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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 16  |  Issue : 1  |  Page : 18-22

Serum tenascin-c in systemic lupus erythematosus and association with clinical expression of the disease


1 Department of Rheumatology and Rehabilitation, Zagazig University, Egypt, Ghada, Egypt
2 Department of Clinical Pathologist, Sharkia General Hospital, Egypt
3 Department of clinical pathology Zagazig University, Egypt

Date of Submission21-Nov-2019
Date of Acceptance23-May-2020
Date of Web Publication23-Mar-2021

Correspondence Address:
Dr. Shaimaa Mustafa Abdelwahab
Department of Rheumatology and Rehabilitation, Zagazig University, Zagazig
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_170_19

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  Abstract 


Background: Tenascin-C (TN-C) is a pro-inflammatory glycoprotein with various biological functions. TN-C plays a major role in cell adhesion, migration, proliferation, and cellular signaling through the induction of pro-inflammatory cytokines.
Aim of the Work: This study was designed to investigate the relationship between serum TN-C levels and disease activity in patients with systemic lupus erthromatosus.
Subjects and Methods: This is a case–control observational study that was carried out on 68 participants and divided into two groups. Group A included 34 systemic lupus erythematosus (SLE) patients and Group B included (34) apparently healthy volunteers. They were age and sex matched with the patients. Clinical examination as well as routine laboratory investigations confirmed their healthy status. All patients were subjected to full history taking, through clinical examination, laboratory investigations as C-reactive protein, erythrocyte sedimentation rate, C3, C4, ANA, and anti-dsDNA. Serum TN-C estimation of serum TN-C was done for SLE patients and the control group using double-antibody sandwich enzyme-linked immunosorbent assay. Disease activity of SLE patients was assessed according to SLE disease activity index 2000 score.
Results: Serum level of TN-C was higher in SLE patients than healthy control but with no statistically significant difference (P > 0.05). There was highly statistically significant difference (P < 0.001) between active and inactive SLE patients regarding TN-C level.
Conclusion: Serum TN-C level is elevated in SLE patients and correlates with disease activity which indicates its possible role in SLE pathogenesis. Thus, TN-C may provide a novel research target for the pathogenesis and therapy of SLE.

Keywords: Serum-tenascin C-systemic lupus erthromatosus-disease activity


How to cite this article:
Abdelwahab SM, Abdelhady AM, Atta DS, Ali GA, Sediq AM. Serum tenascin-c in systemic lupus erythematosus and association with clinical expression of the disease. Indian J Rheumatol 2021;16:18-22

How to cite this URL:
Abdelwahab SM, Abdelhady AM, Atta DS, Ali GA, Sediq AM. Serum tenascin-c in systemic lupus erythematosus and association with clinical expression of the disease. Indian J Rheumatol [serial online] 2021 [cited 2021 Sep 16];16:18-22. Available from: https://www.indianjrheumatol.com/text.asp?2021/16/1/18/301570




  Introduction Top


Systemic lupus erythematosus (SLE) is a chronic relapsing multisystemic autoimmune disorder. SLE is characterized by the production of antibodies to the components of the cell nucleus in association with a diverse combination of clinical manifestations. The primary pathological findings in patients with SLE are those of inflammation, vasculitis, immune complex deposition, and vasculopathy.[1]

In spite of the traditional serological biomarkers such as anti-double-stranded DNA antibodies (anti-dsDNA antibodies), the lack of useful biomarkers for SLE hampers the assessment of disease activity and impedes the evaluation of treatment response. For this reason, there is the growing interest in the exploration of new biomarkers for use as surrogate markers of disease activity and/or to predict flares of the disease.[2]

Tenascin-C (TN-C) is a glycoprotein which in humans is encoded by the TN-C gene. TN-C is a large extracellular matrix glycoprotein that belongs to the damage-associated molecular patterns family.[3]

TN-C interacts with a variety of extracellular matrix molecules and cell surface receptors, thus affecting tissue architecture, tissue resilience, and cell responses. It plays a major role in cell adhesion, migration, proliferation, and cellular signaling through the induction of pro-inflammatory cytokines.[4] TN-C is abundantly expressed during embryogenesis and organogenesis. Its expression is highly restricted in healthy adult tissues.[5],[6]

The expression of TN-C in adults is limited to the site of tissue injury, usually temporary, and the expression level of TN-C returns to normal after tissue repair is completed. In contrast, the sustained high expression of TN-C is common in inflammation, tissue remodeling, and autoimmune diseases.[7] TN-C plays a role in regulating the axis of inflammation in LPS-activated toll-like receptor (TLR) signaling.[8]

Persistent expression of TN-C is associated with a wide variety of pathological conditions. Detection of high-protein levels of TN-C within pathological tissues as well body fluids could be of diagnostic value and might provide a means to earlier detect associated conditions, including heart disease, fibrosis, preeclempsia, rheumatoid arthritis, SLE, and cancer.[9],[10],[11],[12],[13]

In this study, we attempted to evaluate TN-C level in the sera of SLE patients and to determine its relation with disease activity.


  Subjects and Methods Top


This is a case–control observational study was carried out in Rheumatology and Rehabilitation Departments, Faculty of Medicine, Zagazig University Hospitals and included SLE patients are group (A) and the healthy controls are group (B). Thirty-four SLE patients diagnosed according to systemic lupus international collaborating clinics,[14] and 34 age- and sex-matched healthy participants taken as controls. Patients with other inflammatory autoimmune diseases and any associated chronic systemic disease (cardiac, malignancy, or history of sepsis) were excluded from the study. Informed consent was signed by the patients and controls. The study was approved by the Institutional Review Board of the faculty.

SLE disease activity was evaluated by SLE disease activity index 2000 (SLEDAI-2K).[15] All patients were subjected to full history taking, thorough clinical examination, laboratory investigations including complete blood count, 24 h protein, serum creatinine, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) was detected by immunohistochemistry. ANA was done by indirect immunofluorescent assay using kallestad HEP2 cell live substrate (Bio-rad lab orations, Redmond, USA). Anti-dsDNA antibodies titer was done by indirect immunofluorescent antibody using kallested crathidia leucilia substrate (Bio-rad lab orations, Redmond, USA). Serum complement levels (C3 and C4) were detected by the use of immunonephelometry using BN prospect (DADE BEHRING, New York, USA).

Measurement of serum TN-C was performed by the sandwich enzyme-linked immunosorbent assay (ELISA). Double-antibody sandwich ELISA for SLE patients and controls according to manufacturer's protocol by (Sun Red International trade company, Shang-hai, China), serum samples were collected from patients on the same day of examination.

Statistical analysis

All the data were collected, tabulated, and statistically analyzed using the SPSS software version 20.0 for windows (SPSS Inc., Chicago, IL, USA 2011). Quantitative data were expressed as the mean ± standard deviation and (range), and qualitative data were expressed as absolute frequencies (number) and relative frequencies (percentage) t-test was used to compare between two independent groups of normally distributed variables. Mann-Whitnney U-test was used to compare between two independent groups of not normally distributed variables. Percent of categorical variables was compared using the Chi-square test or Fisher's exact test when appropriate. Spearman's correlation coefficient was calculated to assess the relationship between various study variables, (+) sign indicate direct correlation and (−) sign indicate inverse correlation, also values near to 1 indicate strong correlation and values near 0 indicate weak correlation. All tests were two sided. P < 0.05 was considered statistically significant(s), and P ≥ 0.05 was considered statistically insignificant (NS).


  Results Top


Patients and controls data are summarized in [Table 1]; there was no statistical significant difference between the groups regarding their demographic, the most common clinical presentation was arthritis followed by mucocutenous manifestations as showed in [Table 2].
Table 1: Demographic characteristics of both groups

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Table 2: Disease characteristics of systemic lupus erythematosus patients (n=34)

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Although the mean TN-C serum level was higher in SLE patients (520.29 ± 208.7 ng/ml) compared to control (434.97 ± 198.35 ng/ml), there was no statistical significant difference [Table 3].
Table 3: Comparison between Group A and Group B regarding serum Tenascin-C level

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[Table 4] showed that serum TN-C level was statistically significantly (P < 0.05) higher in active SLE patients compared to inactive patients.
Table 4: Comparison between active and inactive systemic lupus erythematosus patients regarding serum tenascin-C level

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There was significant positive correlations between mean serum TN-C level and laboratory data (ESR and CRP) and SLEDAI-2K score [Table 5].
Table 5: Correlation between demographic, laboratory, systemic lupus erythematosus disease activity index 2000 and Tenascin-C level among systemic lupus erythematosus group

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Studying relation between ANA, C3, dsDNA, corticosteroid and DMARDs use, and TN-C level among SLE patients. [Table 6] shows a statistically significant relation between serum TN-C level and C3, C4 P = 0.001, 0.023, respectively. It obvious low level serum C3, C4 associated with high level TN-C.
Table 6: Relation between ANA, C3, dsDNA , corticosteroid and DMARDs use and tenascin-C level among systemic lupus erythematosus patients (n=34)

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Receiver-operating characteristic analysis

[Figure 1] and [Table 7] ROC analysis Optimal cut off; serum TN-C was ≥427 pg/ml to detect SLE activity. Validity of serum TN-C for detecting active and inactive SLE patients with sensitivity = 79.16%, specificity = 90%, positive predictive value = 95%, negative predictive value = 64.3% and accuracy = 82.4%. Serum TN-C good prognostic test to differentiate between active and inactive SLE patients (area under curve [AUC] = 0.817).
Figure 1: Receiver operating characteristic curve shows area under the curve for detecting active and inctive systemic lupus erythematosus patients by serum tenascin-C level (n = 34)

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Table 7: Validity of serum Tenascin-C level for detecting active and inactive systemic lupus erythematosus patients (n=34)

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  Discussion Top


This research was conducted to study the role of TNC in SLE as a biomarker of disease activity in SLE patients. An important prerequisite for testing a biomarker in a clinical setting is its biological plausibility. SLE is a complex autoimmune disease characterized by enhanced autoantibody formation, excessive proinflammatory cytokine production, and damage to multiple organ systems.[3] Predicting the disease course of SLE may allow better targeting of aggressive treatment to improve the therapeutic outcome.[16]

This study showed that there was highly statistically significant difference (P < 0.001) between active and inactive SLE patients regarding mean serum TNC level and a statistically significant (P < 0.05) positive correlation between TNC level and SLEDAI-2K-2K score. The results of Khalil et al.[17] and Závad et al.[18] were in agreement with our findings. These results can be explained by the ability of TN-C to trigger inflammation and directly shape immune responses. Three main binding partners have been identified to be responsible for the inflammatory effects of tenascin-C: TLR4, and integrins α9 β1 and αVβ3. The most widely reported effect of TLR4 activation by TN-C is the induction of soluble proinflammatory mediators, such as interleukin (IL)-6, IL-8, and tumor necrosis factor. This has been observed in a number of cell types, including macrophages, dendritic cells, fibroblasts, and chondrocytes.[19] TN-C signaling through TLR4 has been implicated in inflammasome priming. Inflammasomes are multiprotein, intracellular complexes that drive specific inflammatory responses, including the release of IL-1 β and IL-18, and induction of pyroptosis, a type of programmed cell death.[20]

Anti-dsDNA antibodies and complement levels are the only serological parameters that are routinely used as activity-specific biomarkers in SLE patient care. However, these traditional biomarkers are not always appropriate for clinical monitoring because high levels of anti-dsDNA or low levels of C3/C4 are persistent in some patients with lupus.[21]

In this study, there was a significant correlation between serum TNC level and other laboratory results as CRP, ESR, antidouble stranded and low complement in SLE patients. These result also agreed with the results of Khalil et al. and Závada and et al.,our study did not find any association of treatment and TN-C levels in contrast to Závada et al.

Serum TN-C good prognostic test to differentiate between active and inactive SLE patients (AUC =0.817), TN-C is probably neither disease-specific nor pathology-specific, but rather a more universal and ubiquitous marker of ongoing tissue injury, although it has a potential role for monitoring the disease activity.[3]


  Conclusion Top


Serum TN-C level is elevated in SLE patients and correlates with disease activity which indicates its possible role in SLE pathogenesis. Thus, TN-C may provide a novel research target for the pathogenesis and therapy of SLE.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Rekvig OP. Systemic lupus erythematosus: definitions, contexts, conflicts, enigmas. Front Immunol 2018;9:387.  Back to cited text no. 1
    
2.
Jarukitsopa S, Hoganson DD, Crowson CS, Sokumbi O, Davis MD, Michet CJ Jr., et al. Epidemiology of systemic lupus erythematosus and cutaneous lupus erythematosus in a predominantly white population in the United States. Arthritis Care Res (Hoboken) 2015;67:817-28.  Back to cited text no. 2
    
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Midwood KS, Hussenet T, Langlois B, Orend G. Advances in tenascin-C biology. Cell Mol Life Sci 2011;68:3175-99.  Back to cited text no. 3
    
4.
Midwood KS, Orend G. The role of tenascin-C in tissue injury and tumorigenesis. J Cell Commun Signal 2009;3:287-310.  Back to cited text no. 4
    
5.
Chiquet-Ehrismann R, Mackie EJ, Pearson CA, Sakakura T. Tenascin: An extracellular matrix protein involved in tissue interactions during fetal development and oncogenesis. Cell 1986;47:131-9.  Back to cited text no. 5
    
6.
Yoshida T, Yoshimura E, Numata H, Sakakura Y, Sakakura T. Involvement of tenascin-C in proliferation and migration of laryngeal carcinoma cells. Virchows Arch 1999;435:496-500.  Back to cited text no. 6
    
7.
Udalova IA, Ruhmann M, Thomson SJ, Midwood KS. Expression and immune function of tenascin-C. Crit Rev Immunol 2011;31:115-45.  Back to cited text no. 7
    
8.
Orak U, Celik E, Kavak SB, Demirel İ, Atilgan R, Aydin S. et al. Tenascin C levels in patients with mild and severe preeclampsia. J Matern Fetal Neonatal Med 2016;29:270-3.  Back to cited text no. 8
    
9.
Orend G, Saupe F, Schwenzer A, Midwood K. The Extracellular Matrix and Cancer: Regulation of Tumor Cell Biology by Tenascin-C. Hong Kong: IConcept Press; 2014.  Back to cited text no. 9
    
10.
Schwenzer A, Ang X, Ikuls TR, Ayne JB, Ayles HR, Quirke AM, et al. Identification of an immunodominant peptide from itrullinated tenascin-C as a major target for autoantibodies in rheumatoid arthritis. Ann Rheum Dis 2015;56pp:345-55.  Back to cited text no. 10
    
11.
Ulusoy S, Ozkan G, Mentese A, Guvercin B, Karahan SC, Yavuz A, et al. A new predictor of mortality in hemodialysis patients; Tenascin-C. Life Sci 2015;141:54-60.  Back to cited text no. 11
    
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Franz M, Jung C, Lauten A, Figulla HR, Berndt A. Tenascin-C in cardiovascular remodeling: Potential impact for diagnosis, prognosis estimation and targeted therapy. Cell Adh Migr 2015;9:90-5.  Back to cited text no. 12
    
13.
Imanaka-Yoshida K. Tenascin-C in cardiovascular tissue remodeling: From development to inflammation and repair. Circ J 2012;76:2513-20.  Back to cited text no. 13
    
14.
Petri M, Orabi A, Alarcon G, Gordon C, Merrill J, Fortin P, et al. Derivation and validation of systemic lupus international collaboration clinic classification criteria for systemic lupus erythematosus. Arthritis Rheumatol 2012;64:2677-86.  Back to cited text no. 14
    
15.
Gladman DD, Ibanez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol 2002;29:288-91.  Back to cited text no. 15
    
16.
Gheita TA, Rehim DM, Kenawy SA, Gheita HA. Clinical significance of matrix metalloproteinase-3 in systemic lupus erythematosus patients: A potential biomarker for disease activity and damage. Acta Reumatol Port 2015;40:145-9.  Back to cited text no. 16
    
17.
Khalil F, Rafat NM, Nada MS, Magdy M, Abdelaziz HA. Studying tenascin-C in systemic lupus erythematosus as a new biomarker for disease activity. Al-Azhar Assuit Med J 2018;55:45-8.  Back to cited text no. 17
    
18.
Závada J, Uher M, Svobodová R, Olejárová M, Hušáková M, Ciferská H, et al. Serum tenascin-C discriminates patients with active SLE from inactive patients and healthy controls and predicts the need to escalate immunosuppressive therapy: A cohort study. Arthritis Res Ther 2015;17:341.  Back to cited text no. 18
    
19.
Midwood K, Sacre S, Piccinini AM, Inglis J, Trebaul A, Chan E, et al. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat Med 2009;15:774-80.  Back to cited text no. 19
    
20.
Machino-Ohtsuka T, Tajiri K, Kimura T, Sakai S, Sato A, Yoshida T, et al. Tenascin-C aggravates autoimmune myocarditis via dendritic cell activation and Th17 cell differentiation. J Am Heart Assoc 2014;3:e001052.  Back to cited text no. 20
    
21.
Li T, Prokopec SD, Morrison S, Lou W, Reich H, Gladman D, et al. Anti-nucleosome antibodies outperform traditional biomarkers as longitudinal indicators of disease activity in systemic lupus erythematosus. Rheumatology (Oxford) 2015;54:449-57.  Back to cited text no. 21
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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