|Year : 2018 | Volume
| Issue : 1 | Page : 1-7
A new insight into the immune regulatory functions of vitamin A in children and adolescents
Azza Abd El-Shaheed1, Reham F Fahmy1, Salwa Refat El-Zayat2, Hiba Sibaii2, Nermine N Mahfouz1, Rehab S.I Moustafa1
1 Department of Child Health, National Research Centre, Dokki, Giza, Egypt
2 Department of Medical Physiology, National Research Centre, Dokki, Giza, Egypt
|Date of Submission||28-Nov-2017|
|Date of Acceptance||08-Feb-2018|
|Date of Web Publication||19-Jul-2018|
Reham F Fahmy
Department of Child Health, Medical Division, National Research Center, 33 El Bohouth Street, PO Box 12311, Dokki, Giza, 12622
Source of Support: None, Conflict of Interest: None
Background/Aim Vitamin A deficiency (VAD) is a serious and widespread public health problem. Vitamin A has an important role in regulating human immune function. It increases rates and severity of infections in young children mainly in developing countries. The present study aims to assess the effect of vitamin A on cluster of differentiation 4 (CD4) and thymosin β4 (Tβ4) levels as indicators of adaptive immunity. Moreover, we evaluate the association between serum vitamin A concentration and BMI among Egyptian children and adolescents.
Patients and methods This cross-sectional survey was conducted on 46 apparently healthy participants, including 19 girls and 27 boys aged from 3 to 17 years. We assessed weight and height using standard techniques. Serum vitamin A, CD4, and Tβ4 concentrations were assessed by using enzyme-linked immunosorbent assay kits. We planned to divide the participants into vitamin A-sufficient and vitamin A-deficient groups according to its level.
Results Cutoff for VAD was 44 μg/dl. It was detected in 56.6% of the enrolled participants. Vitamin A was significantly lower in teenagers comparative with children (P=0.04). Vitamin A and Tβ4 levels were significantly decreased in deficient group in comparison with sufficient one at P values of 0.002 and 0.017, respectively, whereas CD4 level was nonsignificantly decreased in vitamin A-deficient patients compared with the sufficient ones. A significant positive correlation was detected between vitamin A and both of CD4 (r=0.348, P=0.018) and Tβ4 (r=0.392, P=0.007). A significant positive correlation was found between vitamin A and BMI (r=0.311, P=0.035).
Conclusion Vitamin A may influence Tβ4 and CD4 levels. This study is the first to explore the effect of vitamin A on Tβ4 level in children and adolescents and correlate it with CD4 level. This finding must be verified using large-scale studies.
Keywords: CD4, children and adolescents, growth, thymosin β4, vitamin A
|How to cite this article:|
Abd El-Shaheed A, Fahmy RF, El-Zayat SR, Sibaii H, Mahfouz NN, Moustafa RS. A new insight into the immune regulatory functions of vitamin A in children and adolescents. J Arab Soc Med Res 2018;13:1-7
|How to cite this URL:|
Abd El-Shaheed A, Fahmy RF, El-Zayat SR, Sibaii H, Mahfouz NN, Moustafa RS. A new insight into the immune regulatory functions of vitamin A in children and adolescents. J Arab Soc Med Res [serial online] 2018 [cited 2018 Dec 9];13:1-7. Available from: http://www.new.asmr.eg.net/text.asp?2018/13/1/1/237214
| Introduction|| |
Vitamin A is an essential micronutrient that is needed in sufficient amounts in our diet to keep a proper physiological well-being. Mammalian living organisms need vitamin A particularly during periods of growth and development. It has important functions in vision, reproduction, and cellular differentiation, and its absence could be life-threatening ,. It includes a set of retinoid compounds with the biologic action of all-trans-retinol . We can get preformed vitamin A from animal sources in the diet (liver, fish liver oils, and dairy products) as retinylpalmitate; on the contrary, carotenoids that are transformed into retinol come from vegetable food sources (dark-green leafy vegetables and deep-orange fruits) . Vitamin A deficiency (VAD) is a main community health quandary in low- and middle-income countries, and at least 250 million children all over the world experience VAD as stated by the WHO . It is the leading cause of preventable blindness in children . Vitamin A is considered one of the broadly studied micronutrients regarding the effect on immune system . It is named anti-infectious vitamin owing to its effect in regulation of human immune function. A relationship between VAD and increased vulnerability to infections has been detected in early studies in animals and humans . Its insufficiency subjects human beings, particularly infants, to diseases of eye, respiratory, and gastrointestinal tract . Vitamin A has significant effects in both cell-mediated and humoral antibody response and supports a Th2-mediated anti-inflammatory cytokine outline. Lack of vitamin A weakens the response of innate immunity (mucosal epithelial regeneration) and adaptive immunity to infections, leading to an impaired capability to offset extra-cellular pathogens . Vitamin A in diet functions through its active metabolite retinoic acid (RA) . Recently, increasing data inform of a more reflective systemic blow of RA on leukocyte role and commitment. Animal examples using genetic handling of RA signaling help us to learn when and how RA controls T-cell fate . The idea that T-helper (Th) cells stably differentiate into two discrete pathways, resulting in Th1 and Th2 cells, was supposed in the late 1980s as an outline to recognize the distinctive patterns of cytokine secretion noticed in cloned, activated CD4 T cells . The notion that effector Th1 and Th2 cell types undergo stable differentiation provoked large concern in understanding how pathogens and host ecological factors, including micronutrients, act together to control T-cell activation and discrimination. VAD makes the environment favorable for the discrimination of naive precursor CD4 T cells into interferon γ-secreting Th1 cells . Alternatively, vitamin A and RA commonly maintain discrimination in the direction of Th2 cells and the production of interleukin-4 and interleukin-5  or augment the proportion of Th2 cytokines compared with Th1 cytokines by decreasing the Th1 reaction . Thymus gland produces β-thymosin hormones which stimulate the proliferation and differentiation of CD4 T lymphocytes . Thymosin β4 (Tβ4) is the main form in mammalian cells and tissues, representing 70–80% of the total thymosin content . Tβ4 is an intracellular protein with 43 amino acids . It was primarily isolated from thymosin fraction 5, and prepared in five steps from calf thymus . It has a number of biological effects. It is drawn in endothelial cell migration and angiogenesis, and its amount increases at sites of injury signifying a great effect of this biopeptide in wound healing . The significance of vitamin A for host defense is indisputable, and the study of its mechanisms is required. Therefore, we aimed to assess the effect of vitamin A on CD4 and Tβ4 levels as indicators of adaptive immunity and to evaluate also the association between serum vitamin A concentration and BMI.
| Patients and methods|| |
This cross-sectional survey was conducted on 46 apparently healthy participants including 19 girls and 27 boys aged from 3 to 17 years. The participants were recruited from the centre of medical excellence at National Research Center. Children were defined as participants younger than 10 years, and teenagers as participants who were 10 years and older, according to the WHO definition . All participants were subjected to full history taking laying stress on age, sex, and symptoms of VAD such as night blindness and diarrhea, and thorough clinical examination, nutritional questionnaire, and anthropometric measurement. Night blindness was assessed for children younger than 8 years by asking the parents if their child had a problem seeing in low levels of light whereas older children answered by themselves . Weight was measured using electronic scale which was regularly checked for its accuracy. Height was measured using a calibrated scale consisting of a wooden platform with a scale and sliding head piece, with children wearing light clothing and no shoes. BMI was calculated as weight (kg)/height (m)2 . We planned to divide the participants into vitamin A-sufficient and vitamin A-deficient groups according to its level. Blood samples (5 ml) were taken for laboratory assessment of vitamin A, CD4, and Tβ4 using enzyme-linked immunosorbent assay kits according to the manufacturer’s instructions (Glory Science Co. Ltd, Del Rio, Texas, USA). Stool samples were collected for detection of parasitic infestations.
Informed consent was obtained from all participants, and the study protocol was approved by the ethical committee of National Research Center, and the study was carried on in accordance with the declaration of Helsinki 1964.
The collected data were coded, tabulated, and statistically analyzed using SPSS program, version 16 (SPSS Inc., Chicago, Illinois, USA). Descriptive statistics were done for numerical parametric data as mean±SE. Inferential analyses were done for quantitative variables using independent t-test. However, correlations were done using Pearson’s correlation (correlation coefficient) for numerical parametric data. P value of less than 0.05 indicated statistical significance. To evaluate the performance of vitamin A, we used receiver operating characteristic curve. The curve was done to illustrate its sensitivity and specificity at different decision cutoff level. In this type of curve, the x-axis represents the false positive rate (1−specificity), and the y-axis represents the true positive rate (sensitivity). The best cutoff is the nearest point to the upper left corner .
| Results|| |
The percentage of VAD was 56.6% of the enrolled participants. Vitamin A-sufficient group included 20 participants, and vitamin A-deficient group included 26 participants. The mean concentration of vitamin A in the sufficient group was significantly higher compared with the deficient group (P=0.002). In addition, the mean of Tβ4 was significantly higher in vitamin A-sufficient group compared with vitamin A-deficient group (P=0.017), whereas the mean of CD4 was nonsignificantly higher in vitamin A-sufficient group compared with vitamin A-deficient group at (P=0.276) as shown in [Table 1]. The cutoff level of vitamin A was 44 μg/dl as determined by the receiver operating characteristic curve and represented in [Figure 1].
|Table 1 Serum levels of vitamin A, cluster of differentiation 4 and thymosin β4 in children and adolescents with vitamin A-sufficient and vitamin A-deficient groups|
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|Figure 1 Receiver operating characteristic (ROC) curve of vitamin A: cutoff level of vitamin A is 44 (μg/dl).|
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Approximately half of the participants were children [23 (50%)], with mean age of 6.37±0.44 years, and the others were teenagers [23 (50%)], with mean age of 12.89±0.44 years. The results showed that the mean concentration of vitamin A was significantly lower in teenagers compared with children (P=0.043).
The present results showed significant positive correlations between vitamin A and both of Tβ4 and CD4 (r=0.392, P=0.007, and r=0.348, P=0.018, respectively) ([Figure 2]a and [Figure 2]b), as well as a significant positive correlation between vitamin A and BMI at r=0.311, P=0.035 ([Figure 2]c). A significant positive correlation between Tβ4 and CD4 was recorded at r=0.308, P=0.037, as shown in [Figure 3].
|Figure 2 (a) Positive correlation between vitamin A and Tβ4. (b) Positive correlation between vitamin A and CD4. (c) Positive correlation between vitamin A and BMI.|
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The results showed in [Table 2] demonstrated that the frequency of night blindness, Entamoeba histolytica infection, respiratory infections, and diarrhea among vitamin A-deficient group were 11.5, 19.2, 15.4, and 38.5%, respectively, whereas the frequency of night blindness, E. histolytica infection, respiratory infections and diarrhea among vitamin A-sufficient group were 5, 30.0, 15.0, and 35.0%, respectively.
|Table 2 Frequency of night blindness, Entamoeba histolytica infection, respiratory infections, and diarrhea among children and adolescents with vitamin A-sufficient and vitamin A-deficient groups|
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| Discussion|| |
Micronutrient is the name used to represent important vitamins and minerals required from the diet to sustain all normal cellular and molecular functions . Sufficient intakes of vitamins and trace elements are needed for the immune system to act competently . Infection and undernutrition are widespread in developing countries and show a synergistic relation . Micronutrient deficiency suppresses immune functions leading to dys-regulation of the reasonable host reaction. This increases the propensity to infections, with amplified morbidity and mortality. Sequentially, infections worsen micronutrient deficiencies by decreasing nutrient intake, augmenting losses, and interfering with utilizations by changing metabolic pathways .
The present study revealed that 56.6% of the recruited participants had VAD. This is in agreement with most studies which showed that VAD is a serious and widespread public health problem affecting about 190 million children aged less than 5 years .
In children, VAD can lead to increased risks of mortality and morbidity associated with infections such as measles and diarrheal infections . Several of these effects can be attributed to the immunological influences of vitamin A .
The current study showed that 19.2% of vitamin A-deficient participant had E. histolytica infection. The association between parasitic infections and vitamin A is diphasic, in which poor vitamin A status could increase vulnerability to parasitic infections and vice versa . We also found that 38.5% of vitamin A-deficient participants had diarrhea. Vitamin A insufficiency could increase the risk of morbidity and mortality in the course of impaired reaction to diarrheal infections . It is essential for maintaining intestinal integrity , and regulating mucin gene expression . It is supposed that vitamin A and its biologically active metabolite ‘RA’ together with additional local ecological factors have a role in gut-associated immunity by enhancing generation of IgA-producing B cells, gut–tropic CD4+ and CD8+T cells, and innate lymphoid cells (a novel lymphocyte subpopulation) . The new findings that ‘RA’ marks the homing of leukocytes to the gut and facilitates the generation of regulatory T cells emphasize a possible effect of RA in mucosal tolerance . Examination of the type of T cells in the intestine of vitamin A-insufficient mice reported that the submucosal lamina propria region was almost devoid of CD4+ CD8+ T cells. The immune response of the intestine to pathogens that have breached the epithelium could be affected by lack of lamina propria T cells . It was found that vitamin A supplementation reduced diarrhea-related deaths by 30% in children aged 6–59 months .
VAD is the principal cause of blindness worldwide . This study reported that 11.5% of the VAD participants had night blindness. A study in Yemen also stated a very low prevalence of ocular manifestations of VAD among children aged 1–5 years . The present study showed that 15.4% of vitamin A-deficient group had respiratory infections. The effect of vitamin A on respiratory infections is varying. Some of public-based studies showed an obvious increase of respiratory symptoms regarding vitamin A supplementation, especially in children who are not experiencing malnutrition. It is not obvious if this noticeable increase in respiratory symptoms is related to a proinflammatory immune reaction linked to the supplements . It is also observed that children with VAD are exposed to severe pneumococcal infections even after receiving Prevnar-13 vaccine (PCV-13) .
The present study revealed that the frequency of night blindness, respiratory infections, and diarrhea was comparable between vitamin A-sufficient group and vitamin A-deficient group, and we attributed this finding to the small number of the recruited participants, and it could be also owing to that VAD was not severe enough to cause symptoms. To reduce the risks associated with vitamin A deficiency, WHO continues to advocate giving periodic high-dose vitamin A supplementations to children at the age of 6–59 months who live in low-income countries, because at the period of strategy arrangement, this interference was shown to lessen all-cause deaths by 23–30% in this age group .
This study showed a significant increase in serum level of Tβ4 in vitamin A-sufficient group compared with vitamin A-deficient group (P=0.017), whereas CD4 level was nonsignificantly higher in vitamin A-sufficient group compared with vitamin A-deficient group (P=0.276). In addition, a significant positive correlation was found between vitamin A and both of CD4 and Tβ4 (r=0.348, P=0.018 and r=0.392, P=0.007, respectively).
Malnutrition, mainly if occurs earlier in life, could hinder the growth and role of lymphoid tissues. This could result in a wide range of immune insults. The adaptive and innate arms of the immune system are negatively influenced by different kinds of nutritional insufficiencies including VAD . Tβ4 was thought to be specially formed and released by the thymic gland, and it has hormonal effects that modulate the immune reaction . It is found in most tissues and cell lines and is present in high concentrations in blood platelets, neutrophils, macrophages, and other lymphoid tissues . The thymus provides most favorable cellular and humoral microenvironment for the development of immunocompetent T lymphocytes . Animal (in vivo and in vitro) and human in-vitro studies confirm that vitamin A and its metabolites (mainly ‘RA’) have a potent effect in the ruling of innate and adaptive immune responses . Regarding innate immune reaction, this includes the integrity of mucosal epithelial  and the numbers, discrimination, and cytokine secretion profiles of monocytes, macrophages, natural killer cells, and neutrophils . Regarding adaptive immune response, it is supposed that vitamin A has an influence in thymic development and maturity of thymocytes , thus VAD could harm thymic task, leading to effects on the peripheral T-cell pool. VAD has an influence on lymphopoiesis, distribution, and cytokine production . Some pediatric supplementation trials have suggested a possible effect of vitamin A on human lymphopoiesis. In a study performed in South Africa, it was found that the total lymphocyte number considerably increased in infants after 42 days of vitamin A supplementation , whereas in another study conducted in Indonesia, vitamin A supplementation resulted in an elevated percentage of CD4-naive T cells (CD4+ CD45 RA+) after 5 weeks, compared with controls . Therefore, the effect of vitamin A supplementation on the increase in the number of T cells, mostly CD4 subpopulation, and its direct effect on cytokine production and T-cell activation  highlights the importance of sufficient vitamin A condition either obtained from intake of preformed retinol or β-carotene, for keeping a good equilibrium of well-synchronized T-cell functions and for avoiding too much or lengthened inflammatory reactions .
Our study showed a significant positive correlation between Tβ4 and CD4 (P=0.037). This is in agreement with Knutsen et al. . This finding could be ascribed to the fact that Tβ4 is the predominant form of thymic hormones  and that its primary function is to stimulate the production of T cells which are targets of thymosin activity .
This study revealed that the mean concentration of serum vitamin A was significantly lower in the teenagers group (38.95±2.77) compared with the children group (66.86±12.77) (P=0.043). This result is in accordance with that observed by de Souza Valente et al.  who reported that retinol inadequacy was significantly higher in adolescents compared with children. However, Hu et al.  and Fiorentino et al.  reported that the mean concentration of serum vitamin A was significantly lower in children compared with teenagers. Our interpretation for this difference in serum vitamin A between children and teenagers is that once a child gets to school age, it is observed that mothers can be less concerned of their children’s diet . In addition, eating habits in the teenager group are characterized by a predilection for fast food with a high-fat and carbohydrate contents and low nutritional value . So, a proper guideline is required to better describe vitamin A condition between different age groups, and research on this issue is obviously needed.
The present study revealed a significant positive correlation between serum vitamin A and BMI (P=0.035). This result comes in accordance with the outcomes of many other studies. In a study conducted in Sudan, vitamin A taken in diet related to attaining weight and height following the control of confounding factors. Increased vitamin A ingestion in diet was linked to decreased threat of stunting and wasting . In another study carried out by Donnen et al.  in Zaire, vitamin A supplementation seemed to enhance growth. It was found that weight increases were elevated considerably in vitamin A-supplemented group compared with the control group in a period of follow-up of 6 months . Reduction of gaining weight could be one of the first signs of vitamin A insufficiency in human beings . Nutrient deficiencies have been linked to reduce linear growth . Because of the influence of vitamin A on child’s growth, attempts to enhance vitamin A condition starting from an earlier age become essential.
| Conclusion|| |
The present study revealed a significant correlation between vitamin A and both of CD4 and Tβ4, suggesting that insufficient intake and state of vitamin A decreases the immunity that could dispose to infections and exaggerates malnutrition.
Further studies are required to better describe the compound effect that vitamin A and retinoic acid encompass on immune system regulation and reaction to infections. A useful public health policy could be achieved by periodic vitamin A supplementation to children of at least 6 months living in low-income countries to enhance child survival and to reduce the hazards of nutritional blindness and of morbidity of infectious basis owing to VAD.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]