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ORIGINAL ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 1  |  Page : 250-254

Role of calgranulin C protein in psoriasis


1 Department of Dermatology, Andrology and STDs, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Dermatology, Ministry of Health, Menoufia, Egypt

Date of Submission14-Oct-2018
Date of Acceptance17-Nov-2018
Date of Web Publication17-Apr-2019

Correspondence Address:
Shimaa A Ibrahim
6th October City, Giza Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_323_18

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  Abstract 


Objective
The objective of this study was to clarify the possible role of calgranulin C (Cal C) protein in psoriasis and to correlate its level with disease severity.
Background
Psoriasis is a chronic inflammatory disease that affects 2–3% of world population. Cal C protein has been implicated in the pathogenesis of various inflammatory diseases. The relation between psoriasis and Cal C protein is discussed in this study.
Patients and methods
This case–control study was conducted on 25 patients with psoriasis vulgaris and 15 age-matched and sex-matched healthy individuals. All patients were subjected to history taking and complete medical examination. Serum levels of Cal C protein were measured by enzyme-linked immunosorbent assay technique. Serum levels of Cal C protein were statistically analyzed in relation to Psoriasis Area and Severity Index score.
Results
High serum level of Cal C protein among cases showed highly significant difference compared with control group (P < 0.001). Moreover, there was a highly significant difference between moderate and severe cases (P < 0.001 for both). There was a significant positive correlation between Cal C protein and Psoriasis Area and Severity Index score (P = 0.01).
Conclusion
Cal C protein was higher in patients with plaque psoriasis than normal population, so it may play a significant role in the pathogenesis of psoriasis and may provide important clues to assist in the development of new therapeutic strategies for patients with psoriasis and also may be used as a marker of psoriasis severity.

Keywords: calgranulin C protein, psoriasis, role


How to cite this article:
Basha MA, Shehata WA, El-Hefnawy SM, Ibrahim SA. Role of calgranulin C protein in psoriasis. Menoufia Med J 2019;32:250-4

How to cite this URL:
Basha MA, Shehata WA, El-Hefnawy SM, Ibrahim SA. Role of calgranulin C protein in psoriasis. Menoufia Med J [serial online] 2019 [cited 2019 Jul 21];32:250-4. Available from: http://www.mmj.eg.net/text.asp?2019/32/1/250/256102




  Introduction Top


Psoriasis is a chronic inflammatory hyperproliferative disease of the skin, scalp, nails, and joints with genetic background affecting ~2–3% of the world population [1]. Chronic plaque psoriasis (psoriasis vulgaris) is by far the most common type, but other morphological variants include guttate psoriasis, flexural or 'inverse' forms (body folds), sebopsoriasis, erythrodermic psoriasis (total body redness and scaling), and pustular psoriasis (localized or generalized palmar plantar disease) [2]. Psoriasis may have profound effects on psychological well-being and social functioning and has significant associated comorbidities, with cardiometabolic dysfunction and psoriatic arthritis (PsA) being at the forefront [3]. It is believed that psoriasis is most likely a T helper (Th) 1/Th17-induced inflammatory disease [4]. Many researchers believe that psoriasis results from interplay between genetic susceptibility, skin barrier defect, and dysregulation of innate and adaptive immunity [5]. T cells, antigen-presenting cells, keratinocytes, Langerhans cell, macrophages, natural killer cells, an array of Th1-type cytokines, and certain growth factors like vascular endothelial growth factor, keratinocyte growth factor, and others have been suggested to play a key role in the pathogenesis of psoriasis [6]. Although a genetic basis exists, environmental triggers exacerbate symptoms. Various lifestyle factors (e.g. smoking, alcohol use, obesity, and emotional stress) have been associated with its morbidity [7]. Calgranulin C (Cal C) belongs to the S100 family of calcium-binding proteins and has been cloned from human cornea and neutrophils. It has been localized to human chromosome 1q21. The predicted protein has 91 amino acids and a molecular weight of 10.6 kDa [8]. Its metal-binding domain was found to bind calcium as well as zinc ions [9]. Among the unique features of this protein family are the clustering of almost all S100 genes on the same chromosomal band, lq21, and also the insertion of two extra residues in the N-terminal loop of EF-hand motif. The structural asymmetry between the two EF-hands is reflected in differences in the Ca2+-binding affinities [10]. S100A12 showed the closest protein that interacts with receptor for advanced glycation endproducts (RAGE), the association with disease activity, and therapeutic response. S100A12 is a proinflammatory RAGE. S100A12 is highly expressed in several inflammatory diseases and has been highlighted as a marker for inflammatory bowel disease [11]. S100A12 may have the strongest potential to activate RAGE. When S100A12 binds to RAGE, a proinflammatory response has been demonstrated in vivo and in vitro with the activation of nuclear factor κB (NF-κB) and increased secretion of interleukin (IL)-6, IL-1β, and tumor necrosis factor-α. Blocking RAGE using anti-RAGE IgG or soluble RAGE, a decoy form of the receptor that limits access of ligands to RAGE, reduced inflammation and atherosclerosis [12]. The exact physiologic role of Cal C is not clear. Its expression in inflammatory dermatoses made it a candidate marker of inflammation [13]. In involved psoriatic epidermis, S100A12 is expressed in the suprabasal epidermal layers [14]. Cal C in psoriasis lowers the intracellular calcium concentration, which in turn leads to the continued proliferation and lack of differentiation of psoriatic keratinocytes. In addition, Cal C could also interfere with the effect of calcium on tyrosine-specific kinases, as tyrosine phosphorylation was found to play a major role in keratinocyte differentiation [15]. S100A12 protien overexpression in psoriatic epidermis has been shown to act through positive feedback loop and stimulates proliferation and growth of keratinocytes [16]. Intracellular signaling via protein kinases induces-NF-κB dependent secretion of different cytokines. NF-κB plays a central role in the pathogenesis of synovitis in rheumatoid arthritis (RA) and PsA [17]. The aim of this study was to clarify the possible role of Cal C protein in psoriasis and to correlate its level with disease severity.


  Patients and Methods Top


The study was approved by Ethical Committee of Menoufia Faculty of Medicine, and a written informed consent form with justification about the reason, methods, results, and complications was obtained from each participant. This case–control study was conducted at Dermatology, Andrology and STDs and Medical Biochemistry Departments of Faculty of Medicine, Menoufia University. A total of 25 patients with psoriasis vulgaris and 15 age-matched and sex-matched healthy controls were included in this study. Exclusion criteria were as follows: patients with other dermatological diseases except psoriasis vulgaris, patients with autoimmune diseases such as systemic lupus erythematosus, patients with inflammatory bowel diseases, patients with chronic diseases such as chronic renal failure, and patients having infectious conditions at the time of blood sampling such as bacterial infection. Full history taking included personal history, detailed history of psoriasis regarding onset, course, and duration of psoriasis and family history of psoriasis. Complete general examination was done. Detailed dermatological examination was performed for assessment of distribution of psoriatic lesions, scalp affection, nails involvement, joint affection, palm and sole affection, and itching and assessment of psoriasis severity using Psoriasis Area and Severity Index (PASI) score [18]. In PASI score, the body is divided into four sections: head (H), arms (A), trunk (T), and legs (L). Each of these areas is scored by itself, and then the four scores are combined into the final PASI score. In each of these areas, the fraction of total surface area affected was graded on a 0–6 scale as follows:

  • Grade 0: 0% of involved area
  • Grade 1: <10% of involved area
  • Grade 2: 10–29% of involved area
  • Grade 3: 30–49% of involved area
  • Grade 4: 50–69% of involved area
  • Grade 5: 70–89% of involved area
  • Grade 6: 90–100% of involved area.


The values for each of the four areas are entered into the formula: 0.1(Eh + Ih + Dh) Ah + 0.2 (Eu + Iu + Du) Au + 0.3(Et + It + Dt) At + 0.4(El + Il + Dl) Al to calculate a score from 0 to 72 [19]. The PASI scores used to define psoriasis severity in the previous clinical trials were categorized into severe was defined by a PASI above 15, intermediate by a PASI between 5 and 15, and mild by a PASI below 5 [20]. Two milliliters of venous blood were withdrawn from every patient under complete aseptic condition, then transferred into a plain tube, and then centrifuged for 10 min at 4000 rpm. The serum obtained was kept frozen at − 20°C till determination of S100A12 (Cal C) levels. S100A12 protein (Cal C) was assayed using Sunred enzyme-linked immunosorbent assay kit (Shanghai Sunred Biological Technology Co. Ltd, Shanghai, China) [21].

Statistical analysis

The gathered data were structured, tabulated, and statistically analyzed using a personal computer with statistical package of social science, version 20 for Windows (SPSS Inc., Chicago, Illinois, USA) and MedCalc 13 for Windows (MedCalc Software bvba, Ostend, Belgium). The following statistics were applied: Student's t-test was used to assess the difference between the studied parameters in the two groups, Mann–Whitney U-test was used to compare ordinal data not normally distributed, and Pearson's correlation (R) was used to evaluate the relation between the studied parameters in the same group. Probability value was considered not statistically significant if more than 0.05, statistically significant if less than 0.05, and highly statistically significant if less than 0.001.


  Results Top


This study was carried out on 40 participants. These include 25 patients with psoriasis and 15 age-matched and sex-matched normal participants as a control group. Cases included 11 (44%) males and 14 (56%) females, with a male-to-female ratio of 1: 1.2. Their age ranged from 8 to 65 years, with mean ± SD of 42.88 ± 12.5 years. Control group included six (40%) males and nine (60%) females, with a male-to-female ratio of 1: 1.5. Their age ranged from 10 to 65 years, with mean ± SD of 35.8 ± 14.7 years as a value. PASI score ranged from 8.2 to 18.9, with mean ± SD of 13.1 ± 3.7 [Table 1]. Patients group was categorized according to the PASI score into the following: group 1: moderate disease, which included 12 (48%) cases with PASI of 8.2–10.9, and group 2: severe disease, which included 13 (52%) cases with PASI of 15.5–18.9. Regarding level of serum Cal C among cases, it ranged from 628.8 to 1455.7 ng/ml, with mean ± SD of 993.03 ± 208.7 ng/ml. However, among control group, its level ranged from 616.1 to 784.1 ng/ml, with mean ± SD of 963.3 ± 47.5 ng/ml. High level of serum Cal C among cases showed highly significant difference compared with control group (P < 0.001) [Table 2] and [Figure 1]. Cal C level in moderate cases ranged from 628.8 to 999.9 ng/ml, with mean ± SD of 868.1 ± 108.7, whereas in severe cases, Cal C level ranged from 830.9 to 1455.7 ng/ml, with mean ± SD of 1108.3 ± 215.1. There was a highly significant difference between moderate cases and severe cases regarding mean serum level of Cal C (P = 0.002) [Table 3]. There was a highly significant positive correlation between serum Cal C and PASI score (R = 0.48, P = 0.01) [Table 4] and [Figure 2].
Table 1: Severity of psoriasis (number and percentage of cases) according to Psoriasis Area and Severity Index score (n=25)

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Table 2 Comparison between cases and control regarding serum calgranulin C (n=40)

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Figure 1: Comparison between cases and controls regarding serum level of calgranulin C (ng/ml) (N = 40).

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Table 3: Severity of psoriasis vulgaris in studied cases according to Psoriasis Area and Severity Index score

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Table 4: Correlation between calgranulin C level and Psoriasis Area and Severity Index score in studied cases (n=25)

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Figure 2: Correlation between PASI score and serum level of calgranulin C in studied cases (n = 25). PASI, Psoriasis Area and Severity Index.

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  Discussion Top


S100A12 is a proinflammatory protein that interacts with RAGE. It is highly expressed in several inflammatory diseases. In psoriasis, the protein is strongly expressed in the suprabasal epidermal layers [11]. S100A12 protein has been suggested to be involved in amplification and perpetuation of the traditional inflammatory response by triggering a positive feedback cycle on the expression of RAGE, and thus to be linked to the pathogenesis of inflammatory disorders [22]. Psoriasis vulgaris is also considered as a chronic inflammatory disease [23]. Serum S100A12 has also been associated with disease activity in RA and PsA [24]. Interestingly, the amount of Cal C expression correlated inversely with the ability of several epithelial cell lines to differentiate and highly expressed in tissues with greatly accelerated epidermal turnover, such as psoriasis, tongue, and oral mucosa [15]. S100A12 proteins prime keratinocytes for enhanced production of proinflammatory and proangiogenic cytokines such as IL-6, IL-8, and tumor necrosis factor-α growth-related gene product. They attract immune cells to the site of inflammation and promote angiogenesis by inducing endothelial cells proliferation and formation of new blood vessels [25]. This study aimed to investigate the role of S100A12 (Cal C) protein in psoriasis vulgaris by measuring its levels in serum of patients with psoriasis in comparison with age-matched and sex-matched healthy controls and their correlation with the severity of psoriasis. This study showed that there was a highly significant difference in the levels of serum Cal C between patients and controls. This was in agreement with Wilsmann-Theis et al. [26] who compared the S100-levels in the peripheral blood of untreated psoriatic patients with healthy controls. In psoriasis, S100A7, S100A8/A9 and S100A12 serum levels were significantly elevated. Moreover, this was in agreement with Foell et al. [27], where serum was obtained from 14 patients with psoriasis (mean disease duration 14.6 ± 8.6 months), whose age ranged from 28 to 67 years, with a mean of 43 years. The concentrations of S100A12 were determined using enzyme-linked immunosorbent assay system, and serum levels of S100A12 were markedly elevated in psoriasis (260 ± 60 ng/ml) compared with healthy controls (60 ± 20 ng/ml). In this study, higher level of Cal C among severe cases was highly significant compared with moderate cases. This work showed positive correlation between Cal C level and PSAI score. Higher level of S100A12 was associated with severe disease. This was in agreement with Wilsmann-Theis et al. [26], who documented a significant correlation between PASI and serum level of S100A12. In contrast, Madland et al. [28], investigated serum level of S100A12 as a marker of disease activity or distinct clinical features in patients 119 with psoriasis. Correlations to clinical variables were calculated, and subgroups of patients were compared. S100A12 levels were elevated in those with psoriasis but did not correlate with clinical variables of disease activity. This study displayed that serum levels of Cal C were increased in patients with psoriasis vulgaris than age-matched and sex-matched controls and was highly positively correlated with the disease severity according to PASI score. So our data suggest that Cal C may play a role in the pathogenesis of psoriasis.


  Conclusion Top


From the results obtained in this study, we may conclude that Cal C serum level was higher in patients with plaque psoriasis than normal population. Cal C may be used as a marker of psoriasis severity. Cal C may play a significant role in the pathogenesis of psoriasis and may provide important clues to assist in the development of new therapeutic strategies for patients with psoriasis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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