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ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 3  |  Page : 1003-1006

The role of CXCL12 chemokine in patients with alopecia areata


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, Andrology and STDs, Menouf General Hospital, Menoufia, Egypt

Date of Submission08-Dec-2018
Date of Decision03-Jan-2019
Date of Acceptance08-Jan-2019
Date of Web Publication30-Sep-2020

Correspondence Address:
Noha A. A. Shaheen
Menouf City, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_393_18

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  Abstract 


Objective
The aim was to study the role of CXCL12 in patients with alopecia areata.
Background
Alopecia areata is an organ-specific autoimmune disease targeting the hair follicles. It causes nonscarring hair loss. It is a lymphocyte cell-mediated inflammatory type of hair loss. Chemokines are the main components of the immune system and play fundamental roles in pathogenesis of inflammatory disorders. CXCL12 is an ELR-CXC chemokine with angiogenic effects. CXCL12 (as ELR-) is strongly chemotactic for lymphocytes and neutrophils. It is plausible that failed angiogenesis in the alopecia areata patients are involved in hair loss. As CXCL12 is an angiogenic chemokine, decreased CXCL12 levels may possibly in turn lead to decreased angiogenesis and cause hair loss in the patients.
Patients and methods
This case–control study was conducted on 50 participants: 25 patients with alopecia areata and 25 age-matched and sex-matched healthy controls during the period from February 2018 to August 2018. All patients were subjected to full history taking, clinical examination, and laboratory investigations. Serum CXCL12 chemokine levels were measured by using the enzyme-linked immunosorbent assay technique.
Results
Serum CXCL12 levels were significantly decreased in alopecia areata patients (mean: 15.55 ± 6.35) compared with healthy controls (mean: 46.94 ± 41.42) (P = 0.005). There is negative significant correlation between CXCL12 and duration of disease (r = −0.491, P = 0.013).
Conclusion
CXCL12 chemokine is decreased in patients with alopecia areata. There is a dependent relationship between CXCL12 serum level and AA. It can be used as a diagnostic biomarker of AA activity.

Keywords: alopecia areata, biomarker, chemokine CXCL12, enzyme-linked immunosorbent assay, skin disease


How to cite this article:
El-Farargy SM, Ghanayem NM, Shaheen NA. The role of CXCL12 chemokine in patients with alopecia areata. Menoufia Med J 2020;33:1003-6

How to cite this URL:
El-Farargy SM, Ghanayem NM, Shaheen NA. The role of CXCL12 chemokine in patients with alopecia areata. Menoufia Med J [serial online] 2020 [cited 2020 Oct 29];33:1003-6. Available from: http://www.mmj.eg.net/text.asp?2020/33/3/1003/296683




  Introduction Top


Alopecia areata is an organ-specific autoimmune disease targeting the hair follicles. It causes nonscarring hair loss. The condition is most commonly seen as circular areas of hair loss, but may sometimes be as extensive as to involve the whole scalp or the whole body [1]. It is a common disease encountered by dermatologists, with a frequency ranging from 0.7 to 3.8% of patients attending dermatology clinics [2]. The exact pathophysiology of the disease is currently unknown. However, evidence suggests that AA is caused by an autoimmune reaction to the hair follicles due to both genetic and environmental factors [3]. Cytokines are strong components of the autoimmune origin of AA. Previous studies of AA has shown that the regulation of local and systemic cytokines play an important role in its pathogenesis [4]. The onset and progression of AA probably requires input from multiple factors including stress, hormones, infectious agents, and several other possible inputs [5]. Alopecia areata manifests as a sudden loss of hair in localized areas. The lesion is usually asymptomatic with round or oval patches with a distinct border. It may be solitary (alopecia areata monolocularis) or numerous (alopecia areata multilocularis) [6]. Exclamation mark hairs are characteristic. These are hairs that have a tapered proximal end and get wider as you go distally [3]. Nail changes are more common in patients with more severe alopecia, such as alopecia areata universalis and alopecia areata totalis [7]. Based on the extent of hair loss, AA can be classified into patchy AA, alopecia totalis involving the entire scalp hair, and alopecia universalis if the total body hair is involved [8]. Chemokines are known as members of a subfamily of homologous (8–10 kDa) proteins belonging to the cytokine family. According to the presence, absence, or position of the cysteine motifs in their N-terminus, chemokines are further categorized into four distinct subgroups as CXC, CC, C, and CX 3C [9]. Chemokines direct cellular movement and relocalization, both of which are essential for many fundamental physiologic processes, which include embryonic development, neovascularization and angiogenesis, immunologic responses, wound healing, and organ repair. In embryonic life, together with other chemoattractive growth factors, CXCL12 directs the proliferation and differentiation of immature progenitor cells by the activation of the adhesion machinery, cytoskeleton rearrangement, the control of cell cycle, and the secretion of proteolytic enzymes [10]. CXCL12 is an ELR-CXC chemokine with angiogenic effects. CXCL12 (as ELR-) is strongly chemotactic for lymphocytes and neutrophils, respectively. CXC chemokines bind to CXC chemokine receptors, the seven transmembrane-G protein-coupled receptors and so far, seven of CXC chemokine receptors [11]. CXCL12 levels were decreased in patients compared with control. It was documented that downregulation of CXCL12 in AA patients may be related to autoimmune conditions due to the fact that this chemokine has dual effects on the immune system and the chemokine can shift its proinflammatory function to anti-inflammatory function. Failed angiogenesis in AA patients are involved in hair loss. As CXCL12 is an angiogenic chemokine, decreases in CXCL12 level may possibly in turn lead to decreased angiogenesis and cause hair loss in the patients [12]. The aim of this study was to study the role of CXCL12 in patients with alopecia areata.


  Patients and Methods Top


This study was approved by the Ethics Committee of Dermatology, Andrology and STDs and Medical Biochemistry Departments of Faculty of Medicine, Menoufia University during the period from February 2018 to August 2018 and informed written consent was taken from each participant. It included 50 participants: 25 patients with AA (group 1) and 25 age- and sex-matched healthy controls (group 2). Patients were collected from the Dermatology Outpatient and Inpatient Clinic, Menoufia University Hospitals and Menouf General Hospital.

Inclusion criteria

The participants were with alopecia areata, their ages ranging from 12 to 50 years, either newly diagnosed or stopped topical, intralesional, or systemic treatment for at least 1 month and/or stopped UVB sessions for at least 6 months before sample taking. Exclusion criteria: included patients with a history of acute or chronic diseases (as thyroid disease, type 1 diabetes mellitus, pernicious anemia, allergic diseases, asthma, scleroderma, vitiligo, psoriasis, systemic lupus erythematous, and other autoimmune diseases because downregulation of CXCL12 in the alopecia areata patients may be related to autoimmune conditions). All studied participants were submitted to the following: (a) full history including personal history (name, age, sex, residence, and occupation), present history (onset, course, duration, and previous treatment in addition to the number of episodes and precipitating factors), past history (systemic, dermatological disorders, and previous operations), family history (similar condition, systemic, and dermatological disorders). (b) Clinical examination: complete general and dermatological examination for exclusion of any disease other than AA and determination of site of AA, clinical variants, number of lesions, and extent of lesion. (c) Laboratory investigation: 5 ml blood was collected from every participant under complete aseptic condition using sterile vacuationers, left to stand at room temperature, then centrifuged at a speed of 2000–3000 rpm for 20 min. The serum obtained was stored at −20°C until analysis of CXCL12. Serum CXCL12 level was measured by enzyme-linked immunosorbent assay (ELISA) using human stromal cell-derived factor (SDF1) ELISA kit provided (RayBiotech company, Peachtree Corners, Gorgia, USA). The kit uses a double-antibody sandwich ELISA to assay the level of human SDF1 in samples. Add SDF1 to the monoclonal antibody enzyme well which is precoated with SDF1 monoclonal antibody, incubation; then, add SDF1 antibodies labeled with biotin, and combined with streptavidin–HRP to form an immune complex; then carry out incubation and washing again to remove the uncombined enzyme. Then add chromogen solution A, B; the color of the liquid changes to blue, and under the effect of acid, the color finally becomes yellow. The chroma of color and the concentration of SDF1 of sample were positively correlated. Data were analyzed using IBM SPSS software package version 20.0. (IBM Corp., Armonk, New York, USA). Qualitative data were described using number and percentage. The Kolmogorov–Smirnov test was used to verify the normality of distribution. Quantitative data were described using range (minimum and maximum), mean, SD, and median. Significance of the obtained results was judged at the 5% level. The used tests were χ2-test, Student's t-test, Mann–Whitney test, Kruskal–Wallis test, Spearman's coefficient, and receiver operating characteristic curve.


  Results Top


The mean age is 29.24 ± 10.50 with group 1 (patients) and it is 27.28 ± 7.38 in group 2 (controls). There is no significant statistical difference between the two studied groups regarding age and sex [Table 1]. There is a significant statistical decrease in CXCL12 level in patients (mean: 15.55 ± 6.35) compared with healthy controls (mean: 46.94 ± 41.42) (P = 0.005) [Table 2]. There is negative significant correlation between CXCL12 and duration of disease, whereas nonsignificant negative correlation existed with age of patients and size of lesion [Table 3]. There is no significant statistical difference in CXCL12 level regarding sex, onset of disease, and course of disease [Table 4]. There is a dependent relationship between AA and CXCL12 serum level. The cutoff value of CXCL12 is less than or equal to 23.20 (ng/ml). The sensitivity was 92%, specificity 52%, positive predictive value 65.7%, and negative predictive value 86.7% for detection of patients versus controls [Table 5].
Table 1: Comparison between the two studied groups regarding demographic data

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Table 2: Comparison between the two studied groups according to CXCL12 level

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Table 3: Correlation coefficient between CXCL12 level and each of age, size of lesion, and duration of disease in group 1 (n=25)

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Table 4: Relation between CXCL12 level and different parameters in group 1 (n=25)

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Table 5: Agreement (sensitivity, specificity) for CXCL12 level diagnosis cases versus control

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  Discussion Top


In this study, the majority of AA patients were men (60%) but in the control group 60% were women with no significant difference between both groups regarding age and sex. These results agree with those of Kavak et al. [13], Zainodini et al. [12], and Bilgic et al. [14]. The study of Bilgic et al. [14] included a total of 40 (28 men/12 women) patients with AA and 40 (28 men/12 women) healthy controls. The mean age did not differ significantly between the patient and control groups. Also, the Yang et al. [15] study has shown a male predominance ranging from 2:1 to 1.1: 1. Kyriakis et al. [16] reported a significant male preponderance. For both sexes, the peak prevalence was observed in the age group of 31–40 years.

Contrarily, according to Fricke and Miteva [17] no significant difference in the incidence of AA was found between men and women.

Also in contrast, different hospital-based studies from across the world have cited a female predominance, ranging from a ratio of 2.6: 1 to 1.2: 1 [18],[19].

The present study showed that there was a highly significant decrease in CXCL12 among patients than the control group. These results are in line with the study of Nance et al. [20], Karin [21], and Zainodini et al. [12]. Zainodini et al. [12] results showed that the CXCL12 levels were decreased in patients compared with control. These concluded that CXCL12 chemokines could be considered as a biomarker in AA diagnosis and therapy. These chemokines play a significant role in the angiogenesis/angiostasis phenomenon. It was documented that downregulation of CXCL12 in AA patients may be related to autoimmune conditions due to the fact that this chemokine has dual effects on the immune system and the chemokine can shift its proinflammatory function to anti-inflammatory function. Failed angiogenesis in AA patients are involved in hair loss. As CXCL12 is an angiogenic chemokine, decreases in CXCL12 level may possibly in turn lead to decreased angiogenesis and cause hair loss in the patients [12]. It was revealed that vascular endothelial-like growth factor as an angiogenetic factor decreased in AA patients [20]. Hence decreased expression of CXCL12 in AA patients is in parallel with the downregulation of vascular endothelial-like growth factor [21].

The current study reported that there is a dependent relationship between AA and CXCL12 level. At a cutoff value of less than or equal to 23.20 (ng/ml), CXCL12 has a sensitivity of 92%, specificity of 52%, positive predictive value of 65.7%, and negative predictive value of 86.7% for differentiation between patients with alopecia areata versus controls.

The limitations of the current study include its retrospective design; the small study group prevented us from determining the group variances of AA, and a limited follow-up period. The influence of aging on the pathogenesis, clinical course, and outcome of AA requires further investigation with a controlled prospective study design, which could lead to guidelines for the treatment of AA correlated by the CXCL12 level.

It was reported that CXCL chemokines may play important roles in the development of AA and thus could be considered either as a useful biomarker of disease activity or therapeutic target for AA therapy [12].


  Conclusion Top


From this study, we can conclude that CXCL12 chemokine is decreased in patients with alopecia areata. There is a dependent relationship between CXCL12 serum level and AA. It can be used as a diagnostic biomarker of AA activity.

Recommendation

From this study, we can recommend that further large-scaled studies involving other CXCL chemokines are recommended to expand and validate current findings. Clinical trials could lead to guidelines for the use of CXCL12 chemokine in AA therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



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



 

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