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| ORIGINAL RESEARCH |
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| Year : 2023 | Volume
: 15
| Issue : 2 | Page : 194-199 |
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TLR4 expression in the saliva of systemic lupus erythematosus correlated with the serum vitamin D/25-hydroxyvitamin D: A cross-sectional study
Hendri Susanto1, Diah Savitri Ernawati2, Awalia3
1 Department of Oral Medicine, Faculty of Dentistry, Universitas Gadjah Mada, Yogyakarta, Indonesia
2 Department of Oral Medicine Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
3 Department of Internal Medicine, Dr. Soetomo Hospital, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| Date of Submission | 12-Mar-2022 |
| Date of Decision | 20-Mar-2023 |
| Date of Acceptance | 20-Mar-2023 |
| Date of Web Publication | 28-Apr-2023 |
Correspondence Address:
Dr. Hendri Susanto
Department of Oral Medicine, Faculty of Dentistry, Universitas Gadjah Mada, Denta Sekip Utara, Yogyakarta 55281
Indonesia
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jioh.jioh_61_22
Aim: This study aimed to examine the correlation between serum vitamin D (25-hydroxyvitamin D [25(OH)D]) and the transmembrane Toll-like receptor (TLR) 4 expression on CD11b+ cells in systemic lupus erythematosus (SLE) saliva. Materials and Methods: A cross-sectional study was conducted on 30 SLE patients who regularly visited to rheumatology clinic and met the following criteria: no systemic diseases, no smoking, no drinking and use of oral contraceptives, no steroid and immunosuppressant medications, no pregnancy, no wearing of dentures, and orthodontic appliances. The subject’s blood samples were taken for electrochemiluminescence immunoassay analyzer methods of examining 25(OH)D level. Full unstimulated whole saliva collection for the measurement of TLR4 expression. The descriptive demographic data, the chi-square, t test, and linear regression (95% confidence level) were used to analyze the association between blood 25(OH)D concentrations and immune cells expressing TLR4 in saliva CD11b+ cells. Results: SLE subjects had an average blood concentration of 25(OH)D of 9.9 ± 4.6 ng/mL. in saliva CD11b+ cells, TLR4 expression was 26.0 ± 20.9%. r = 0.473 and P < 0.05 indicated a correlation between the saliva CD11b+ cells expressing TLR4 and the serum level of 25(OH)D. Only 25(OH)D predicted TLR4 expression of the saliva CD11b+ cells. Conclusions: TLR4 expression of Saliva CD11b+ cells correlated with the concentrations of serum 25(OH)D in SLE. Hence, vitamin D/25(OH)D may control the immune response of SLE patients’ oral cavity. Keywords: 25-Hydroxyvitamin D, Saliva, Serum, Systemic Lupus Erythematosus, Toll-like Receptor 4
How to cite this article:
Susanto H, Ernawati DS, Awalia. TLR4 expression in the saliva of systemic lupus erythematosus correlated with the serum vitamin D/25-hydroxyvitamin D: A cross-sectional study. J Int Oral Health 2023;15:194-9 |
How to cite this URL:
Susanto H, Ernawati DS, Awalia. TLR4 expression in the saliva of systemic lupus erythematosus correlated with the serum vitamin D/25-hydroxyvitamin D: A cross-sectional study. J Int Oral Health [serial online] 2023 [cited 2023 Jun 1];15:194-9. Available from: https://www.jioh.org/text.asp?2023/15/2/194/375371 |
| Introduction | |  |
The deficiency of vitamin D may involve in the development of systemic lupus erythematosus (SLE). Evidence showed that the concentration of vitamin D in SLE was lower compared to healthy people.[1] Lower concentrations of vitamin D/25-hydroxyvitamin D (25(OH)D) in the active SLE patients’ serum was found compared with SLE with inactive status.[2] Increased disease activity of SLE had low vitamin D concentrations, whereas high serum concentrations of vitamin D correlated with decreased disease progression.[3] Vitamin D concentration was also increased by supplementation of vitamin D in SLE with the concentrations of serum vitamin D/25(OH)D lower than 10 ng/mL for about 2 years duration and correlated with both the increase of the concentration of vitamin D and low fatigue severity in SLE patients.[4]
SLE may occur as a result of the impairment of vitamin D function in immune regulation. The innate immune system’s transmembrane Toll-like receptor (TLR) proteins may aid in not only the development of autoantibodies but also cytokines in SLE. TLR7 and 9 have been used to TLR7 and TLR9 inhibitors as therapy option for SLE. TLR 7 and TLR9 may help to produce autoantibodies in SLE.[5],[6] The auto-antibody DNA production in SLE was also hypothesized to be influenced by TLR2.[5],[7] Low TLR2 expression in SLE serum compared with healthy controls, according to a study, and this was associated with a higher degree of SLE severity.[8] Recent study revealed a link between low serum vitamin D/25(OH)D concentration and the TLR2 production by immune cells in SLE patients’ saliva, suggesting that vitamin D may help SLE patients’ oral tissue response immunely.[9] Numerous microorganisms reside in the oral cavity. By triggering an antimicrobial peptide to detect and block pathogens from penetrating the mucosa of oral cavity, low-concentration vitamin D may disrupt the TLR2 function. One of the pathogen recognition receptors (PRRs), TLR4 involved in identifying microbes in the oral cavity.[10] As blood vitamin D and the expression of TLR2 in immune cells in oral cavity were correlated, vitamin D may also correlate with the expression of TLR4 in the oral cavity. Not only TLR2 but also TLR4 involve in innate immune response to fight different oral bacteria, particularly those linked to periodontal diseases. Also, a study suggested pseudomembranous candidiasis may be common in SLE patients, and TLR2 may have a role in response against the infection in oral cavity caused by Candida spp.[11],[12] Moreover, TLR4 respond specifically to the lipopolysaccharide that the periodontopathogen, Porphyromonas gingivalis produces. [10],[13]. Studies revealed that SLE patients had a significant prevalence of periodontal diseases. [14],[15] The deregulation of the oral immune response may be the reason of the rise in oral cavity infections in SLE patients. The decrease of vitamin D’s immunomodulation function may have an effect on TLR4, which is involved in oral cavity immune response of SLE. The explanation might be the low vitamin D concentration partly reduce the function of TLR4 in oral cavity’s innate immune response. Thus, the objective of this current study was to examine the correlation between the saliva immune cells expressing TLR4 and the serum concentration of vitamin D/25(OH)D in SLE patients.
| Materials and Methods | | |
Study design
The cross-sectional study included patients with SLE who frequently visited the Rheumatology clinic, Department of Internal Medicine, Dr. Soetomo Hospital, located in Surabaya, Indonesia, from September to December 2018. Dr. Soetomo Hospital’s Ethical Committee for Research gave the ethics approval (0284/KEPK/V/2018) for this study. The Declaration of Helsinki (1975) ethical principal has been followed during every procedure.
Sampling criteria
According to the American College of Rheumatology criteria 1997 criteria, SLE patients were the subjects of the current study[16] by straightforward random selection. Patients who did not have additional disorders were nonsmokers, nonalcoholic, and did not use oral contraceptives (only for women) met the inclusion criteria. The exclusion criteria included being pregnant, taking steroids or immunosuppressants for longer than 6 months, having a history of allergic reactions, and donning dentures and orthodontic appliances. When subjects learned about the study, they were requested to join. Participants in the study will be required to sign a free written Informed consent form.
Study method
A questionnaire was used to gather information on age, gender, ethnicity, marital status, and level of education. All participants were venipunctured in the upper right limb’s median cubital vein to obtain blood samples. To measure 25(OH)D, electrochemiluminescence immunoassay analyzer methods were used. A 3-mL blood sample from each participant was taken when they visited a rheumatologist during the study periods. Vitamin D/25(OH)D deficiency determine by vitamin D <20 ng/mL. Insufficiency of vitamin D, when vitamin D: 21–29 ng/mL. Serum vitamin D/25(OH)D should be higher than 30 ng/mL.[17] Dr. Soetomo Hospital Clinical Pathology Laboratorium examined the blood sample. Following the acquisition of a blood sample during a visit to the rheumatology clinic, a whole unstimulated saliva sample was taken. Immune cell expression in saliva was examined using antihuman CD11bFITC-conjugated antibody from Biolegend. While TLR4 expression was examined using anti-human TLR4PerCP-conjugated antibody (Santa Cruz, Texas, USA). According to previous work, flow cytometry was used to assess the expression of CD11b+ and TLR4 exp.[9] The Faculty of Medicine at Brawijaya University’s Biomedis Laboratories hosted the saliva test.
Statistical analysis
The Statistical Package for the Social Sciences software program, USA, version 17.0, was used to analyze the data. The 95% confidence interval, coefficient correlation (r), alpha 0.05, and power analysis (P) were all set at 0.5. Using descriptive statistic, the subject’s demographic information was examined. To determine if the data were in normal distribution or not, the Shapiro–Wilk test was applied. When the data were in a normal distribution, the independent t test of Mann–Whitney U test was used to compare the expression of TLR4 of saliva CD11b+ between serum 25(OH)D category. Using the Pearson correlation test, The association between the serum level of vitamin D/25(OH)D and the saliva TLR4 expression of CD11b+ was examined. The Spearman correlation test was employed when the data were not regularly distributed. When predicting the expression of TLR4, linear regression analysis employed the serum 25(OH)D ratio.
| Results | | |
Thirty SLE patients in total who meet inclusion criteria took apart in this study during the study period between topics. Nineteen of the subjects were female. The majority of subjects (40%) were high school graduates, with a mean age of 27. Married women made up 40% of participants. In contrast, the majority of the subjects (73.3%) were the Javanese ancestry. There were 28 participants (93%), of which 20 utilized methyl prednisolone as medicine. SLE typically lasts 2.7 months [Table 1].
Serum 25(OH)D was low in all SLE subjects. Vitamin D deficiency (<20 ng/mL) was defined as having a blood 25(OH)D of 9.9 ± 4.6 ng/mL. The level of TLR4 expression in saliva CD11b+ was 25.3 ± 20.7% [Table 2]. | Table 2: The mean value of serum 25(OH)D concentration and TLR4 expression in immune cells (CD11b+) of saliva of SLE
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Based on Shapiro–Wilk analysis, the expression of TLR4 in saliva CD11b+ and the concentration of serum 25(OH)D was not normally distributed (P < 0.05). TLR4 expression was compared between categories of serum 25(OH)D concentrations category using the Mann–Whitney U test. The Spearman correlation test was performed between serum 25(OH)D concentrations and the expression of TLR 4 in saliva CD11b+ of SLE. Across the category of blood 25(OH)D concentrations, there was a significant difference in TLR4 expression (P = 0.018, P < 0.05) [Table 3]. The result of the Spearman correlation test analysis revealed an r = 0.473 (P < 0.05) positive significant connection between the level of serum 25(OH)D and TLR4 expression in saliva CD11b+ [Table 4]. 25(OH)D predicted the TLR4 expression in saliva CD11b+, according to a linear regression analysis using the TLR4 expression as dependent variable [Table 5]. | Table 3: The comparison of mean value of TLR4 expression in immune cells (CD11b+) of saliva of SLE based on vitamin D category
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 | Table 4: The result of the Spearman correlation test between serum 25(OH)D concentration and TLR4 expression in CD11b+
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 | Table 5: Multiple linear regression analysis 25(OH)D predictor for TLR4 expression of Immune cells (cd11b+) in the saliva of SLE
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| Discussion | | |
This study was the first report that showed the correlation between the TLR4 expression in saliva CD11b+ and the level of blood 25(OH)D in SLE. The finding indicated that the mean age of the SLE subjects in this study was 27, and the majority of them were female (96%), with ages ranging from 12 to 50. These results were consistent with the information that 90% of SLE cases are more common in women, and the gender ratio is 9–15:1.[18] In addition, getting older age could increase the risk of developing SLE. Patients with SLE ca range in age from 18 to 65, and in this study, the median age of SLE patients is 30 years.[19]
The SLE participants were vitamin D deficient.[20] A comparatively low consumption of high in vitamin D contained food, as well as a deficiency in the body’s ability to synthesize vitamin D through skin exposure to ultraviolet B radiation from sunshine, may cause low vitamin D levels.[21] It is possible to claim that a low concentration of vitamin D can cause vitamin D dysfunction as an immunomodulator and that deficiency of vitamin D may contribute to the pathophysiology of SLE. Vitamin D’s potential role to modulate immune system might be related to available of vitamin D receptors in variety of cells in the body, not only in cells of innate immunity such as macrophages and neutrophils but also in antigen-presenting cells, dendritic cells, T cells, i.e., CD4 and CD8 which is involved in cellular mediated immune system.[22] The biomarker of the body’s vitamin D status used in this study was serum vitamin D, and its mean value was 9.9 ng/mL. Vitamin D deficiency is defined as serum vitamin D concentration below 20 ng/mL, which was seen in all SLE participants.[17]
According to the study’s findings, SLE patients with high vitamin D/25(OH)D concentration had considerably higher TLR4 expression in saliva Immune cells CD11b+ than SLE with low vitamin D/25(OH)D concentrations. The invasion of microorganisms in the oral cavity stimulated TLR4 expression, which is present in epithelial cells, saliva generated from blood, and salivary gland cells.[10],[23],[24] One of the innate immune system’s PRRs in the oral cavity is TLR4. The initial component of TLR4 protein, which is expressed on the cell surface, is responsible for identifying the pathogen-associated molecular patterns (PAMPs) or ligands. The second portion is located inside cells. Immune cells’ expression of TLR4 is regulated by PAMPs secreted by bacteria. The lipopolysaccharide generated by various microbes, including Aggregatibacter actinomycetemcomitans, Escherichia coli, Fusobacterium nucleatum, and P. gingivalis, is recognized by TLR4.[10] one of the harmful bacteria in periodontal infections is P. gingivalis.[13] Cathelicidin, calprotectin, and defensins, which are antimicrobial components of the oral mucosa, may be produced as a result of the interaction between TLR4 and PAMPs originated from lipopolysaccharide of P. gingivalis. Constant exposure of PAMPs to TLR4 may result in the production of antimicrobial peptides that are effective against bacteria in addition to triggering pro-inflammatory cytokines, which result from the pathway of nuclear factor kappa beta into the tissue. The initiation and the increased severity of periodontal diseases may be induced by the imbalance status that results from the TLR4 dysfunction and the stimulation of proinflammatory cytokines.[10],[23] A deficiency in vitamin D may be the cause of TLR4 impairment.
The results of this study also demonstrated that SLE patients with high vitamin D/25(OH)D concentrations had considerably higher levels of TLR4 expression in saliva than those who had low vitamin D/25(OH)D concentrations. A low serum vitamin D/25(OH)D concentration might result in low expression of TLR4, and serum vitamin D/25(OH)D is predicted for the expression of TLR4 in saliva CD11b+. The expression of TLR4 in saliva CD11b+ correlated significantly with serum vitamin D/25(OH)D concentration. Saliva CD11b+ TLR expression may be affected by vitamin D/25(OH)D as well. The result of this study was consistent with those of our earlier study, which showed a favorable correlation between serum vitamin D/25(OH)D concentrations and TLR2 expression in SLE saliva’s immune cells.[9] Salivary CD11b+ cells expressed TLR2 and TLR4, which both play protective roles in an innate immune response.[9],[23]
The anti-inflammatory of vitamin D may be facilitated by vitamin D receptor (VDR), which may be expressed in CD11b+. The activation of TLR4 expression may also result in the production of antimicrobial peptides and cytokines that promote inflammation.[10] However, there is no change in TLR4 expression with vitamin D administration, and the administration of vitamin D may raise the expression of TLR2 in peripheral blood mononuclear cells.[25] A number of studies have demonstrated that 1,25 dihydroxycholecalciferol D, which is an active form of vitamin D3 inhibits the expression of TLR4 in dendritic cells and monocyte.[26],[27] as well as in baby who had necrotizing enterocolitis via VDR.[28]. In addition, a recent study has shown that vitamin D3 inhibited endometrial cell’s production of pro-inflammatory cytokines triggered by lipopolysaccharide via TLR4 (such as Tumor necrosis factor alfa, interleukin-6).[29] The concentration of vitamin D affects its ability to reduce inflammation. Only at the optional concentration of vitamin D does it have an anti-inflammatory effect; when it is present at typical concentrations, it may not have much of an impact.[30] The rationale might be that decreased levels of serum vitamin D may also contribute to the rise in periodontal diseases in SLE patients. As lipopolysaccharide produced by bacteria like P. gingivalis activates TLR4, low serum vitamin D concentration may prevent vitamin D from acting as an anti-inflammatory against oral infections brought on by P. gingivalis. The results of other studies, which differ from this one in that they involved subjects with Helicobacter pylori infection, demonstrated that the expression of TLR4 was adversely correlated with vitamin D of whole blood cells.[31] The various background and subject counts, as well as the study’s methodology and factors, could be responsible for these disparate outcomes. These might be the study’s limitations. The fact that the periodontal tissue of the patients was not examined to determine whether or not periodontal diseases were present is another drawback of our study. There needs to be more research on the potential contribution of periodontal diseases in stimulating the TLR4 expression in saliva immune cells (CD11b+) and the correlation with vitamin D/vitamin D/25(OH)D concentrations. Periodontal disease may be the oral disease that affects the TLR4 expression in the saliva of SLE patients.
Moreover, medications may have an impact on vitamin D levels. A typical anti-inflammatory medication used as a steroid in SLE is methylprednisolone. Methylprednisolone might work against vitamin D.[19],[32] When taking methylprednisolone for up to 6 months, there are no impacts on vitamin D in the body.[33],[34] Medication for SLE was studied for no longer than six months. As a result, the impact of methylprednisolone on vitamin D levels and vitamin D’s role in the immune system may be minimal. Other medications’ effects on the serum vitamin D concentrations of the SLE patients in this study, however, are still unknown.
Although this study showed the was a correlation between TLR4 expression in saliva immune cells (CD11b+) and the concentrations of vitamin D/vitamin D/25(OH)D in SLE subjects, the complex relationship between vitamin D deficiency and oral diseases may exist due to the numerous variables involved in the pathogenesis of SLE which may affect other systems of the body, including oral cavity. Moreover, there is a complex interaction between oral ecosystem and immune system that may be influenced not only by internal regulation of body systems but also by external factors, such as nutrition factors, and one of the important nutrition factors is vitamin D.
A present study showed a limited number of SLE patients; vitamin D deficiency may not only a risk factor for systemic lupus erythematous development but also affected oral immune system, which decreases the defense mechanism and may result in TLR 4-mediated oral diseases. The vitamin D supplement may have a protective role in oral health. Further study can be done in large population groups with different ethnic backgrounds. A study can be done on control subjects for comparison of values may be needed to investigate the effect of vitamin D on SLE oral cavity immunity system.
| Conclusion | | |
The oral immune system’s regulation in SLE may be negatively impacted by a substantial positive correlation between saliva CD11b+ cells that expressed TLR4 and low blood 25(OH)D levels.
Acknowledgements
We would like to acknowledge Dr. Soetomo Hospital Surabaya, all members of Biomedis Laboratorium, Faculty of Medicine, Brawijaya University, Malang, and Tawada Laboratorium.
Financial support and sponsorship
Funding has been made available from Universitas Gadjah Mada.
Conflicts of interest
There are no conflicts of interest.
Author contributions
HS: research concept and design, writing article, data analysis & interpretation, final approval of the article, data collection & assembly data; DSE: writing the article, critical revision of the article; A: writing the article, critical revision of the article, final approval of the article.
Ethical policy and Institutional Review Board statement
This study was approved by the Ethical Committee for Research of Dr. Soetomo Hospital, Surabaya, Indonesia (0284/KEPK/V/2018). All the procedures were performed as per the ethical guidelines laid down by the Declaration of Helsinki (1975).
Declaration of patient consent
All participants who matched the criteria were informed about the study, and written consent was taken from each participant with an explanation of the purpose of the study.
Data availability statement
The dataset used in the current study is available on request from [email protected].
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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