الفهرس 
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Abstract
Vit D is now known to have a number of vital functions beyond its traditional role in bone metabolism, including an evident immunoregulatory function; consequently a definite role in airways health especially in allergic diseases such as BA. It is a highly prevalent and expensive allergic disease. It is characterized by chronic airway inflammation associated with AHR resulting in reversible airflow obstruction.
Genetic predisposition and environmental exposure are the major risk factors affecting this disease development. The initiation of allergic airway inflammation is started by sensitization to an environmental allergen in a predisposed individual. Classically, CD4+ Th2 cells were implicated in the asthma pathogenesis as these cells differentiate into Th1, Th2, Th17 and Treg cells depending on the different cytokines available. Now, CD8+ T cells were found to be essential in the allergic inflammation and airway sensitivity in addition to Treg and Th17 cells, but their specific role in BA is still controversial. IFN-γ is a cytokine inducing and modulating many immune responses and its serum level is correlated with the disease severity of chronic inflammatory airway diseases, as BA. It was shown that higher serum levels of IFN-γ were linked to insufficient Vit D serum levels.
Vit D has genomic and non-genomic functional pathways, however its effect on the different cells of the immune system as neutrophils, dendritic cells, B cells and macrophages is genomic as it binds to its nuclear VDR forming a heterodimer with the retinoid X receptor. It is proposed that VDR polymorphisms might play a role in increased susceptibility to BA.
Cytochrome P450 cholesterol side-chain cleavage (P450scc) enzyme (encoded by the CYP11A1 gene) is responsible for converting cholesterol to pregnenolone which is the first step and rate-limiting step of steroid hormones biosynthesis. This pivotal enzyme links steroidogenesis in T cells to proallergic differentiation pathways. Data from the literature suggest that the steroidogenic enzyme CYP11A1 have an essential contribution in the polarization of CD8+ T cells from an IFN-γ to an IL-13 producing effector cell. This role implies this enzyme is a critical regulator of the development of lung allergic responses. It was found that mutations in the CYP11A1 gene can lead to steroid hormone deficiency. Moreover, there is an epistatic effect between CYP11A1 and VDR genes polymorphisms that may be relevant in asthmatic children.
This study was designed to determine the effect of Vit D supplementation in Egyptian asthmatic children on asthma control level, PFTs, CD8 T cells count and IFN- γ serum level in addition to the possible association between CYP11A1 and VDR gene polymorphism.
This study was carried out on 95 asthmatic children aged 6 to 15 years, recruited from the Asthma and Allergy Clinic of AUCH after taking an informed written consent from the guardian and oral consent from the children, during the period starting from March 2017 to July 2018. Full detailed history was obtained from all participating children followed by clinical examination and asthma control level assessment. The children then performed spirometry to assess their pulmonary functions (FEV1/FVC and PEFR). In addition, venous blood samples were collected and divided into 3 portions. The first and second portions were both collected on EDTA (whole blood samples) for CD8 T cells count and genetic analysis of CYP11A1 and VDR SNPs (rs11632698, rs7975232 (Apa I ), rs731236 (TaqI ), respectively) by sequencing. The final portion was centrifuged for separation of serum that assayed for Vit D and INF-γ levels.
The patients received Vit D supplement; Vidrop, cholecalciferol 2800 IU/ml from Medical Union Pharmaceuticals (MUP) at daily dose of 600 IU/day for 12 months in addition to their usual treatment.
After three months, the patients were reassessed by clinical examination and PFTs. CD8 cell count, Vit D and IFN-γ serum levels were also repeated. By the end of the year, the patients were finally evaluated by clinical examination and PFTs. The asthma control level was assessed every 2 weeks for three months and monthly afterwards.
The results of the present study revealed that Vit D supplement in asthmatic children significantly ameliorated their asthma control level and PFTs after three months and one year. Moreover, Vit D serum level significantly increased while serum level IFN-γ and CD8 T cells count significantly decreased.
Patients with ameliorated control level according to the aforementioned survey, regardless of the results of PFTs, were classified as Rs (59 patients; 62.1%) while patients with no change in control level were classified as NRs (36 patients; 37.9%). While there was also no significant difference between Rs and NRs as regards all studied parameters before the intervention, the Rs showed a significantly better FEV1/FVC after 3 months.
After genetic analysis of the study population, both VDR SNPs (rs7975232 (Apa I ) and rs731236 (TaqI )) were distributed significantly different between the Rs and the NRs while no significant difference was found as regards the genotype distribution of rs11632698 (CYP11A1 SNP). With further analysis, the change of the mean level of CD8+T cells count in the wild genotype of rs7975232 was significantly higher in the Rs versus NRs and the change of the mean Vit D serum level of the polymorphic genotype of rs11632698 was also found significantly higher in the NRs versus Rs.
from the results of the present study, it is obvious that Vit D supplementation was beneficial to the Egyptian asthmatic children as it improved their level of asthma control and PFTs while the possible implication of CYP11A1, and VDR (TaqI and ApaI) SNPs might explain the variation in the patients’ response but further investigations of the mechanistic links and the different pathways between Vit D, CD8+ T cells and IFN-γ are required.