - b intensity ( autumn / winter ) , associated with lower vitamin d levels [ 45 , 46 ] .
other authors reported a negative association of maternal vitamin d intake during pregnancy with the risk of food allergen sensitization in early childhood .
accordingly , vitamin d deficiency might contribute to early - life sensitization by further compromising the immaturity of the infant immune system .
multiple - hit  model in which vitamin d deficiency , in addition to compromising immune tolerance , increases susceptibility to infections and alters microbial ecology at the gastrointestinal tract , contributing to abnormal intestinal barrier permeability .
these factors might synergistically promote maladaptive allergic responses to food antigens , which manifest as food allergy in genetically susceptible subjects .
the authors suggest that correction of vitamin d deficiency during pregnancy and childhood might promote immunologic tolerance , suppress proallergic immune responses , improve mucosal defenses , optimize microbial flora , and thereby limit food allergy epidemic in children .
as mentioned previously humans acquire most of their vitamin d through sun exposure and about 10% via ingested food .
vitamin d is absorbed through the gut as either vitamin d2 ( ergocalciferol ) or vitamin d3 ( cholecalciferol ) .
natural sources of vitamin d include a few foods such as fatty fish ( e.g. , salmon , eel , and sardine ) , fish liver , or cod liver oil .
animal foods such as fatty fish , liver , fish liver oils , cheese , and egg yolks contain vitamin d3 . in some industrial countries ,
other sources of vitamin d are fortified foods ( most often milk , margarine and/or butter , and breakfast cereals ) and dietary supplements . according to european food safety authority ( efsa ) ,
mean intake of vitamin d in european countries varies according to sex , age , and supplementation habits . in adults ,
mean intake of vitamin d from foods varied from 1.1  g / day in spain to 8.2  g / day in finland .
the range of vitamin d intake reported from 14 european countries is considerable . in high consumers ( 95th percentile ) ,
intake from foods is up to 16  g / day and about 1.5-fold this value in those that consume supplements in addition to foods . for infants ,
mean intake from foods and supplements was available from finland ( 8.9  g / day ) and the netherlands ( 12.5  g / day ) . in children
15 years , mean intake from foods varied from 1.7  g / day , in denmark , to 5.6  g / day , in greece
. in older children , mean or median intake from foods only varied from 1.4  g / day in spain and ireland to 2.7  g / day in the netherlands .
the main factors which determine 25(oh)d serum levels are skin pigmentation , sun exposure , age , gender , latitude of residence , winter season , dietary habits , and dietary vitamin d fortification .
below latitude of approximately 35 north , uv - b radiation is sufficient for vitamin d3 synthesis all year round . at higher latitudes
many countries recommend the intake of supplements with vitamin d usually containing 525  g ( 2001000  iu ) cholecalciferol or ergocalciferol .
cholecalciferol is more effective than ergocalciferol in elevating total 25(oh)d concentrations and maintaining those levels for a longer time .
currently , efsa proposed a daily intake of 100  g ( equal to 400  iu ) vitamin d for adults including pregnant and lactating women .
vitamin d intake in children and adolescents was adapted to 100  g / day for ages of 1117 years , considering the phases of rapid bone formation and growth in this age group . for children aged 110 years , the upper limit dose of 50  g / day was suggested , taking into account their smaller body size . for infants , the upper limit dose of 25  g / day was recommended . in the uk ,
elderly people ( > 65 years ) are recommended to take 10  g ( 400  iu ) of vitamin d as a supplemental dose .
the nordic dietary vitamin d recommendation for children of 3 years to adults of 60 years is 7.5  g / day ( 300  iu ) vitamin d. infants younger than 3 years and adults over 65 years old are recommended to take 10  g / day ( 400  iu ) .
the institute of medicine 's committee ( iom ) in the new 2011 report on dietary requirements for vitamin d concludes that dietary reference intake for this nutrient can only be established according to bone health outcomes .
the report estimated that children over 1-year old need at least 600  iu of vitamin d a day , with a maximum upper limit of 2500  iu for children aged 13 years , 3000 iu for children from 4- to 8-year old , and 4000  iu / day for children aged 9 or more years old . according to extraskeletal outcomes ( e.g. , respiratory health )
clinical trial results are needed to make definitive recommendations about the optimal dose of vitamin d for immune system functioning , for asthma prevention , and for the use of vitamin d with inhaled corticosteroids to prevent steroid resistance .
several trials are under way for asthma prevention ( clinicaltrials.gov , identifiers nct00920621 and nct00856947 ) , for steroid efficacy ( nct01248065 ) , or for prevention of exacerbations ( nct00978315 ) .
in recent years , many studies have been published on the effects of vitamin d and its role in various diseases .
furthermore , several studies have sought to determine the effect that vitamin d has on the immune system and specifically allergic diseases .
it is worth noting that different in vivo and in vitro human studies have shown effects of vitamin d on allergy , asthma , lung function , airway responsiveness , and bronchodilator response .
it seems that this hormone might lead to an innovative treatment of these increasingly common conditions .
an essential issue for any vitamin d intervention concerns its dosage . the currently recommended levels of circulating serum 25(oh)d are thought to be the minimum needed for bone health , but the optimal levels for immune system function , prevention of atopy , and defense against respiratory infections are still not known .
it seems that maternal supplementation during pregnancy may prevent asthma and allergy and vitamin d supplementation after birth will also probably be necessary to maintain normal immune function in the long term .
the remarkable variation in prevalence of allergic diseases and asthma between european countries suggests that geographical latitude and mediterranean diet are important factors which determine the beneficial role of vitamin d in our region
. it would be advisable to measure the vitamin d serum level in children and adults who are part of high risk groups for vitamin d deficiency .
another group would be children with respiratory viral infections and atopy in early life which are at high risk for asthma in later childhood .
vitamin d supplementation is only recommended for patients who have serum level less than 20  ng / ml .
randomized clinical trials regarding treatment with vitamin d supplementation will help determine the effects on the immune system and any potential role in preventing allergic disease .
 the relationship between vitamin d status and asthma has been subject to several studies in the last decade . 
 epidemiological data suggest that incidence of asthma and atopic diseases increased significantly in most westernized countries . 
 the significant variation between countries suggests that besides genetic factors , environmental aspects play a role in the pathogenesis of atopy . 
 the prevalence of hypovitaminosis d is high in many industrialized countries . 
 in addition to its relationship with bone metabolism , vitamin d is recognized as an immunomodulator , with important effects on both adaptive and innate immunity . 
 correlations between vitamin d status and asthma have been formulated , with a considerable interest in assessing whether this vitamin protects against or reduces asthma morbidity . in this review , 
 we discuss recent findings regarding vitamin d status throughout europe and its influence over asthma and allergic rhinitis prevalence . 
 geographical latitude and dietary habits may explain the lower prevalence of allergic disease in albania . 
 we also consider the effects of vitamin d supplementation in allergic disease . 
 several clinical trials are under way and their results are needed in order to make definitive recommendations about the optimal dose of vitamin d for prevention and treatment of asthma and allergic disease . 