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Relationship Levels of 25-hydroxyvitamin D [25(OH)D] Serum Against Specific IgE Levels and The Degrees of Allergy Rhinitis

Willy Silyen ¹, Rus Suheryanto¹, J Bambang Soemantri¹

¹Ear Nose Throat Head and Neck Surgery.Faculty of Medicine University of Brawijaya/Saiful Anwar Hospital, Malang, Indonesia.

ABSTRACT: Allergic rhinitisis an inflammatory disease of the nasal mucosa which is based on there action of type 1 hypersensitivity and is mediated byI gE. Significant impact of allergic rhinitis cause decreased inthe quality of life and increase dexpenses for treatment.Calciferol is a good immunomodulator in inhibiting IL-4, IL-5 and IL-13 that Th2 differentiation and IgE production will decline. This study aims to determine the relationship calciferol levels with specific IgE levels and the degree of allergic rhinitis. This analytic observational study involved 24 people with allergic rhinitis as case group and 24 people without allergic rhinitis as a control group. Calciferol levels difference between case and control groups were analyzed by independent t test, calciferol levels relationships with specific IgE levels were analyzed by Pearson correlation test and differences in levels of calciferol on the degree of allergic rhinitis were analyzed by ANOVA test. Calciferol levels significantly different from the case group than the control group (P <0.05), there was no correlation with the levels of calciferol with specific IgE levels (p> 0.05), and there is a significant difference in the degree of calciferol levels with allergic rhinitis (p <0:05). The conclusion of this study is calciferol levels significantly different between cases and controls, calciferol levels not associated with specific IgE levels and there is a significant difference calciferol levels with some degree of allergic rhinitis. Further research is needed to determine the relationship within calciferol levels of inflammatory mediators that play a role in the activation of specific IgE as IL-4 and IL-13, and serum calciferol levels with vitamin D receptor.

Keywords –allergic rhinitis, calciferol, spesific IgE, degree of allergic rhinitis.

INTRODUCTION

Allergic rhinitis is a global health problem and the number of events has increased in many countries.¹ Significant impact of allergic rhinitis is decreased quality of life and increased of medical costs.^2,3

Increasing incidence of allergic diseases in western countries and then connected with a longer periode of indoor used. It is then associated with lower levels of calciferol [25(OH)D] due to a lack of ultraviolet light exposure.⁴

Exposure to sunlight, especially ultraviolet B (UVB) with wavelength 290-315 nm causing photootolytic conversion 7,8-dehydroxycholesterol, then transported to the liver and converted by CYP27A1 to 25-hydroxy vitamin D [25(OH)D] .⁵ Once synthesized in the liver, vitamin D will be transported to the kidneys and hydroxylation process of atom C-1 (1-α-hydroxylase) occurs by CYP27B to 1,25(OH)2D that is the active form of vitamin D.^5,6

Picture 1. Calciferol metabolism

Allergic rhinitis is an inflammatory disease of the nasal mucosa which is based on type 1 hypersensitivity reactions and mediated by IgE.⁷ Some cytokines produced by Th2, particularly IL-4 and IL-13 will induce the ε germline gene transcription that will activate B cells to produce IgE.⁸

Calciferol’s main target are dendritic cells. Calciferol inhibits maturation of dendritic cells by decreasing the expression of costimulator molecules CD40, CD80 and CD86. Production of cytokines IL-12 decreased and increase production of IL-10 and Treg cells.^9,10

Barriers Regulation of IgE occurs through a mechanism of ε germline transcription resistance. Calciferol would bind to the VDR  and then with RXR and bind to VDRE at the target gene (Iε) and form a heterodimer complex. The next will be pulling co-repressor SMRT, HDAC1 and HDAC3 to join in Iε. VDR-RXR-VDRE-co-repressor SMRT-HDAC1 and HDAC3 complex bond were formed causing DNA chromatin condensation and inhibits transcription process of ε germline so IgE CSR process was not occured.^11,12

Picture 2. Transcription inhibition ϵ germline caused by DNA chromatin condensation

I.              METHODS

            This study involved 24 people with allergic rhinitis as case group who had positive skin prick test result and an outpatient in Allergy-Immunology of ENT Department Saiful Anwar Hospital Malang. The control group were 24 people obtained from subjects with no complaints or allegations of negative allergic rhinitis with negative skin prick test results and willing to go into research.

     Data collection was done by interview through questionnaires to collect information about age, gender and medical history.

Measurements were conducted at the Biomedical Laboratory of The Faculty of Medicine, Brawijaya University Malang. Calciferol and specific IgE levels in blood serum samples that had been collected was measured using ELISA. Calciferol optimal levels was >30 ng/ml, insufficiency was15-29 ng/ml and deficiency was <15 ng/ml. Specific IgE levels were considered abnormal if the level are > 0.35 kU/l.

Differences in cholecalciferol serum levels in patients with allergic rhinitis compared to controls were analyzed using independent t-test. Relationship between cholecalciferol serum levels and specific IgE levels were analyzed using Pearson correlation test. Difference between cholecalciferol serum levels in the degeree of allergic rhinitis were analyzed using ANOVA.

II.            RESULTS

Homogenecity test data between case and control groups showed that the data between the two groups were homogeneous (p> 0:05).

            The proportion of women (54.2%) is almost the same compared to men (45.8%) in the case group while in the control group, the proportion of men (66.7%) is higher than for women (33.3%). Distribution of age groups in both case and control groups at the most is the age of 19-24 years (41.7% in case group and 50% in control group).

Most nose complaints in cases group is sneezing complained of by all subjects (100%), followed by a rhinorhea at 91.7% and clogged nose (83.3%). The most comorbidity are complaints in the skin (37.5%), followed by asthma (8.3%) and eye (4.2%). In the result of physical ENT examination there were no eardrum retraction16.7%, nasal mucosal edema and livid 45.8% and granular posterior pharyngeal wall 12.5%. Degree of allergic rhinitis by ARIA has the same number in each group. The most type of inhalant allergens are house dust mite (91.7%), dog dander (79.2%), and cotton (50%).

Table 1. Basic characteristic based on gender and age

Table 2. Clinical characteristic

Descriptively, calciferol serum levels were lower in the case group (12.62 ng / ml) compared to the control group (18:18 ng / ml). Unpaired t test results showed the mean cholecalciferol serum levels in the case group were significantly  lower than the control group (p <0.05).

Table 3. Unpaired t test cholecalciferol serum levels between cases group and control group

	Group	N	Mean ± SD	P
Calciferol levels	Case	24	12.62	0.000
	Control	24	18.18

Scatter plot diagram shows that the specific IgE meet linearity requirements, the determinant coefficient (R² = 0.122). This shows the relationship of these variables only by 12.2%, while the remaining 87.8% did not have a relationship.

Picture 3.Scatter plot diagram of calciferol relationships with specific IgE levels

Pearson correlation test results of cholecalciferol serum levels with specific IgE showed no significant correlation (p> 0:05) (Table 4). The results above indicate that there is no relationship between cholecalciferol serum levels and specific IgE levels.

Table 4. Pearson correlation result of calciferol levels with specific IgE

		Spesific IgE
Calciferol levels	P	0.94

          ANOVA test results obtained indicated that no significant relationship between calsiferol serum level with allergic rhinitis degree based on ARIA (p = 0.31) (Table 5).  

When looking at the unpaired t test in average rate of calsiferol serum rate between mild intermittent and moderate-severe persistent degree, there were significant relationship between calciferol serum with both degree of allergic rhinitis (p = 0.02) (Table 6).

Table 5. ANOVA test results between calsiferol serum level with allergic rhinitis degree 
               based on ARIA

	Degree of allergic rhintis	n	Mean ± SD	p
Calciferol levels	Mild intermittent	6	15.99	0.31
	Moderate severe intermittent	6	11.70
	Mild persistent	6	11.71
	Moderate severe persistent	6	11.10
	Total	24

Table 6. Result of unpaired t-test between calciferol serum levels and mild intermiten rinitis and                moderate-severe persistent rinitis.

	Degree of allergic rhintis	n	Mean ± SD	p
Calciferol levels	Mild intermittent	6	15.99	0.02
	Moderate severe persistent	6	11.10

III.           DISCUSSION

This study obtained a result that there were significant differences in calciferol serum between case and controls. Arshi¹³ showed cholecalciferol serum levels in patients with allergic rhinitis were significantly lower compared with controls. Research conducted by Frieri¹⁴ mentioned that low serum levels of cholecalciferol associated with the occurrence of allergic rhinitis, asthma and atopic dermatitis. This showed calciferol has a role in inflammatory settings based on the type 1 hypersensitivity reaction and is mediated by IgE.

          Calciferol’s main target is dendritic cells with the aim of suppressing excessive immune system so to balance the immune system. Barriers to dendritic cells maturity by calciferol will increase the production of anti-inflammatory cytokine IL-10. In vitro studies conducted by Penna⁹ showed that IL-10 can be increased up to 7-fold in dendritic cells that have been given calciferol. Increased IL-10 induced a state of anergy by blocking kostimulator CD28 signals on the surface of Th2 cells. Those barriers reduced the production of cytokines IL-4, IL-5 and increased the production of IFNγ.¹⁵ IL-10 has the ability as a protective factor, high levels of IL-10 will prevent cell mast degranulation.¹⁶ Increased Treg cells after inhibition of dendritic cells maturity occurs due to increased expression of CTLA-4 and FoxP3 and IL-10 induction.¹⁷ Treg cells have a role in maintaining the balance of the immune system.¹⁸

Calciferol can also work directly on T cells because these cells expressed VDR. Calciferol inhibits T cells that produce IL-2 so that T cell differentiation is not occured.¹⁹

The mean cholecalciferol serum levels in control groups were significantly different from the case group but within insuficient levels which means below normal limits. Until now no literature available that contains normal value levels of Indonesian cholecalciferol, so the calciferol levels that obtained through the research could not be ascertained whether it is insufficient or possibilities within normal limits.

In this study showed that cholecalciferol serum levels were decreased and specific IgE levels increased, but the correlation tests showed no significant relationship.

Milanovic¹² concluded that calciferol play a major role in inhibiting IgE regulatory mechanism through inhibition of ε germline transcription. Decreased levels of serum calciferol will lead to increased levels of specific IgE.

Geha²⁰ said that inhibition to CSR IgE process can also be done by the cytokines IFNγ that inhibit the development of Th2 so that the production of IL-4 and IL-13 decreased, in addition IFN-γ can directly suppress transcription of ε germline. B cell receptor (BCR) can inhibit the activity of IL-4 and CD40 to activate transcription of ε germline. CTLA4 prevent CSR process through the inhibition of NF-κB and STAT 6. IL-21 decrease IgE production through inhibition of ε germline transcription. This suggests the possibility that elevated levels of specific IgE is not only due to decreased levels of serum cholecalciferol, but it may be due to decreased IFN-γ, BCR, CTLA4 and IL-21.

There are significant differences between calciferol serum level with mild intermittent allergic rhinitis and moderate-severe persistent rhinitis. Research conducted by Brehm²¹, reported that there was a meaningful relationship between calciferol serum rate of asthma severity and visits to the hospital. Peroni²² reported that calciferol rate was significantly higher in patients with atopic dermatitis in mild degrees compared with moderate and severe degrees. There are differences only in certain degree of allergic rhinitis indicate that the process is not entirely influenced by the calciferol. Explanation of the mechanisms that occur up to now have not known very well.

IV.          CONCLUSIONS

The conclusion of this study is calciferol levels significantly different between cases and controls, calciferol levels not associated with specific IgE levels and there is a significant difference calciferol levels with some degree of allergic rhinitis. Further research is needed to determine the relationship within calciferol levels of inflammatory mediators that play a role in the activation of specific IgE as IL-4 and IL-13, and serum calciferol levels with vitamin D receptor.

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