|Ahead of print publication
Serum tenascin-c in systemic lupus erythematosus and association with clinical expression of the disease
Shaimaa Mustafa Abdelwahab1, Adlia Mohamed Abdelhady1, Doaa S Atta2, Ghada Abdelsalam Ali2, Amany M Sediq3
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 Submission||21-Nov-2019|
|Date of Acceptance||23-May-2020|
Shaimaa Mustafa Abdelwahab,
Department of Rheumatology and Rehabilitation, Zagazig University, Zagazig
Source of Support: None, Conflict of Interest: None
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 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 [Epub ahead of print] [cited 2021 Jan 23]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=301570
| Introduction|| |
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.
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.
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.
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. TN-C is abundantly expressed during embryogenesis and organogenesis. Its expression is highly restricted in healthy adult tissues.,
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. TN-C plays a role in regulating the axis of inflammation in LPS-activated toll-like receptor (TLR) signaling.
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.,,,,
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|| |
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, 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). 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.
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|| |
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 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|| |
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. Predicting the disease course of SLE may allow better targeting of aggressive treatment to improve the therapeutic outcome.
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. and Závad et al. 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. 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.
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.
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.
| 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.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]