Report
Increased serum levels of interleukin-23 circulating in patients with non-segmental generalized vitiligo Mario Vaccaro1, MD, PhD, Serafinella P. Cannav o1, MD, PhD, Selene Imbesi2, MD, Mariateresa Cristani3, MS, Olga Barbuzza2, MD, PhD, Valeria Tigano2, MS, and Sebastiano Gangemi2,4, MD, PhD
1 Institute of Dermatology, University of Messina, Messina, Italy, 2Department of Clinical and Experimental Medicine, School and Division of Allergy and Clinical Immunology, University of Messina, Messina, Italy, 3Department FarmacoBiologico, School of Pharmacy, University of Messina, Messina, Italy, and 4Institute of Biomedicine and Molecular Immunology “A. Monroy” (IBIM), Consiglio Nazionale delle Ricerche (CNR), Palermo, Italy
Abstract Introduction Vitiligo is a common progressive depigmentation of the skin due to selective destruction of melanocytes. Nowadays increasing evidences support the hypothesis of an autoimmune etiology. Methods In order to sustain the role of T-helper-17 lymphocytes in the pathogenesis of vitiligo, we measured the serum levels of interleukin (IL)-23 (an important regulator of this subset) using a quantitative enzyme immunoassay technique in 12 males and 16 females (ages ranging from 18 to 58 years) affected by non-segmental vitiligo and compared the results with a group of healthy donors. Results IL-23 serum levels were significantly higher in patients with vitiligo as compared
Correspondence Mario Vaccaro, MD, PhD Institute of Dermatology Policlinico Universitario Via Consolare Valeria 98125 Messina Italy E-mail: [email protected]
with controls. There was a significant positive correlation of IL-23 serum levels with disease duration and extent of vitiligo and disease activity. Conclusions The inhibition of IL-23 might be a novel strategy in the therapy of autoimmune inflammatory diseases like vitiligo.
doi: 10.1111/ijd.12392
Introduction Vitiligo is a common progressive depigmentation of the skin due to selective destruction of melanocytes. Although its cause is still to be exactly defined, the hypothesis of an autoimmune etiology is supported by increasing evidence. Many factors have been implicated in vitiligo development, such as infections, stress, neural abnormalities, melatonin receptor alterations, and genetic susceptibility.1,2 Peripheral blood and skin biopsies of patients with vitiligo show that T-cells, mononuclear cells, proinflammatory cytokines, and autoantibodies can damage melanocytes.3 Perilesional cytotoxic T-cells seem to be responsible for the depigmentation process and able to mediate targeted autoimmune tissue destruction.4 Furthermore, a significant change of epidermal cytokines in involved skin of patients with vitiligo compared with uninvolved skin and skin of healthy controls has been described. Experimental evidences have shown a role ª 2014 The International Society of Dermatology
of tumor necrosis factor (TNF)-a in the pathogenesis of non-segmental vitiligo; in fact, successful treatment of vitiligo with TNF-a inhibitors has been recently reported.5 Cutaneous depigmentation involves cytotoxic activity of autoreactive T-cells; it was hypothesized that depigmentation can progress when the activity of regulatory T-cells (Treg) is reduced. A reduced percentage of Treg in non-lesional, perilesional, and lesional vitiligo skin was observed through an evaluation by immunoenzymatic double-staining for CD3 and FoxP3. The paucity of Treg in vitiligo skin is likely crucial for perpetual antimelanocyte reactivity in progressive disease.6 Th17 cells are acquiring an increasingly more important role in the pathogenesis of autoimmune diseases. They produce interleukin (IL)-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25), IL-17F, IL-6, TNF-a, IL-22, and IL-26.7,8 The production of IL-17A and IL-17F by T-lymphocytes is regulated proximally by IL-23 produced by dendritic cells, independently of cell-to-cell contact or traditional International Journal of Dermatology 2014
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Increased serum levels of IL-23 circulating in patients with non-segmental generalized vitiligo
TCR activation. IL-23 is a member of the IL-12 family, which activates the effector function of Th17 cells to promote inflammatory responses. It has been established that IL-23 is essential for the development of autoimmune diseases, including psoriatic skin inflammation, inflammatory bowel disease, autoimmune diabetes, and experimental autoimmune encephalomyelitis. This cytokine induces the production of Th17 cells, so it was thought that IL-23 mediates autoimmunity by secretion of the IL-17 family.8 In patients with vitiligo, increased serum IL-17 levels were observed, suggesting that IL-17 may participate in the immune response in early-onset disease.9 These data are in favor of the involvement of Th17 cells in the pathogenic mechanism of vitiligo. In order to sustain the role of Th17 cells in this disease, we analyzed the serum levels of IL-23 in affected patients and compared the results with a group of healthy donors. To our knowledge, no similar studies have been conducted to measure IL-23 levels in patients with vitiligo.
Vaccaro et al.
were presented as median and quartiles. Differences between data series were analyzed by the Mann–Whitney test, and correlations by Spearman’s rank correlation coefficient. Statistical significance was set at P < 0.05. The graphs were performed with GraphPad Prism for Windows version 5.01 (GraphPad Software Inc. La Jolla, CA, USA).
Results IL-23 serum levels were significantly higher in patients with vitiligo as compared with controls (median: 5.25; I quartile: 2.56; III quartile: 18.17 pg/ml vs. median: 2.44; I quartile: 2.28; III quartile: 3, P = 0.012; Fig. 1). There was a significant positive correlation of IL-23 serum levels with disease duration (q = 0.45, P < 0.05) and extent of vitiligo (q = 0.57, P < 0.05) and disease activity (q = 0.68, P < 0.05). No significant correlation between gender, age, autoimmune thyroiditis, and IL-23 levels was found. Discussion
Materials and methods A total of 28 patients with non-segmental generalized vitiligo were included in the study: 12 males and 16 females, with age ranging from 18 to 58 years (median 44 years, I quartile 31.5 years, III quartile 54 years). The duration of vitiligo ranged from 1 to 18 years (median 4 years, I quartile 3 years, III quartile 6 years); the mean extent was 51 24.3% of involved body surface area (BSA) (range 35–90%). Disease was classified as active (an increase of affected BSA in the last 6 months) in 17 patients. History and general examination revealed autoimmune thyroiditis in three patients, autoimmune diabetes mellitus in two patients, alopecia areata in one patient, and psychological stress related to lifestyle in four patients. A family history of vitiligo was present in three patients. Twenty controls matched for age and gender were included in this study. Written informed consent was obtained from patients and healthy
The involvement of Th17 cells has been suggested by some authors, who found increased serum levels of the cytokines produced by these cells. IL-17 and IL-22 seem significantly associated with vitiligo. High levels of IL-17 have been observed in lesional skin and serum of patients affected by the disease.10 IL-22 may provoke inflammation that leads to destruction of melanocytes and has been significantly associated with vitiligo in the active stage.11 IL-23 induces the differentiation of Th17 cells in a proinflammatory context, especially in the presence of transforming growth factor (TGF)-b and IL-6.12 IL-23R is expressed by inflammatory macrophages, which are activated to produce IL-1, TNF-a, and IL-23 itself. IL-23 seems to have a central role in autoimmunity. It has been associated with psoriasis, chronic inflammatory bowel disease, and rheumatoid arthritis.9
controls enrolled in the study. Serum samples were obtained using a serum separator tube and allowing samples to clot for 30 minutes before centrifugation (15 minutes at approximately 1000 g); serum aliquots were stored at
20 °C until the assay. To investigate
whether cytokine imbalance plays a role in the pathogenesis of vitiligo, we performed a case–control association study by enzyme-linked immunosorbent assay of IL-23 in our patient. The assay was performed by using a commercially available kit (R&D System Europe, Abingdon, UK); a microplate reader capable of measuring absorbance at 450 nm (correction wavelength set at 540 nm) was used to measure the intensity of color developed in each well. The statistical analysis was performed with SPSS for Windows (version 13.0: SPSS Inc. Chicago, IL, USA). Data International Journal of Dermatology 2014
Figure 1 Comparison of interleukin (IL)-23 serum concentrations in patients affected by vitiligo and in controls (P = 0.012, Mann–Whitney test). The lines represent the median ª 2014 The International Society of Dermatology
Vaccaro et al.
Increased serum levels of IL-23 circulating in patients with non-segmental generalized vitiligo
Growing evidences suggest that cytokines that are important in autoimmunity play a role in depigmentation. The level of soluble IL-2R, expression of activation of T-cells, and the production of IL-6 by mononuclear cells are significantly increased in patients with vitiligo. Elevated IL-8 serum levels have also been reported; this cytokine may attract neutrophils to skin lesions, amplifying inflammation.13 TNF-a and IL-6 inhibit pigmentation and could promote keratinocyte apoptosis. Keratinocytes contribute to melanocyte homeostasis. Changes in expression of keratinocyte-derived mediators have been described as responsible for altered melanogenesis; stem cell factor and endothelin-1, two melanogenic mediators, are significantly reduced in lesional epidermis.14 Reduced serum levels of TGF-b have been observed in patients with generalized vitiligo; this may have a role in the enhancement of cellular immunity, implicated in the pathogenesis.15 Some authors also reported the association between the larger number of T-lymphocytes in the periphery of vitiligo lesions and angiogenesis; they observed a significantly increased number of CD34- and vascular endothelial growth factor-positive vessels and detected mast cells in the center of the lesion rather than in the periphery.16 Emerging evidences demonstrate that IL-23 plays an important role in central regulation of the cellular mechanisms involved in inflammation. IL-23 may induce an autocrine loop within the innate immune system, leading to the production of numerous mediators of inflammation.17 Here we report for the first time increased serum levels of IL-23, a cytokine able to induce the differentiation of Th17 cells, in patients affected by vitiligo compared with controls. In addition to the frequent associations observed between vitiligo and other autoimmune disorders, this result strengthens the hypothesis that Th17 lymphocyte cells play a central role in the pathogenesis of the disease. In conclusion, the inhibition of IL-23 might be a novel and promising therapeutic strategy (i.e. monoclonal antibody that binds to the p40 subunit common to both IL-12 and IL-23), able to improve the clinical course of vitiligo, a disease not yet adequately treatable. Of course, a careful evaluation of the risk/benefit ratio of such treatment (e.g. possible increase of cancer risk and/or tumor progression) must be carried out for each case, keeping in mind that vitiligo is not a life-threatening disease but neither is it merely a cosmetic problem. References 1 Lambe T, Leung JC, Bouriez-Jones T, et al. CD4 T cell-dependent autoimmunity against melanocyte
ª 2014 The International Society of Dermatology
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neoantigen induces spontaneous vitiligo and depends upon Fas-Fas ligand interactions. J Immunol 2006; 177: 3055–3062. Le Poole IC, Das PK, van den Wijngaard RM, et al. Review of the etiopathomechanism of vitiligo: a convergence theory. Exp Dermatol 1993; 2: 145–153. Sandoval-Cruz M, Garcˇa-Carrasco M, S anchez-Porras R, et al. Immunopathogenesis of vitiligo. Autoimmun Rev 2011; 10: 762–765. Zamani M, Spaepen M, Sghar SS, et al. Linkage and association of HLA class genes with vitiligo in a Dutch population. Br J Dermatol 2001; 145: 90–94. Kim NH, Torchia D, Rouhani P, et al. Tumor necrosis factor-a in vitiligo: direct correlation between tissue levels and clinical parameters. Cutan Ocul Toxicol 2011; 30: 225–227. Klarquist J, Denman CJ, Hernandez C, et al. Reduced skin homing by functional Treg in vitiligo. Pigment Cell Melanoma Res 2012; 23: 276–286. Moseley TA, Haudenschild DR, Rose L, et al. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 2003; 14: 155–174. Croxford AL, Mair F, Becher B. IL-23: one cytokine in control of autoimmunity. Eur J Immunol 2012; 42: 2263–2273. Duvallet E, Semerano L, Assier E, et al. Interleukin-23: a key cytokine in inflammatory diseases. Ann Med 2011; 43: 503–511. Bassiouny DA, Shaker O. Role of interleukin-17 in the pathogenesis of vitiligo. Clin Exp Dermatol 2012; 36: 292–297. R€ atsep R, Kingo K, Karelson M, et al. Gene expression study of IL10 family genes in vitiligo skin biopsies, peripheral blood mononuclear cells and sera. Br J Dermatol 2008; 159: 1275–1281. Maddur MS, Miossec P, Kaveri SV, et al. Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. Am J Pathol 2012; 181: 8–18. Rezaei N, Gavalas NG, Weetman AP, et al. Autoimmunity as an aetiological factor in vitiligo. J Eur Acad Dermatol Venereol 2007; 21: 865–876. Moretti S, Fabbri P, Baroni G, et al. Keratinocyte dysfunction in vitiligo epidermis: cytokine microenvironment and correlation to keratinocyte apoptosis. Histol Histopathol 2009; 24: 849–857. Basak PY, Adiloglu AK, Ceyhan AM. The role of helper and regulatory T cells in the pathogenesis of vitiligo. J Am Acad Dermatol 2009; 60: 256–260. Aroni K, Voudouris S, Ionnadis E, et al. Increased angiogenesis and mast cells in the centre compared to the periphery of the vitiligo lesions. Arch Dermatol Res 2010; 302: 601–607. Tang C, Chen S, Qian H, et al. IL-23: as a drug target for autoimmune inflammatory diseases. Immunology 2011; 135: 112–124.
International Journal of Dermatology 2014
3
Increased serum levels of interleukin-23 circulating in patients with non-segmental generalized vitiligo Mario Vaccaro1, MD, PhD, Serafinella P. Cannav o1, MD, PhD, Selene Imbesi2, MD, Mariateresa Cristani3, MS, Olga Barbuzza2, MD, PhD, Valeria Tigano2, MS, and Sebastiano Gangemi2,4, MD, PhD
1 Institute of Dermatology, University of Messina, Messina, Italy, 2Department of Clinical and Experimental Medicine, School and Division of Allergy and Clinical Immunology, University of Messina, Messina, Italy, 3Department FarmacoBiologico, School of Pharmacy, University of Messina, Messina, Italy, and 4Institute of Biomedicine and Molecular Immunology “A. Monroy” (IBIM), Consiglio Nazionale delle Ricerche (CNR), Palermo, Italy
Abstract Introduction Vitiligo is a common progressive depigmentation of the skin due to selective destruction of melanocytes. Nowadays increasing evidences support the hypothesis of an autoimmune etiology. Methods In order to sustain the role of T-helper-17 lymphocytes in the pathogenesis of vitiligo, we measured the serum levels of interleukin (IL)-23 (an important regulator of this subset) using a quantitative enzyme immunoassay technique in 12 males and 16 females (ages ranging from 18 to 58 years) affected by non-segmental vitiligo and compared the results with a group of healthy donors. Results IL-23 serum levels were significantly higher in patients with vitiligo as compared
Correspondence Mario Vaccaro, MD, PhD Institute of Dermatology Policlinico Universitario Via Consolare Valeria 98125 Messina Italy E-mail: [email protected]
with controls. There was a significant positive correlation of IL-23 serum levels with disease duration and extent of vitiligo and disease activity. Conclusions The inhibition of IL-23 might be a novel strategy in the therapy of autoimmune inflammatory diseases like vitiligo.
doi: 10.1111/ijd.12392
Introduction Vitiligo is a common progressive depigmentation of the skin due to selective destruction of melanocytes. Although its cause is still to be exactly defined, the hypothesis of an autoimmune etiology is supported by increasing evidence. Many factors have been implicated in vitiligo development, such as infections, stress, neural abnormalities, melatonin receptor alterations, and genetic susceptibility.1,2 Peripheral blood and skin biopsies of patients with vitiligo show that T-cells, mononuclear cells, proinflammatory cytokines, and autoantibodies can damage melanocytes.3 Perilesional cytotoxic T-cells seem to be responsible for the depigmentation process and able to mediate targeted autoimmune tissue destruction.4 Furthermore, a significant change of epidermal cytokines in involved skin of patients with vitiligo compared with uninvolved skin and skin of healthy controls has been described. Experimental evidences have shown a role ª 2014 The International Society of Dermatology
of tumor necrosis factor (TNF)-a in the pathogenesis of non-segmental vitiligo; in fact, successful treatment of vitiligo with TNF-a inhibitors has been recently reported.5 Cutaneous depigmentation involves cytotoxic activity of autoreactive T-cells; it was hypothesized that depigmentation can progress when the activity of regulatory T-cells (Treg) is reduced. A reduced percentage of Treg in non-lesional, perilesional, and lesional vitiligo skin was observed through an evaluation by immunoenzymatic double-staining for CD3 and FoxP3. The paucity of Treg in vitiligo skin is likely crucial for perpetual antimelanocyte reactivity in progressive disease.6 Th17 cells are acquiring an increasingly more important role in the pathogenesis of autoimmune diseases. They produce interleukin (IL)-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25), IL-17F, IL-6, TNF-a, IL-22, and IL-26.7,8 The production of IL-17A and IL-17F by T-lymphocytes is regulated proximally by IL-23 produced by dendritic cells, independently of cell-to-cell contact or traditional International Journal of Dermatology 2014
1
2
Report
Increased serum levels of IL-23 circulating in patients with non-segmental generalized vitiligo
TCR activation. IL-23 is a member of the IL-12 family, which activates the effector function of Th17 cells to promote inflammatory responses. It has been established that IL-23 is essential for the development of autoimmune diseases, including psoriatic skin inflammation, inflammatory bowel disease, autoimmune diabetes, and experimental autoimmune encephalomyelitis. This cytokine induces the production of Th17 cells, so it was thought that IL-23 mediates autoimmunity by secretion of the IL-17 family.8 In patients with vitiligo, increased serum IL-17 levels were observed, suggesting that IL-17 may participate in the immune response in early-onset disease.9 These data are in favor of the involvement of Th17 cells in the pathogenic mechanism of vitiligo. In order to sustain the role of Th17 cells in this disease, we analyzed the serum levels of IL-23 in affected patients and compared the results with a group of healthy donors. To our knowledge, no similar studies have been conducted to measure IL-23 levels in patients with vitiligo.
Vaccaro et al.
were presented as median and quartiles. Differences between data series were analyzed by the Mann–Whitney test, and correlations by Spearman’s rank correlation coefficient. Statistical significance was set at P < 0.05. The graphs were performed with GraphPad Prism for Windows version 5.01 (GraphPad Software Inc. La Jolla, CA, USA).
Results IL-23 serum levels were significantly higher in patients with vitiligo as compared with controls (median: 5.25; I quartile: 2.56; III quartile: 18.17 pg/ml vs. median: 2.44; I quartile: 2.28; III quartile: 3, P = 0.012; Fig. 1). There was a significant positive correlation of IL-23 serum levels with disease duration (q = 0.45, P < 0.05) and extent of vitiligo (q = 0.57, P < 0.05) and disease activity (q = 0.68, P < 0.05). No significant correlation between gender, age, autoimmune thyroiditis, and IL-23 levels was found. Discussion
Materials and methods A total of 28 patients with non-segmental generalized vitiligo were included in the study: 12 males and 16 females, with age ranging from 18 to 58 years (median 44 years, I quartile 31.5 years, III quartile 54 years). The duration of vitiligo ranged from 1 to 18 years (median 4 years, I quartile 3 years, III quartile 6 years); the mean extent was 51 24.3% of involved body surface area (BSA) (range 35–90%). Disease was classified as active (an increase of affected BSA in the last 6 months) in 17 patients. History and general examination revealed autoimmune thyroiditis in three patients, autoimmune diabetes mellitus in two patients, alopecia areata in one patient, and psychological stress related to lifestyle in four patients. A family history of vitiligo was present in three patients. Twenty controls matched for age and gender were included in this study. Written informed consent was obtained from patients and healthy
The involvement of Th17 cells has been suggested by some authors, who found increased serum levels of the cytokines produced by these cells. IL-17 and IL-22 seem significantly associated with vitiligo. High levels of IL-17 have been observed in lesional skin and serum of patients affected by the disease.10 IL-22 may provoke inflammation that leads to destruction of melanocytes and has been significantly associated with vitiligo in the active stage.11 IL-23 induces the differentiation of Th17 cells in a proinflammatory context, especially in the presence of transforming growth factor (TGF)-b and IL-6.12 IL-23R is expressed by inflammatory macrophages, which are activated to produce IL-1, TNF-a, and IL-23 itself. IL-23 seems to have a central role in autoimmunity. It has been associated with psoriasis, chronic inflammatory bowel disease, and rheumatoid arthritis.9
controls enrolled in the study. Serum samples were obtained using a serum separator tube and allowing samples to clot for 30 minutes before centrifugation (15 minutes at approximately 1000 g); serum aliquots were stored at
20 °C until the assay. To investigate
whether cytokine imbalance plays a role in the pathogenesis of vitiligo, we performed a case–control association study by enzyme-linked immunosorbent assay of IL-23 in our patient. The assay was performed by using a commercially available kit (R&D System Europe, Abingdon, UK); a microplate reader capable of measuring absorbance at 450 nm (correction wavelength set at 540 nm) was used to measure the intensity of color developed in each well. The statistical analysis was performed with SPSS for Windows (version 13.0: SPSS Inc. Chicago, IL, USA). Data International Journal of Dermatology 2014
Figure 1 Comparison of interleukin (IL)-23 serum concentrations in patients affected by vitiligo and in controls (P = 0.012, Mann–Whitney test). The lines represent the median ª 2014 The International Society of Dermatology
Vaccaro et al.
Increased serum levels of IL-23 circulating in patients with non-segmental generalized vitiligo
Growing evidences suggest that cytokines that are important in autoimmunity play a role in depigmentation. The level of soluble IL-2R, expression of activation of T-cells, and the production of IL-6 by mononuclear cells are significantly increased in patients with vitiligo. Elevated IL-8 serum levels have also been reported; this cytokine may attract neutrophils to skin lesions, amplifying inflammation.13 TNF-a and IL-6 inhibit pigmentation and could promote keratinocyte apoptosis. Keratinocytes contribute to melanocyte homeostasis. Changes in expression of keratinocyte-derived mediators have been described as responsible for altered melanogenesis; stem cell factor and endothelin-1, two melanogenic mediators, are significantly reduced in lesional epidermis.14 Reduced serum levels of TGF-b have been observed in patients with generalized vitiligo; this may have a role in the enhancement of cellular immunity, implicated in the pathogenesis.15 Some authors also reported the association between the larger number of T-lymphocytes in the periphery of vitiligo lesions and angiogenesis; they observed a significantly increased number of CD34- and vascular endothelial growth factor-positive vessels and detected mast cells in the center of the lesion rather than in the periphery.16 Emerging evidences demonstrate that IL-23 plays an important role in central regulation of the cellular mechanisms involved in inflammation. IL-23 may induce an autocrine loop within the innate immune system, leading to the production of numerous mediators of inflammation.17 Here we report for the first time increased serum levels of IL-23, a cytokine able to induce the differentiation of Th17 cells, in patients affected by vitiligo compared with controls. In addition to the frequent associations observed between vitiligo and other autoimmune disorders, this result strengthens the hypothesis that Th17 lymphocyte cells play a central role in the pathogenesis of the disease. In conclusion, the inhibition of IL-23 might be a novel and promising therapeutic strategy (i.e. monoclonal antibody that binds to the p40 subunit common to both IL-12 and IL-23), able to improve the clinical course of vitiligo, a disease not yet adequately treatable. Of course, a careful evaluation of the risk/benefit ratio of such treatment (e.g. possible increase of cancer risk and/or tumor progression) must be carried out for each case, keeping in mind that vitiligo is not a life-threatening disease but neither is it merely a cosmetic problem. References 1 Lambe T, Leung JC, Bouriez-Jones T, et al. CD4 T cell-dependent autoimmunity against melanocyte
ª 2014 The International Society of Dermatology
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neoantigen induces spontaneous vitiligo and depends upon Fas-Fas ligand interactions. J Immunol 2006; 177: 3055–3062. Le Poole IC, Das PK, van den Wijngaard RM, et al. Review of the etiopathomechanism of vitiligo: a convergence theory. Exp Dermatol 1993; 2: 145–153. Sandoval-Cruz M, Garcˇa-Carrasco M, S anchez-Porras R, et al. Immunopathogenesis of vitiligo. Autoimmun Rev 2011; 10: 762–765. Zamani M, Spaepen M, Sghar SS, et al. Linkage and association of HLA class genes with vitiligo in a Dutch population. Br J Dermatol 2001; 145: 90–94. Kim NH, Torchia D, Rouhani P, et al. Tumor necrosis factor-a in vitiligo: direct correlation between tissue levels and clinical parameters. Cutan Ocul Toxicol 2011; 30: 225–227. Klarquist J, Denman CJ, Hernandez C, et al. Reduced skin homing by functional Treg in vitiligo. Pigment Cell Melanoma Res 2012; 23: 276–286. Moseley TA, Haudenschild DR, Rose L, et al. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 2003; 14: 155–174. Croxford AL, Mair F, Becher B. IL-23: one cytokine in control of autoimmunity. Eur J Immunol 2012; 42: 2263–2273. Duvallet E, Semerano L, Assier E, et al. Interleukin-23: a key cytokine in inflammatory diseases. Ann Med 2011; 43: 503–511. Bassiouny DA, Shaker O. Role of interleukin-17 in the pathogenesis of vitiligo. Clin Exp Dermatol 2012; 36: 292–297. R€ atsep R, Kingo K, Karelson M, et al. Gene expression study of IL10 family genes in vitiligo skin biopsies, peripheral blood mononuclear cells and sera. Br J Dermatol 2008; 159: 1275–1281. Maddur MS, Miossec P, Kaveri SV, et al. Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. Am J Pathol 2012; 181: 8–18. Rezaei N, Gavalas NG, Weetman AP, et al. Autoimmunity as an aetiological factor in vitiligo. J Eur Acad Dermatol Venereol 2007; 21: 865–876. Moretti S, Fabbri P, Baroni G, et al. Keratinocyte dysfunction in vitiligo epidermis: cytokine microenvironment and correlation to keratinocyte apoptosis. Histol Histopathol 2009; 24: 849–857. Basak PY, Adiloglu AK, Ceyhan AM. The role of helper and regulatory T cells in the pathogenesis of vitiligo. J Am Acad Dermatol 2009; 60: 256–260. Aroni K, Voudouris S, Ionnadis E, et al. Increased angiogenesis and mast cells in the centre compared to the periphery of the vitiligo lesions. Arch Dermatol Res 2010; 302: 601–607. Tang C, Chen S, Qian H, et al. IL-23: as a drug target for autoimmune inflammatory diseases. Immunology 2011; 135: 112–124.
International Journal of Dermatology 2014
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