Abstract
Background:
Vitiligo is an acquired chronic autoimmune skin disorder with an estimated prevalence of 1% worldwide. The CD8+ T-cell-mediated chemokines such as CXCR3, CXCL9 and CXCL10 are the non-specific action immunomodulators that are responsible for the depigmentation and progression in vitiligo.
Aim:
This study aimed to explore the expression levels of serum CXCL9-11 in vitiligo patients who received the transplantation of cultured autologous melanocytes (TCAMs) before and after the operation and correlate their expressions with clinical stage, subtype and course of the vitiligo disease.
Materials and Methods:
The expression levels of serum CXCL9-11 were measured in the peripheral blood of 26 progressive vitiligo patients, 24 stable vitiligo, 13 TCAM patients and 30 healthy control (HC) cases using enzyme-linked immunosorbent assay (ELISA). The potential correlations between their expressions and disease features such as stage, type and surgical treatment were evaluated using Student's t-test.
Results:
The expression levels of serum CXCL9-11 increased by ~1.4, ~1.6 and ~2.3-fold in vitiligo patients compared with HCs (P < 0.01). The expression levels of all chemokines were significantly higher in progressive vitiligo patients than in stable vitiligo (P < 0.01). The increasing expression levels of serum CXCL9, CXCL10 and CXCL11 were significantly related to the different types of vitiligo patients (P < 0.05). Preoperative expression levels of serum CXCL9-11 were significantly higher than the post-operative expression levels (P < 0.01).
Conclusion:
Our results demonstrate that increasing expression levels of the CXC family play a key role in the immunopathogenesis of vitiligo. The abnormal expression of the CXC family may be considered an effective and therapeutic target for TCAM treatment.
Key Words: CXCL9, CXCL10, CXCL11, TCAM, vitiligo
Introduction
Vitiligo is an acquired chronic depigmenting skin disorder with an estimated prevalence between 0.5 and 2 per cent of the population worldwide.[1,2] Vitiligo has a strong impact on a patient's daily life because of its refractory, recurrent, discosmetic and chronic features and brings great economic and psychological burden to patients and society.[3,4]
The pathogenesis of vitiligo includes autoimmune destruction of melanocytes, genetic predisposition and abnormal redox reaction.[5] Among them, autoimmune and organ-specific autoantibodies reaction is widely accepted for the pathogenesis of vitiligo.[1,6] The migration of immune cells, mainly the CD8+ T cells, is a necessary step to initiate the systematic autoimmune response, and chemokine is one of the essential factors in this process. The high levels of pro-oxidant substances such as interferon (INF)-γ in the microenvironment lead to increased production of CXCL9 and CXCL10 from keratinocytes, resulting in the recruitment of pathogenic CD8+ T cells that instigate the autoimmune destruction of melanocytes and the production of paracrine factors.[7] CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC) are induced by interferon to bind a CXCR3 common receptor, mainly expressed on the surface of memory T cells, activated CD4+ T cells, CD8+ T cells and natural killer (NK) cells.[8] The impairment of melanocytes mediated by CD8+ T cells is the main cause of depigmentation in skin lesions of vitiligo patients.[9] CXCR3, CXCL9 and CXCL10 expressions are elevated in vitiligo patients compared with normal controls, while their expressions can be inhibited by glucocorticoid treatment.[10,11] There is a need to understand the role of CXCR3, CXCL9 and CXCL10 as potential markers for therapeutic and other vitiligo countermeasures.[12]
The therapeutic approaches to vitiligo comprise medical, phototherapeutic and surgical modalities. The purpose of these treatments is to prevent the ongoing destruction of melanocytes and to provide mediators that can stimulate the growth and proliferation of existing melanocytes, promoting skin repigmentation.[13] Stable vitiligo patients with poor response to other treatments can use cellular transplantation that has a 50% successful rate.[14] Transplantation of cultured autologous melanocytes (TCAMs) relies on cell culture technology in vitro to amplify the melanocyte numbers and then transplant to the patient's depigmentation skin lesions. TCAM is one of the most effective methods to treat vitiligo, with the advantages of less area of required skin and a larger target skin area. It has become the first-line choice for vitiligo patients.[15,16] Although the overexpression of CXCL9, CXCL10 and CXCL11 has been reported in peripheral blood or tissue fluid of vitiligo patients,[17,18] their role of biomarker of vitiligo activity and of predictive value of TCAM success remains elusive.
This study aimed to explore the expressions of CXCL9, CXCL10 and CXCL11 in vitiligo patients before and after TCAM and to correlate their expressions with clinic stage, subtype and course of the vitiligo disease.
Materials and Methods
Subjects
Sixty-six patients diagnosed with non-segmental vitiligo were recruited from the People's Hospital of Xinjiang Uygur Autonomous Region (PHXUAR) from January 2018 to December 2018. The diagnosis, classification and staging were classified according to the guideline of the Vitiligo Global Issues Consensus Conference (PMID: No. 22417114). The exclusion criteria were as follows: 1) patients with other autoimmune diseases or skin diseases; 2) mucosal and acral tip vitiligo with lesions limited to glabrous skin region; 3) poor compliance with less Vitiligo Area Scoring Index (VASI), failure to cooperate with the baseline VASI scores in the TCAM and follow-up; 4) several systematic diseases; 5) pregnant and lactating women; and 6) participating in simultaneous clinical trials. All the patients were divided into three groups: 26 progressive vitiligo patients in stage II/IV, 24 stable vitiligo patients in stage II/III and 13 TCAM patients. Thirty healthy volunteers were included with no history of vitiligo, autoimmune disease or chronic disorders. The vitiligo lesions of all selected patients were stable for 6 months or longer. This study was approved by the Ethics Committee of PHXUAR (KY2021031713). A written consent form was obtained from participants before the study.
Clinical data and blood samples
The demographic information of the subjects was recorded. Before the intervention, 5 ml of peripheral venous blood (PBMC) was collected from all the participants to detect the concentrations of CXCL9, CXCL10 and CXCL11 by ELISA kit (Wuhan, Boster Biological Technology, China).
Melanocyte isolation
The normal skin in the middle of the abdomen of the vitiligo patient at the stable stage was selected as the donor according to the standard suction blister grafting (SBG) procedure (PMID: No. 29731587). The tissue was cut into small pieces and digested with 0.25% trypsin for 12 h at 4℃. After digestion, the cells were centrifuged at 1500 revolutions per minute (rpm) for 3 minutes, the supernatant was discarded and the process was repeated twice. The precipitate was collected and added to the melanocyte culture medium and then incubated at 37°C with 5% CO2 in a humidified incubator (Eppendorf, Hamburg, Germany). A levodopa stain was performed to identify the melanocyte.
TCAM procedure and efficacy evaluation
The melanocyte suspension was evenly inoculated into the transplant site using Pasteur pipettes, and then, the surgical area was covered with sterile Vaseline gauze and a sterile moist dressing was applied externally. The gauze was removed 7–10 days after the operation. The efficacy of the TCAM was evaluated after 6 months by analysing operation images of TCAM. The repigmentation rates were determined based on the Vitiligo Diagnosis and Treatment Consensus (2014 Edition) (PMID: No. 26247842). The VASI was used to evaluate the curative effect in the equation:
VASI= ∑ (the number of body lesions accounts for the palm units) × the percentage of depigmentation in the area.
The white spots partly shrinking or disappearing in the area restoring to the normal skin colour accounting for ≥90% and 50–90% of the skin lesion or <90% of the skin lesion without repigmentation and/or enlargement were considered significantly effective, effective or non-effective, respectively.
Statistical methods
All statistical analyses were performed using SPSS v22.0 (Illinois, CA, USA). Numerical data were expressed as mean ± standard deviation or median (range). A Student's t-test was performed to compare the expression levels of cytokines in patients with different stages. The differences in cytokine expression levels before and after TCAM were compared by a paired t-test. A P value < 0.05 was considered statistically significant.
Results
Baseline information
Among the healthy controls (HCs), 11 of 30 were males and the rest (19) were female. The average age of HCs was 27.20 ± 9.50 (17–37) years [Table 1]. Patients diagnosed with non-segmental vitiligo had an average age of 33.54+ 16.95 (17–55) years and a gender ratio of 31/19 (M/F) [Table 1]. Among non-segmental vitiligo patients, 24 (48.0%) were in the stable stage, whereas 26 (52.0%) were in the progressive stage [Table 1]. Based on types, 32 (64.0%) had sporadic, 14 (28.0%) had localised and 4 (8.0%) had generalised type [Table 2]. Fifty-four (13 f 24) of patients with stable segmental vitiligo received TCAM. All the patients with TCAM operation had no hyperplasia or new leukoplakia at the donor or graft sites.
Table 1.
Clinical characteristics of the studied subjects
| Healthy controls (n=30) | Vitiligo patients | |||
|---|---|---|---|---|
|
| ||||
| Progressive (n=26) | Stable (n=24) | TCAM (n=13) | ||
| Gender (M/F) | 11/19 | 16/10 | 15/9 | 6/7 |
| Age | ||||
| Years | 17-37 | 19-54 | 17-53 | 10-55 |
| Mean+SD | 27.20+9.50 | 38.12+19.01 | 32.12+15.24 | 27.85+12.41 |
| Disease duration | ||||
| Years | - | 0.02-30 | 0.04-15 | 0.5-2 |
| Mean+SD | - | 3.36+6.36 | 2.24+3.43 | 0.60+0.49 |
| Other autoimmune diseases (%) | - | 3 (11.5%) | 0 | 0 |
TCAM, transplantation of cultured autologous melanocytes
Table 2.
Expression levels of serum CXCL9, CXCL10 and CXCL11 in different types of vitiligo patients
| Cytokines | Localised type (n=26) | Sporadic type (n=24) | Generalised type (n=4) | P | ||
|---|---|---|---|---|---|---|
|
| ||||||
| Localised vs sporadic | Sporadic vs generalised | Localised vs generalised | ||||
| CXCL9 (pg/ml) | 77.06+46.96 | 93.14+35.22 | 136.20+27.06 | 0.4562 | <0.05 | <0.05 |
| CXCL10 (pg/ml) | 162.11+64.61 | 174.51+57.29 | 338.29+20.87 | 0.647 | <0.05 | <0.05 |
| CXCL11 (pg/ml) | 124.76+61.13 | 150.10+77.72 | 307.91+56.33 | 0.446 | <0.05 | <0.05 |
A Student’s t-test was performed to compare the expression levels of CXCL9-11 among different types of vitiligo patients. A P<0.05 is considered significant
Comparison of serum CXCL9, CXCL10 and CXCL11 expressions between vitiligo patients and HCs
Serum concentrations of CXCL9, CXCL10 and CXCL11 in patients with vitiligo were 92.08 ± 40.48, 184.14 ± 73.14 and 155.63 ± 84.81 pg/ml, respectively. The concentrations of CXCL9, CXCL10 and CXCL11 in the controls were 37.53 ± 8.97, 96.43 ± 18.43 and 55.39 ± 18.71 pg/ml. The results showed that the CXCL9-11 expressions in vitiligo were significantly higher than the HCs (all P < 0.01) [Table 3].
Table 3.
Expression levels of serum CXCL9, CXCL10 and CXCL11 in vitiligo patients and healthy controls
| Cytokines | Healthy controls (n=30) | Vitiligo patients (n=50) | P |
|---|---|---|---|
| CXCL9 (pg/ml) | 37.53+8.97 | 92.08+40.48 | <0.01 |
| CXCL10 (pg/ml) | 96.43+18.43 | 184.14+73.14 | <0.01 |
| CXCL11 (pg/ml) | 55.39+18.71 | 155.63+84.81 | <0.01 |
A Student’s t-test was performed to compare the expression levels of CXCL9-11 between vitiligo patents and healthy controls. A P<0.05 is considered significant
The expression levels of serum CXCL9, CXCL10 and CXCL11 of vitiligo patients at different stages
The concentrations of serum CXCL9, CXCL10 and CXCL11 in patients with progressive vitiligo were 107.89 ± 44.00, 224.52 ± 63.37 and 214.42 ± 78.39 pg/ml, respectively. The concentrations in patients with vitiligo in the stable phase were 74.95 ± 28.25, 140.40 ± 53.96 and 91.94 ± 22.46 pg/ml. The serum concentration of CXCL9, CXCL10 and CXCL was significantly higher in the progressive stage than in the stable stage (all P < 0.01) [Table 4].
Table 4.
Expressions levels of serum CXCL9, CXCL10 and CXCL11 in vitiligo patients of different stages
| Cytokines | Progressive stage (n=26) | Stable stage (n=24) | P |
|---|---|---|---|
| CXCL9 (pg/ml) | 107.89+44.00 | 74.95+28.25 | <0.01 |
| CXCL10 (pg/ml) | 224.52+63.37 | 140.40+53.96 | <0.01 |
| CXCL11 (pg/ml) | 214.42+78.39 | 94.63+22.46 | <0.01 |
A Student’s t-test was performed to compare the expression levels of CXCL9-11 between progressive vitiligo and stable vitiligo patients. A P<0.05 is considered significant
The expression levels of serum CXCL9, CXCL10 and CXCL11 in different types of vitiligo patients
In this study, vitiligo patients were divided into sporadic, localised and generalised types based on the diagnosis and treatment consensus of vitiligo established by the dermatological and venereal diseases committee of Chinese and Western medicine in 2018. The serum concentrations of CXCL9, CXCL10 and CXCL11 in generalised type vitiligo patients were significantly higher than localised vitiligo patients (P < 0.05) and sporadic vitiligo patients (P < 0.05) [Table 2]. The CXCL9, CXCL10 and CXCL11 expressions in sporadical vitiligo patients had an upstream trend than localised vitiligo; however, no statistically significant difference was found (P > 0.05) [Table 2]. Our results suggested that the serum CXCL9, CXCL10 and CXCL11 expressions may be related to the lesion area and disease severity in vitiligo patients.
Expressions of serum CXCL9, CXCL10 and CXCL11 in vitiligo patients underwent TCAMs
Fasting blood of 13 patients with stable vitiligo was collected before and 6 months after the operation, and the expression differences in CXCL9, CXCL10 and CXCL11 were observed. It showed that the expressions of CXCL9, CXCL10 and CXCL11 in vitiligo patients in the stable stage were significantly downregulated after the operation (P < 0.01) [Table 5].
Table 5.
Expression levels of serum CXCL9, CXCL10 and CXCL11 in stable vitiligo before and after the operation
| Cytokines | Pre-operation (n=13) | Post-operation (n=13) | P |
|---|---|---|---|
| CXCL9 (pg/ml) | 83.94+12.71 | 64.55+13.58 | <0.01 |
| CXCL10 (pg/ml) | 135.15+32.46 | 103.12+35.18 | <0.01 |
| CXCL11 (pg/ml) | 105.06+22.34 | 78.40+28.17 | <0.01 |
A paired t-test was performed to compare the expression levels of CXCL9-11 between vitiligo patents before and after operation. A P<0.05 is considered significant
Discussion
CXCL9, CXCL10 and CXCL11 play an essential role in autoimmune diseases, including autoimmune thyroid disease,[19] Sjogren's syndrome,[20] systemic lupus erythematosus (SLE),[21] hepatitis C (HCV)[22] and acquired immunodeficiency syndrome (AIDS).[23] CXCR3 and its ligands such as CXCL9, CXCL10 and CXCL11 can selectively induce Th1 cells to the inflammatory site, and CXCL11 can promote the proliferation and differentiation of Th1 cells through CXCR3.[24] The overexpression of CXCL9 and CXCL10 has been reported in vitiligo patients.[25,26,27] For instance, James et al. found that CXCL9 has a higher specificity and sensitivity than CXCL10 in the diagnosis of vitiligo stage. In addition, the expressions of CXCL9 and CXCL10 in patients with non-segmental progressive vitiligo were significantly higher than those in patients with stable vitiligo, accompanied by the overexpression of CXCR3 in PBMCs.[28] In this study, the upregulated levels of serum CXCL9, CXCL10 and CXCL11 were identified in the vitiligo patients with progressive stage or generalised type in comparison with other groups, including healthy people. Our results are in agreement with the previous studies, suggesting that the expressions of serum CXCL9, CXCL10 and CXCL11 are positively connected with the area of the rash. Thus, the expressions of chemokines provide a clue for the lesion area and disease severity.
Bourgeoning studies have reported the CXCR3-targeted therapy in several autoimmune disease models, including type 1 diabetes mellitus and multiple sclerosis.[29,30] Wild-type mice are inclined to severe experimental autoimmune encephalomyelitis compared with CXCR3-/- CXCL10-/- mice, while exhaustion of CXCR3 antibodies may eliminate the CXCR3+ T cells, which induces the pathogenic effector T cells in autoimmunity.[31] In the vitiligo mouse model, CXCR3 antibodies can significantly reverse the clinical manifestations of vitiligo, with reduced epidermal melanocyte-specific antigen expression.[32] Therefore, the depletion of CXCR3+ CTL cells and the neutralisation of CXCL9, CXCL10 and CXCL11 antibodies may promote repigmentation and CXCR3 axis could be considered a potential therapeutic target for vitiligo treatment. Nowadays, TCAM has become the first-line treatment for vitiligo patients.[33] TCAM is to use autologous cultured melanocytes to repair the skin lesions, usually applied in large skin lesions transplantation with an evenly distributed pigment, especially for patients with segmental vitiligo.[34,35] Our previous clinical observation demonstrated that the effective rate of TCAM could reach 79.89% and the recovery rate was 51.85%, suggesting that TCAM is one of the effective approaches for vitiligo treatment. Wang et al.[11] found the significant downregulated CXCL10 in PBMCS of progressive vitiligo patients who received intramuscular injections of compound betamethasone combined with 0.1% tacrolimus ointment 3 months later. In the current study, the vitiligo patients who underwent the TCAM had lower levels of CXCL9, CXCL10 and CXCL11 6 months after the operation compared with their baseline concentrations, suggesting that the TCAM approach could improve the immune microenvironment in vitiligo patients, thus reducing the serum concentration of chemokines.
To the best of our knowledge, this is the first time that the downregulation of CXCL9, CXCL10 and CXCL11 was identified in vitiligo patients after TCAM. Moreover, our findings imply that the upregulation of CXCL9, CXCL10 and CXCL11 in vitiligo patients is correlated with the pathogenesis of vitiligo.
There are some limitations in this study. The number of vitiligo patients with generalised vitiligo is relatively low. Secondly, the relationship between chemokine expressions and treatment sufficiency/prognosis of vitiligo is not analysed. At last, the signalling pathways involved in chemokine interaction are extremely complicated, and the profound mechanism remains elusive. Given the extremely low incidence of vitiligo, obtaining larger numbers of clinically and biologically documented patient samples was not feasible. Obviously, more studies are needed to standardise and characterise the clinical applicability of serum cytokines as candidate biomarkers identified in this study.
In conclusion, CXCL9-11 was related to the disease progression and lesion area, confirming the vital role of the abnormal expression of CXC family chemokines in the pathogenesis of vitiligo. In addition, the expressions of serum CXCL9-11 decreased after TCAM treatment, implying that TCAM operation can change the immune microenvironment in the skin lesions and blood of vitiligo patients.
Financial support and sponsorship
miR-223-3p targets FOXO3, mediates the involvement of CD8+ T cells in the development mechanism of melanocyte apoptosis in vitiligo (National Natural Science Foundation of China, No. 82173406) and establishes a standardised research system and biological sample management platform for the pathogenesis of common and difficult skin diseases in Xinjiang (Autonomous Region Science and Technology Program Project, No. 2021B03001-1).
Conflicts of interest
The authors declare that there are no conflicts of interest regarding the publication of this study.
Acknowledgment
The authors would like to express their appreciation to Xinjiang Key Laboratory of Dermatology Research for sample collection and cooperation.
References
- 1.Ezzedine K, Eleftheriadou V, Whitton M, van Geel N. Vitiligo. Lancet. 2015;386:74–84. doi: 10.1016/S0140-6736(14)60763-7. [DOI] [PubMed] [Google Scholar]
- 2.Iannella G, Greco A, Didona D, Didona B, Granata G, Manno A, et al. Vitiligo: Pathogenesis, clinical variant, s and treatment approaches. Autoimmun Rev. 2016;15:335–43. doi: 10.1016/j.autrev.2015.12.006. [DOI] [PubMed] [Google Scholar]
- 3.Ezzedine K, Lim HW, Suzuki T, Katayama I, Hamzavi I, Lan CCE, et al. Revised classification/nomenclature of vitiligo and related issues: The vitiligo global issues consensus conference. Pigment Cell Melanoma Res. 2012;25:E1–13. doi: 10.1111/j.1755-148X.2012.00997.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Gan EY, Eleftheriadou V, Esmat S, Hamzavi I, Passeron T, Böhm M, et al. Repigmentation in vitiligo: Position paper of the vitiligo global issues consensus conference. Pigment Cell Melanoma Res. 2017;30:28–40. doi: 10.1111/pcmr.12561. [DOI] [PubMed] [Google Scholar]
- 5.Rodrigues M, Ezzedine K, Hamzavi I, Pandya AG, Harris JE, Group VW. discoveries in the pathogenesis and classification of vitiligo. J Am Acad Dermatol. 2017;77:1–13. doi: 10.1016/j.jaad.2016.10.048. [DOI] [PubMed] [Google Scholar]
- 6.Gey A, Diallo A, Seneschal J, Léauté-Labrèze C, Boralevi F, Jouary T, et al. Autoimmune thyroid disease in vitiligo: Multivariate analysis indicates intricate pathomechanisms. Br J Dermatol. 2013;168:756–61. doi: 10.1111/bjd.12166. [DOI] [PubMed] [Google Scholar]
- 7.Jin T, Xu X, Hereld D, Chemotaxis, chemokine receptors, and human disease. Chemotaxis, chemokine receptors, and human disease. Cytokine. 2008;44:1–8. doi: 10.1016/j.cyto.2008.06.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Rashighi M, Harris JE. Interfering with the IFN-γ/CXCL10 pathway to develop new targeted treatments for vitiligo. Ann Transl Med. 2015;3:343. doi: 10.3978/j.issn.2305-5839.2015.11.36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Hickman HD, Reynoso GV, Ngudiankama BF, Cush SS, Gibbs J, Bennink JR, et al. CXCR3 chemokine receptor enables local CD8 (+) T cell migration for the destruction of virus-infected cells. Immunity. 2015;42:524–37. doi: 10.1016/j.immuni.2015.02.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Rashighi M, Agarwal P, Richmond JM, Harris TH, Dresser K, Su M-W, et al. CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo. Sci Transl Med. 2014;6:223ra23. doi: 10.1126/scitranslmed.3007811. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Wang XX, Wang QQ, Wu JQ, Jiang M, Chen L, Zhang CF, et al. Increased expression of CXCR3 and its ligands in patients with vitiligo and CXCL10 as a potential clinical marker for vitiligo. Br J Dermatol. 2016;174:1318–26. doi: 10.1111/bjd.14416. [DOI] [PubMed] [Google Scholar]
- 12.Sushama S, Dixit N, Gautam RK, Arora P, Khurana A, Anubhuti A. Cytokine profile (IL-2, IL-6, IL-17, IL-22, and TNF- α) in vitiligo-new insight into the pathogenesis of the disease. J Cosmet Dermatol. 2019;18:337–41. doi: 10.1111/jocd.12517. [DOI] [PubMed] [Google Scholar]
- 13.Daniel BS, Wirrall R. Vitiligo treatment update. Australas J Dermatol. 2015;56:85–92. doi: 10.1111/ajd.12256. [DOI] [PubMed] [Google Scholar]
- 14.Zokaei S, Farhud DD, Keykhaei M, Yeganeh MZ, Rahimi H, Moravvej H. Cultured epidermal melanocyte transplantation in vitiligo: A review article. Iran J Public Health. 2019;48:388–99. [PMC free article] [PubMed] [Google Scholar]
- 15.Rashighi M, Harris JE. Vitiligo pathogenesis and emerging treatments. Dermatol Clin. 2017;35:257–65. doi: 10.1016/j.det.2016.11.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Searle T, Al-Niaimi F, Ali FR. Vitiligo: An update on systemic treatments. Clin Exp Dermatol. 2021;46:248–58. doi: 10.1111/ced.14435. [DOI] [PubMed] [Google Scholar]
- 17.Aguilera-Durán G, Romo-Mancillas A. Computational study of c-x-c chemokine receptor (cxcr) 3 binding with its natural agonists chemokine (c-x-c motif) ligand (cxcl) 9, 10 and 11 and with synthetic antagonists: Insights of receptor activation towards drug design for vitiligo. Molecules. 2020;25:4413. doi: 10.3390/molecules25194413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Strassner JP, Rashighi M, Refat MA, Richmond JM, Harris JE. Suction blistering the lesional skin of vitiligo patients reveals useful biomarkers of disease activity. J Am Acad Dermatol. 2017;76:847–55.e5. doi: 10.1016/j.jaad.2016.12.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Fallahi P, Ferrari SM, Ragusa F, Ruffilli I, Elia G, Paparo SR, et al. Th1 chemokines in autoimmune endocrine disorders. J Clin Endocrinol Metab. 2020;105:dgz289. doi: 10.1210/clinem/dgz289. [DOI] [PubMed] [Google Scholar]
- 20.Zhou J, Yu Q. Disruption of CXCR3 function impede the development of Sjögren's syndrome-like xerostomia in non-obese diabetic mice. Lab Invest. 2018;98:620–28. doi: 10.1038/s41374-017-0013-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Nielepkowicz-Goździńska A, Fendler W, Robak E, Kulczycka-Siennicka L, Górski P, Pietras T, et al. the role of CXC chemokines in pulmonary fibrosis of systemic lupus erythematosus patients. Arch Immunol Ther Exp (Warsz) 2015;63:465–73. doi: 10.1007/s00005-015-0356-8. [DOI] [PubMed] [Google Scholar]
- 22.Pineda-Tenor D, Berenguer J, Jiménez-Sousa MA, Guzmán-Fulgencio M, Aldámiz-Echevarria T, Carrero A, et al. CXCL9, CXCL10 and CXCL11 polymorphisms are associated with sustained virologic response in HIV/HCV-coinfected patients. J Clin Virol. 2014;61:423–9. doi: 10.1016/j.jcv.2014.08.020. [DOI] [PubMed] [Google Scholar]
- 23.Yin X, Wang Z, Wu T, Ma M, Zhang Z, Chu Z, et al. The combination of CXCL9, CXCL10 and CXCL11 levels during primary HIV infection predicts HIV disease progression. J Transl Med. 2019;17:417. doi: 10.1186/s12967-019-02172-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Zohar Y, Wildbaum G, Novak R, Salzman AL, Thelen M, Alon R, et al. CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis. J Clin Invest. 2018;128:1200–1. doi: 10.1172/JCI120358. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Maouia A, Sormani L, Youssef M, Helal AN, Kassab A, Passeron T. Differential expression of CXCL9, CXCL10, and IFN-γin vitiligo and alopecia areata patients. Pigment Cell Melanoma Res. 2017;30:259–61. doi: 10.1111/pcmr.12559. [DOI] [PubMed] [Google Scholar]
- 26.Smith JS, Rajagopal S, Atwater AR. Chemokine signaling in allergic contact dermatitis: Toward targeted therapies. Dermatitis. 2018;29:179–86. doi: 10.1097/DER.0000000000000391. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Abdallah M, El-Mofty M, Anbar T, Rasheed H, Esmat S, Al-Tawdy A, et al. CXCL-10 and Interleukin-6 are reliable serum markers for vitiligo activity: A multicenter cross-sectional study. Pigment Cell Melanoma Res. 2018;31:330–6. doi: 10.1111/pcmr.12667. [DOI] [PubMed] [Google Scholar]
- 28.Berchiche YA, Sakmar TP. CXC chemokine receptor 3 alternative splice variants selectively activate different signaling pathways. Mol Pharmacol. 2016;90:483–95. doi: 10.1124/mol.116.105502. [DOI] [PubMed] [Google Scholar]
- 29.Nigi L, Brusco N, Grieco GE, Licata G, Krogvold L, Marselli L, et al. Pancreatic alpha-cells contribute together with beta-cells to cxcl10 expression in type 1 diabetes. Front Endocrinol (Lausanne) 2020;11:630. doi: 10.3389/fendo.2020.00630. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Zhou Ya-Qun, Liu Dai-Qiang, Chen Shu-Ping, Sun J, Zhou Xue-Rong, Xing C, et al. The role of CXCR3 in neurological diseases. Curr Neuropharmacol. 2019;17:142–50. doi: 10.2174/1570159X15666171109161140. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Klein RS, Izikson L, Means T, Gibson HD, Lin E, Sobel RA, et al. IFN-inducible protein 10/CXC chemokine ligand 10-independent induction of experimental autoimmune encephalomyelitis. J Immunol. 2004;172:550–9. doi: 10.4049/jimmunol.172.1.550. [DOI] [PubMed] [Google Scholar]
- 32.Richmond JM, Masterjohn E, Chu R, Tedstone J, Youd ME, Harris JE. CXCR3 depleting antibodies prevent and reverse vitiligo in mice. J Invest Dermatol. 2017;137:982–5. doi: 10.1016/j.jid.2016.10.048. [DOI] [PubMed] [Google Scholar]
- 33.Thakur V, Bishnoi A, Vinay K, Kumaran SM, Parsad D. Vitiligo: Translational research and effective therapeutic strategies. Pigment Cell Melanoma Res. 2021;34:814–26. doi: 10.1111/pcmr.12974. [DOI] [PubMed] [Google Scholar]
- 34.Mei-Cai Z, Ma H-Y, Zhan Z, Liu C-G, Luo W, Zhao G. Detection of auto antibodies and transplantation of cultured autologous melanocytes for the treatment of vitiligo. Exp Ther Med. 2017;13:23–8. doi: 10.3892/etm.2016.3949. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Redondo P, de Azcarate AG, Núñez-Córdoba JM, Andreu EJ, García-Guzman M, Aguado L, et al. Efficacy of autologous melanocyte transplantation on amniotic membrane in patients with stable leukoderma: A randomized clinical trial. JAMA Dermatol. 2015;151:897–9. doi: 10.1001/jamadermatol.2015.0299. [DOI] [PubMed] [Google Scholar]