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Alsahebfosoul F, Rahimpourkoldeh S, Eskandari N, Shaygannejad V, Ganjalikhani Hakemi M, Dabiri A, et al . Gene Expression of CD226 and Its Serum Levels in Patients With Multiple Sclerosis. Caspian.J.Neurol.Sci. 2018; 4 (14) :91-97
URL: http://cjns.gums.ac.ir/article-1-233-en.html
1- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
2- Isfahan Neurosciences Research Center, Alzahra Hospital, Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran
3- Department of Immunology, International Campus, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Introduction
Multiple Sclerosis (MS) is a chronic disabling inflammatory, and demyelinating disease, caused by immune responses directed against myelin proteins and progressive axonal loss in the Central Nervous System (CNS) [1]. MS is one of the most common causes of primary neurological disability in young people, and its incidence increases in late adolescence [2]. It is most prevalent in the late 20’s and early 30’s [3].
Females are affected approximately 2.5 times more than males [4]. The environmental, genetic, and epigenetic factors explain the risk for developing MS [5]. There are different relationships between the prevalence of MS and environmental factors, including sun exposure, vitamin D deficiency, and Epstein-Barr Virus (EBV) [6]. Importantly, these environmental factors can affect pathogenetic pathways and some of them can have a modifying impact [7].
MS is not classified as a genetic disease. However, there is genetic risk that may be inherited in MS [8]. Recent Genome-Wide Association Study (GWAS) has identified a total of 110 distinct genetic regions associated with MS [9]. HLA-DRB1*1501 allele is the first known potential genetic risk factor, with 14%–30% prevalence in countries with high MS risk [10]. CD4+T helper cells regulate appropriate cellular and humoral immune responses to a broad range of pathogens and get involved in many diseases progress. The balance of the earliest determined CD4+T helper cell subsets, Th1 and Th2, play an important role in autoimmune diseases [11]. Dysregulated balance of Th1 and Th2 cells can cause MS. Th1 cells are considered initially as the principal pathogenic T cells in MS [12].
The prevalence of MS extensively varies in different geographic regions, races, and genders [13]. There has been a significant concern for the epidemiology of MS in Iran during the last decade. The ratio of MS has been increasing rapidly in Iran, particularly among females and in Isfahan Province [14]. MS is a variable and unpredictable disease that places a substantial burden on patients, their families, and the health service [15].
Considerable progress has been made in prevention, improvement, and reduction of the severity of MS attacks. The expression of Cluster of Differentiation 226 (CD226) can be one of the contributing factors, especially in the Iranian population with MS. Genome-wide association study in autoimmune patients has identified allelic variants in some T cell costimulatory molecular pathways as genetic risk factors in disease pathogenesis. This includes allelic variants in CD226 (DNAX Accessory Molecule1 [DNAM-1], DNAX Accessory Molecule-1), located at 18q22.3 gene encodes a 67 kDa [336 amino acid (aa)] cell surface membrane protein with 2 immunoglobulin V set domains (aa31–aa125 and aa135–aa240) with an extracellular region [16, 17].
CD226 is expressed on the majority of Natural Killer (NK) cells, T cells, monocytes, and platelets [18]. This molecule has a role in enhancing the cytotoxic function of NK cells [19], demonstrating that CD226 is associated with Leukocyte Function Antigen 1 (LFA-1) to induce IFN-γ production in naive CD4+T cells [16]. CD226 is one of the immunoglobulin super family members and binds 2 different cell surface ligands, including poliovirus receptor (CD155) and Nectin-2 (CD112) [20].
CD112 and Necl-5 (CD155) are CAM (Costimulatory Activating Molecule) members, that form homodimers (for nectin-2) or heterodimers in their functions for cell adhesion [18]. The interaction of DNAM-1 (CD226) with its ligands is implicated in the functions of a variety of immune cells. Nectin-2 can stimulate the reaction of NK cells and cytolytic T lymphocytes through its interaction with DNAM-1 [21]. CD226 costimulatory signals potentially promote Th1 differentiation [22], but it cannot lead to differentiation of neither Th2 nor Th0 cells, enhancing IFN-γ production by naive T cells [23]. 
Another study reported that knockdown of CD226 on human T cells resulted in a decrease in T-bet and IFN-γ expression. However, the role of CD226 on Th2 and Th17 cells remains unknown [23]. The expression of DNAM-1 in Experimental Autoimmune Encephalomyelitis (EAE) and DNAM-1 were exhibited in the skin of patients with Systemic Sclerosis (SSc) [24]. CD226 is involved in the up-regulation of T cells. Treatment with anti-CD226 in vivo results in a significant reduction of Th1 cell expansion and in the induction of antigen presenting cells that prohibit T cell activation [25].
In total, CD226 could be an important biomarker in differentially regulating the pro-inflammatory (Th1/Th17)/anti-inflammatory (Th2) balance, indicating that the CD226 could be targeted in therapeutic approaches to autoimmune diseases like MS [17]. Therefore, the present study aimed to evaluate gene expression level of CD226 and its serum levels in patients with MS.

Materials and Methods
 Study participants

A total of 30 healthy individuals and 30 new cases of Relapsing-Remitting MS (RRMS) patients diagnosed according to McDonald’s criteria were included in this study. The exclusion criteria for selecting healthy controls were as follows: Suffering from any autoimmune disease, previous organ transplantation and suffering from any inflammatory disease according to the results of erythrocyte sedimentation rate and C-reactive protein. None of the patients experienced relapse within 3 months prior to the onset of the study and were not on corticosteroid agents for at least 3 months before the onset of the research. Patients on corticosteroid therapy, and immunosuppressive drugs were excluded due to the possible effect of these agents on CD226 expression and its serum level. Table 1 presents the demographic characteristics of the participants.

Determination of CD226 mRNA expression levels
Blood samples (3 mL) were collected from all participants using an EDTA collection tube. Total RNA was extracted from the whole blood samples using a Total RNA Extraction Mini Kit (Yekta Tajhiz, Tehran, Iran). After isolation, the quality of RNA was checked by gel electrophoresis, and RNA quantity was measured using nanodrop (OD 260 nm) (Nanophotometer Pipette, Helmholtz, Nauenberg, Germany).
At the reverse transcription step, 5 ng of total RNA was used to synthesize the complementary DNA with oligo (dT) primer using the RevertAid First Strand cDNA Synthesis Kit (Thermo Scientific, USA). Quantitative real-time PCR analyses were performed using RealQ Plus 2x Master Mix Green (Ampliqon, Denmark) and Step One Plus Real-Time PCR System (Applied Biosystems).
β-Actin Gene (ACTB) was used as an endogenous control and samples were run in triplicate. Specific primers for CD226 was obtained from the report of Ye Xal. et al. and primers for ACTB as the housekeeping gene was designed by Allele ID 7.6 and BLAST (NCBI online server) [26]. Table 2 lists the sequences of primers. The relative amount of target mRNA expression was estimated by the comparative 2-ΔΔCT method which normalizes the copy number of the target mRNA to that of an endogenous reference gene (ACTB) [27].
 



 



 



 
Determination of CD226 serum level
Blood samples (3 mL) were collected from the patients with MS and the controls, using serum-separating tubes. The blood samples were centrifuged at 1500×g for 4 min and the cell-free sera were stored at -80ºC for the Enzyme-Linked Immunosorbent Assay (ELISA). The soluble CD226 levels were measured in duplicate wells using human CD226 ELISA kit (Eastbiopharm Cat. No: CK-E91994) according to the manufacturer’s instructions. The standard curve was drawn using the derived values based on data from the ELISA reader (Hiperion, Germany). Optical Density (OD) at 450 nm wavelength was recorded in the blood samples of both groups. The sensitivity was 2.4 ng/L.

Statistical analysis
The Shapiro-Wilk test was used to study the normality of the data. The data were then analyzed by the Mann-Whitney U test. For all evaluations, P<0.05 was considered as statistically significant. All statistical analyses were performed using SPSS.

Results
Levels of CD226 gene expression
The mean number of CD226 mRNA expressing blood was 7 in MS and was 6.76 in healthy controls. We compared CD226 gene expression between healthy controls and new cases of MS in which none of the patients of this group experienced relapse during recent 3 months and were not on corticosteroid agents since at least recent 3 months. As shown in Figure 1, eventhough CD226 expression increased in the patients, the difference was not statistically significant (P=0.341).
 

 
CD226 serum level
Soluble CD226 was detected in the serum of all patients with MS and healthy subjects. The mean values of CD226 serum level were 2.19 ng/mL in the case group and 2.18 ng/ in the control group. We did not detect any significant difference of CD226 serum levels in the MS and control groups (P=0.978) (Table 3). The assessment of protein expression by ELISA confirmed the result of real-time technique. There was a correlation between the numbers of CD226 mRNA expressing in the whole blood and serum levels of soluble CD226 (P<0.05).

Discussion
Multiple Sclerosis is an autoimmune and neurodegenerative disease of the CNS. CD226 is involved in the upregulation of Th1 and Th17 cells. Using flow cytometry for recognizing the exact cells that express CD226 is important, because Th1 and Th17 cells play the most important role in pathogenesis of MS [28]. Here, we investigated expression of CD226 in RRMS.
Our results showed no statistically significant difference in the level of CD226 gene expression in peripheral blood sample of new cases of RRMS patients and healthy individuals. In contrast to our data, Gross et al. demonstrated that CD226 expression reduced in MS patients. They also concluded that the higher threshold for NK-cell activation is attributable to the reduced CD226 expression [29].
Another study also showed the association of non-synonymous exchange (Gly307Ser) in the gene for CD226 variant with SSc and Wegener’s Granulomatosis (WG) also demonstrated that (Single Nucleotide Polymorphism) SNPs located at CD226 gene, such as rs727088 and rs763361, can influence CD226 mRNA levels and different variant of these allels can be protective or predispose to autoimmune diseases [30, 33]. The SNPs of each person along with the gene expression of CD226 are necessary for the exact conclusion [34]. 
The data regarding gene expression showed no significant changes in CD226 protein expression levels. Since the coinhibitory receptor T cell Ig and ITIM domain (TIGIT) and the costimulatory factor CD226 bind to the common ligand CD155 and the TIGIT transduce inhibitory signals and compete with CD226 for binding with CD155 on the surface of antigen presenting cells [35, 36]. It also seems necessary to demonstrate further research on the gene expression of TIGIT.
The lack of association in this study also may be due to sample size or the course of MS disease, as others considered a greater sample size in their studies. Extensive variation in the prevalence of MS in different geographical districts and races may also contributed to the difference in the result of this study compared to other studies.

Conclusion
We determined no significant expression change of CD226 in the blood samples of patients with MS. Therefore, measuring the expression of CD226 gene is questionable as a biomarker for the diagnosis or improvement of MS. Since CD226 targeting would exclusively target proinflammatory Th1 and Th17 cells, and these cells have the most important role in the pathogenesis of MS [28], additional studies are therefore required to measure CD226 expression in certain subsets.

Ethical Considerations
Compliance with ethical guidelines

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee. This study was approved by the Ethics Committee of Isfahan University of Medical Sciences (Grant No: 396067).

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest
The authors certify that they have no affiliation with or involvement in any organization or entity with any financial interest, or non-financial interest in the subject matter or materials dismissed in this manuscript.

Acknowledgements
I hereby appreciate all the people I have had the pleasure to work during this project.



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Type of Study: Research | Subject: General
Received: 2018/01/5 | Accepted: 2018/05/23 | Published: 2018/07/1

References
1. Rossi B, Constantin G. Live imaging of immune responses in experimental models of Multiple Sclerosis. Front Immunol. 2016; 7:506. [DOI:10.3389/fimmu.2016.00506] [PMID] [PMCID] [DOI:10.3389/fimmu.2016.00506]
2. Evans C, Beland SG, Kulaga S, Wolfson C, Kingwell E, Marriott J, et al. Incidence and prevalence of Multiple Sclerosis in the Americas: A systematic review. Neuroepidemiology. 2013; 40(3):195-210. [DOI:10.1159/000342779] [PMID] [DOI:10.1159/000342779]
3. Ascherio A, Munger KL, Lunemann JD. The initiation and prevention of Multiple Sclerosis. Nat Rev Neurol. 2012; 8(11):602-12. [DOI:10.1038/nrneurol.2012.198] [PMID] [PMCID] [DOI:10.1038/nrneurol.2012.198]
4. Kamm CP, Uitdehaag BM, Polman CH. Multiple Sclerosis: current knowledge and future outlook. Eur Neurol. 2014; 72(3-4):132-41. [DOI:10.1159/000360528] [PMID] [DOI:10.1159/000360528]
5. Rejali M, Hosseini SM, Kazemi Tabaee MS, Etemadifar M. Assessing the risk factors for Multiple Sclerosis in women of reproductive age suffering the disease in Isfahan province. Int J Prev Med. 2016; 7:58. [DOI:10.4103/2008-7802.178532] [PMID] [PMCID] [DOI:10.4103/2008-7802.178532]
6. O'Gorman C, Lucas R, Taylor B. Environmental risk factors for Multiple Sclerosis: A review with a focus on molecular mechanisms. Int J Mol Sci. 2012; 13(9):11718-52. [DOI:10.3390/ijms130911718] [PMID] [PMCID] [DOI:10.3390/ijms130911718]
7. Olsson T, Barcellos LF, Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for Multiple Sclerosis. Nat Rev Neurol. 2017; 13(1):25-36. [DOI:10.1038/nrneurol.2016.187] [PMID] [DOI:10.1038/nrneurol.2016.187]
8. Sawcer S, Ban M, Wason J, Dudbridge F. What role for genetics in the prediction of Multiple Sclerosis? Ann Neurol. 2010; 67(1):3-10. [DOI:10.1002/ana.21911] [PMID] [PMCID] [DOI:10.1002/ana.21911]
9. Wang Y, Bos SD, Harbo HF, Thompson WK, Schork AJ, Bettella F, et al. Genetic overlap between Multiple Sclerosis and several cardiovascular disease risk factors. Mult Scler. 2016; 22(14):1783-93. [DOI:10.1177/1352458516635873] [PMID] [PMCID] [DOI:10.1177/1352458516635873]
10. Handunnetthi L, Ramagopalan SV, Ebers GC. Multiple Sclerosis, vitamin D, and HLA-DRB1*15. Neurology. 2010; 74(23):1905-10. [DOI:10.1212/WNL.0b013e3181e24124] [PMID] [PMCID] [DOI:10.1212/WNL.0b013e3181e24124]
11. Zhang Y, Zhang Y, Gu W, He L, Sun B. Th1/Th2 cell's function in immune system. Adv Exp Med Biol. 2014; 841:45-65. [DOI:10.1007/978-94-017-9487-9_3] [PMID] [DOI:10.1007/978-94-017-9487-9_3]
12. Fletcher JM, Lalor SJ, Sweeney CM, Tubridy N, Mills KH. T cells in Multiple Sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol. 2010; 162(1):1-11. [DOI:10.1111/j.1365-2249.2010.04143.x] [PMID] [PMCID] [DOI:10.1111/j.1365-2249.2010.04143.x]
13. Leray E, Moreau T, Fromont A, Edan G. Epidemiology of Multiple Sclerosis. Rev Neurol (Paris). 2016; 172(1):3-13. [DOI:10.1016/j.neurol.2015.10.006] [PMID] [DOI:10.1016/j.neurol.2015.10.006]
14. Etemadifar M, Sajjadi S, Nasr Z, Firoozeei TS, Abtahi SH, Akbari M, et al. Epidemiology of Multiple Sclerosis in Iran: a systematic review. Eur Neurol. 2013; 70(5-6):356-63. [DOI:10.1159/000355140] [PMID] [DOI:10.1159/000355140]
15. Burks JS, Bigley GK, Hill HH. Rehabilitation challenges in Multiple Sclerosis. Ann Indian Acad Neurol. 2009; 12(4):296-306. [DOI:10.4103/0972-2327.58273] [PMID] [PMCID] [DOI:10.4103/0972-2327.58273]
16. Lozano E, Dominguez-Villar M, Kuchroo V, Hafler DA. The TIGIT/CD226 axis regulates human T cell function. J Immunol. 2012; 188(8):3869-75. [DOI:10.4049/jimmunol.1103627] [PMID] [PMCID] [DOI:10.4049/jimmunol.1103627]
17. Maiti AK, Kim-Howard X, Viswanathan P, Guillen L, Qian X, Rojas-Villarraga A, et al. Non-synonymous variant (Gly307Ser) in CD226 is associated with susceptibility to multiple autoimmune diseases. Rheumatology (Oxford). 2010; 49(7):1239-44. [DOI:10.1093/rheumatology/kep470] [PMID] [PMCID] [DOI:10.1093/rheumatology/kep470]
18. Liu J, Qian X, Chen Z, Xu X, Gao F, Zhang S, et al. Crystal structure of cell adhesion molecule nectin-2/CD112 and its binding to immune receptor DNAM-1/CD226. J Immunol. 2012; 188(11):5511-20. [DOI:10.4049/jimmunol.1200324] [PMID] [DOI:10.4049/jimmunol.1200324]
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