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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 40  |  Issue : 1  |  Page : 34-37

Evaluation of interleukin-18 and soluble interleukin-2 receptor serum levels in patients with alopecia areata: an Egyptian study


1 Department of Dermatology, Andrology & STDs, Faculty of Medicine, Mansoura University, Mansoura, Egypt
2 Department of Dermatology, Benha Teaching Hospital, Benha, Egypt
3 Department of Clinical Pathology, Benha Teaching Hospital, Benha, Egypt

Date of Submission01-Jul-2019
Date of Acceptance26-Nov-2019
Date of Web Publication6-Jan-2020

Correspondence Address:
Mohammad A Gaballah
Department of Dermatology, Andrology & STDs, Faculty of Medicine, Mansoura University, El-Gomhoria Street, Mansoura, 35516
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejdv.ejdv_34_19

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  Abstract 


Background Alopecia areata (AA) is a chronic inflammatory disorder of hair follicle cycling characterized by nonscarring hair loss. Interleukin-18 (IL-18) is a proinflammatory cytokine that was implicated in various inflammatory and autoimmune skin diseases, including AA. IL-2 initiates and develops the immune response through binding to interleukin-2 receptor (IL-2R) on T cells. Levels of soluble IL-2R (sIL-2R) may be estimated as a sign of T-cell activation in serum of patients having many disorders involving aberrant immune activation, including AA.
Objective To estimate of the serum levels of IL-18 and sIL-2R as immunological factors in patients with AA and to test the correlation between these serum levels and disease severity.
Patients and methods A total of 46 patients with AA and 40 age-matched and sex-matched healthy individuals as controls were included. All participants were subjected to thorough history taking, full general examination, and detailed dermatological examination for diagnosis of cases and determination of extent of the lesions. The severity of AA was graded as mild (three or less patches of alopecia with a widest diameter of 3 cm or less or the disease limited to the eyelashes and eyebrows) or severe (existence of more than three patches of alopecia or a patch >3 cm at the widest diameter or alopecia totalis or alopecia universalis). Estimation of serum levels of IL-18 and sIL-2R was done by enzyme-linked immunosorbent assay.
Results Serum IL-18 was significantly higher in patients with AA compared with the controls. Serum sIL-2R was nonsignificantly increased among patients with AA than the controls. Patients with severe disease had significantly higher serum IL-18 and nonsignificantly higher serum sIL-2R compared with patients with mild disease.
Conclusion AA is associated with elevation of serum IL-18 and sIL-2R, and their levels increase with the increase in the severity of the disease. The exact role of serum IL-18 and sIL-2R in AA should be investigated in future studies.

Keywords: alopecia areata, interleukin-18, soluble interleukin-2 receptors


How to cite this article:
El-Gayyar MA, State AF, Helmy ME, Amer ER, Ibrahim LY, Gaballah MA. Evaluation of interleukin-18 and soluble interleukin-2 receptor serum levels in patients with alopecia areata: an Egyptian study. Egypt J Dermatol Venerol 2020;40:34-7

How to cite this URL:
El-Gayyar MA, State AF, Helmy ME, Amer ER, Ibrahim LY, Gaballah MA. Evaluation of interleukin-18 and soluble interleukin-2 receptor serum levels in patients with alopecia areata: an Egyptian study. Egypt J Dermatol Venerol [serial online] 2020 [cited 2020 Apr 9];40:34-7. Available from: http://www.ejdv.eg.net/text.asp?2020/40/1/34/275183




  Introduction Top


Alopecia areata (AA) is a chronic inflammatory disorder of hair follicle cycling owing to the collapse of the anagen-specific immune privilege with infiltration of the hair follicle by T lymphocytes, and characterized by nonscarring hair loss [1],[2],[3]. The cause of AA is still not identified precisely; however, genetic, environmental, and immunological factors may play a role. Moreover, stress is a famous triggering and aggravating factors for the disease [4].

Interleukin-18 (IL-18) is a proinflammatory cytokine produced by activated macrophages dendritic cells and affects the T helper 1 (Th1) response owing to its ability to induce interferon gamma (IFN-γ) production in T cells and natural killer cells. IL-18 was concerned in different inflammatory and autoimmune skin diseases, including AA [5]. The function of the IL-18 depends on cytokine environment. IL-18 with IL-12 or IL-15 increases Th1 response, whereas IL-18 without IL-12 stimulates Th2 response, including allergic reactions [6].

IL-2 is a glycoprotein produced by activated T cells and increases the proliferation, cytokine production, and cytolytic activities of T cells and natural killer cells. IL-2 initiates and develops the immune response by binding to interleukin-2 receptor (IL-2R) on T cells [7]. One of the IL-2R components can be measured as a soluble serum protein (sIL-2R). Blood levels of sIL-2R may be a sign of T-cell activation in serum of patients having many disorders involving aberrant immune activation, including AA [8].

The aim of the present work was estimation of the serum levels of IL-18 and sIL-2R as immunological factors in patients with AA and to test the correlation between these serum levels and the disease severity.


  Patients and methods Top


The current case–control study was carried out on 86 subjects (46 patients with AA and 40 age-matched and sex-matched healthy individuals as controls). They were selected from the outpatient clinic of Dermatology, Andrology and STDs Department, Mansoura University Hospital. Informed written consents were taken from all participants, and the study protocol was approved by the Institutional Research Board of Faculty of Medicine, Mansoura University.

Patients who received any treatment within the previous 3 months from the study, as well as patients with any disease based on the immune pathomechanism, other autoimmune diseases and active inflammatory skin diseases, which could influence serum concentrations of IL-18 and sIL-2R, were excluded.

The healthy volunteers had no family or personal history of AA, autoimmune diseases, and active inflammatory skin diseases.

All participants were subjected to thorough history taking, full general examination, and detailed dermatological examination for diagnosis of cases and determination of the extent of the lesions. The severity of AA was graded as mild (three or less patches of alopecia with a widest diameter of 3 cm or less or the disease limited to the eyelashes and eyebrows) or severe (existence of more than 3 patches of alopecia or a patch >3 cm at the widest diameter or alopecia totalis or alopecia universalis) [9].

Overall, 5-ml venous blood sample was collected from each participant in a metal-free sterile tube. They were allowed to clot for 15 min and were centrifuged at 7000 rpm for serum preparation, which was stored at −80°C till analysis. Determination of serum levels of IL-18 and sIL-2R was done by enzyme-linked immunosorbent assay technique by the use of a commercial kit from Elabscience Biotechnology Company Inc. (Houston, Texas, USA).

Statistical analysis

Data were analyzed with SPSS, version 21 (IBM Corporation, New Orchard Road, Armonk, New York, USA). The normality of data was first tested with one-sample Kolmogorov–Smirnov test. Qualitative data were described using number and percent. Association between categorical variables was tested using χ2 test. Monte Carlo test as correction for χ2 test if more than 20% of cells have count less than 5. Continuous variables were presented as mean±SD. The two groups were compared with Student t test. For all aforementioned statistical tests done, the threshold of significance is fixed at 0.05 (P≤0.05).


  Results Top


There was no statistically significant difference between patients and controls regarding age and sex. The lesions were equally distributed at the temporal and vertex (34.7% each) followed by the occiput (30.6%). There was significantly higher serum IL-18 among patients with AA compared with the controls. However, the serum sIL-2R was nonsignificantly increased among patients with AA than the controls. Patients with severe disease had statistically significant higher serum IL-18 and nonsignificantly higher serum sIL-2R compared with patients with mild disease ([Table 1],[Table 2],[Table 3],[Table 4]).
Table 1 Demographic characteristics of the patients and controls

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Table 2 Clinical characteristics of alopecia areata

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Table 3 Serum interleukin-18 and soluble interleukin-2 receptor levels in patients and controls

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Table 4 Mean serum levels of interleukin-18 and soluble interleukin-2 receptor in patients according to disease severity

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  Discussion Top


In the current work, the number of female patients was higher than number of male patients. Wasserman et al. [10] reported that both males and females are affected equally in AA, whereas Sato-Kawamura et al. [11] reported that AA is more in females. Yet, Lew et al. [12] stated that AA occurred more in male patients in their case series.

Our results also showed that serum IL-18 was significantly higher among patients with AA compared with control group and significantly higher in patients with severe disease compared with patients with mild disease. Similarly, Lee et al. [13] found that serum IL-18 only in patients with extensive AA, not mild AA, was significantly higher than in the controls. However, unlike the current study, they found no significant difference between the patients with extensive and localized AA.

Gilhar et al. [1] showed that serum IL-18 was significantly higher in severe AA than control. They also reported that IFN-γ was the main inducing factor of AA in a murine model. IL-18 was identified as an IFN-γ-inducing factor [4].

Disequilibrium in the production of cytokines with a relative increase of proinflammatory cytokines such as IL-18 versus anti-inflammatory cytokines such as IL-4 and IL-10 may be involved in the persistence of AA lesions, as was shown in human scalp biopsies [14].

Colafrancesco et al. [15] reported in their study on serum IL-18 in adult-onset Still’s disease that high serum IL-18 was detected in patients with an active disease, and its concentration correlates with disease activity.

IL-18 and IL-2 together synergistically enhanced the proliferation, cytolytic activity, and IFN-γ production of peripheral blood mononuclear cells [16].

In the present study, there was nonsignificant increase in the sIL-2R serum level among patients with AA than the controls, and the patients with severe AA had nonsignificant higher sIL-2 serum concentration compared with patients with mild AA.

This is in agreement with Lee et al. [13] who found that serum sIL-2R was nonsignificantly different among the patients with extensive AA, the patients with localized AA, and the controls. Their patients with AA were all chronic, stable, and refractory for treatment. On the contrary, in patients with AA in active phase, the sIL-2R concentrations were significantly higher than in stable phase and in controls.

Role of sIL-2R could be T-lymphocyte activation, with subsequent secretion of IL-2 and IL-2R expression, which may participate in the pathogenesis of AA [8].

The sIL-2R shares in the development of memory T cell, which depends on the increase of the number and function of antigen selected T cell clones, and they take part in enduring cell-mediated immunity [17].Teraki et al. [18] reported that serum levels of IL-1 and IL-4 were significantly elevated in localized AA, whereas IL-2 and IFN-γ were mainly elevated in extensive AA, possibly implying that the progression to the extensive form might be mediated by Th1 cytokines. Kasumagić-Halilovic et al. [19] found that serum IL-2 was significantly increase in AA, indicating that IL-2 may play a role in the pathogenesis of AA, and this may reflect the inflammatory symptoms in AA, and that the control of IL-2 production might be important to the management of this disease. Yet, no associations were found between clinical type, severity of the disease, duration of the disease, and serum IL-2.

On contrary, Castela et al. [20] reported an impaired inhibitory role of circulating CD4+CD25+ regulatory T cells that might play an important function in AA, and the subcutaneous injection low-dose of recombinant IL-2 might be used for treating severe AA by promoting the recruitment of regulatory T cells.


  Conclusion Top


AA is associated with elevation of serum IL-18 and sIL-2R levels, and their levels increase with increase in the severity of the disease. Serum level of IL-18 may reflect the severity of AA. The exact role of serum IL-18 and sIL-2R in AA should be additionally investigated in future studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Gilhar A, Kam Y, Assy B, Kalish R. Alopecia areata induced in C3H/HeJ mice by interferon: evidence for loss of immune privilege. J Investig Dermatol 2005; 124:288–289.  Back to cited text no. 1
    
2.
Paus R, Nickoloff BJ, Ito TA. ‘Hairy’ privilege. Trends Immunol 2005; 26:32–40.  Back to cited text no. 2
    
3.
Gilhar A, Paus R, Kalish RS. Lymphocytes, neuropeptides, and genes involved in alopecia areata. J Clin Invest 2007; 117:2019–2027  Back to cited text no. 3
    
4.
Manolache L, Benea V. Stress in patients with alopecia areata and vitiligo. J Eur Acad Dermatol Venereol 2007; 21:921–928.  Back to cited text no. 4
    
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Wittmann M, Macdonald A, Renne J. IL-18 and skin inflammation. Autoimmun Rev 2009; 9:45–48.  Back to cited text no. 5
    
6.
Lee J, Cho D, Park H. Interleukin 18 and cutaneous inflammatory disease. Int J Mol Sci 2015; 16:29357–29369.  Back to cited text no. 6
    
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Liao W, Lin JX, Leonard WJ. IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Curr Opin Immunol 2011; 23:598–604.  Back to cited text no. 7
    
8.
Valsecchi R, Imberti G, Martino D, Cainelli T. Alopecia areata and interleukin-2 receptor. Dermatology 1992; 184:126–128.  Back to cited text no. 8
    
9.
Thomas E, Kadyan R. Alopecia areata and autoimmunity: a clinical study. Indian J Dermatol 2008; 53:70–74.  Back to cited text no. 9
[PUBMED]  [Full text]  
10.
Wasserman D, Guzman-Sanchez DA, Scott K, McMichael A. Alopecia areata. Int J Dermatol 2007; 46:121–131.  Back to cited text no. 10
    
11.
Sato-Kawamura GM, Aiba S, Tagami H. Acute diffuse and total alopecia of the female scalp. A new subtype of diffuse alopecia areata that has a favorable prognosis. Dermatology 2002; 205:367–373.  Back to cited text no. 11
    
12.
Lew B, Shin M, Sim W. Acute diffuse and total alopecia: a new subtype of alopecia areata with a favorable prognosis. JAAD 2009; 60:85–93.  Back to cited text no. 12
    
13.
Lee D, Hong S, Park S, Hur D, Shon J, Shin J, Hwang S, Sung H. Serum levels of IL-18 and sIL-2R in patients with alopecia areata receiving combined therapy with oral cyclosporine and steroids. Exp Dermatol 2010; 19:145–147.  Back to cited text no. 13
    
14.
Bodemer C, Peuchmaur M, Fraitaig S, Chatenoud L, Brousse N, De Prost Y. Role of cytotoxic T cells in chronic alopecia areata. J Investig Dermatol 2000; 114:112–116.  Back to cited text no. 14
    
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Colafrancesco S, Priori R, Alessandri C, Perricone C, Pendolino M, Picarelli G, Valesini G. IL-18 serum level in adult onset still’s disease: a marker of disease activity. Int J Inflam 2012; 2012: 156890.  Back to cited text no. 15
    
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Son Y, Dallal RM, Mailliard RB, Egawa S, Jonak ZL, Lotze MT. Interleukin-18 (IL-18) synergizes with IL-2 to enhance cytotoxicity, interferon-γ production, and expansion of natural killer. Cancer Res 2001; 1:884–888.  Back to cited text no. 16
    
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Malek TR, Castro I. Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity 2010; 33:153–165.  Back to cited text no. 17
    
18.
Teraki Y, Imanishi K, Shiohara T. Cytokines in alopecia areata. Acta Dermatol Venereol 1996; 76:421–423.  Back to cited text no. 18
    
19.
Kasumagić-Halilovic E, Cavaljuga S, Ovcina-Kurtovic N, Zecevic L. Serum levels of interleukin-2 in patients with alopecia areata: relationship with clinical type and duration of the disease. Skin Append Disord 2018; 4:286–290.  Back to cited text no. 19
    
20.
Castela E, Le Duff F, Butori C, Ticchioni M, Hofman P, Bahadoran P et al. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA Dermatol 2014; 150:748–751.  Back to cited text no. 20
    



 
 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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