transforming-growth-factor-beta and Vitiligo

Vitiligo is a noncontagious autoimmune skin depigmenting disease. Regulatory T cells (Tregs) play a key role in maintaining peripheral tolerance; however, Tregs' number, suppressive function, and associated suppressive molecules (FOXP3, IL-10, and TGF-

Topics: Autoimmune Diseases; Cytokines; Forkhead Transcription Factors; Humans; Interleukin-10; MicroRNAs; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Vitiligo

Topics: Administration, Topical; Adolescent; Adult; Aged; Case-Control Studies; Combined Modality Therapy; Female; Glycyrrhizic Acid; Humans; Interleukin-17; Lasers, Gas; Male; Middle Aged; Pigmentation; Transforming Growth Factor beta; Triamcinolone Acetonide; Vitiligo; Young Adult

Non-segmental vitiligo (NSV) results from autoimmune destruction of melanocytes. The altered levels of various cytokines have been proposed in the pathogenesis of vitiligo. However, the exact immune mechanisms have not yet been fully elucidated.. To investigate the role of epidermal and systemic cytokines in active and stable NSV patients.. Serum levels of inflammatory cytokines were checked in 42 active and 30 stable NSV patients with 30 controls. The lesional, perilesional and normal skin sections were subjected to H&E staining. The mRNA expression of inflammatory cytokines and their respective receptors were assessed by quantitative PCR in lesional skin of both active and stable NSV skin. The MITF and IL-17A were immunolocalized in lesional, perilesional and normal skin tissue.. Significant increase in the expression of inflammatory cytokines, IL-17A, IL-1β and TGF-β was observed in active patients, whereas no change was observed in stable patients. A marked reduction in epidermal thickness was observed in lesional skin sections. Significant increase in IL-17A and significant decrease in microphthalmia associated transcription factor (MITF) expression was observed in lesional and perilesional skin sections. Moreover, qPCR analysis showed significant alterations in the mRNA levels of IL-17A, IL-1β, IFN-γ, TGF-β and their respective receptors in active and stable vitiligo patient samples.. Increased levels of IL-17A and IL-1β cytokines and decreased expression of MITF suggested a possible role of these cytokines in dysregulation of melanocytic activity in the lesional skin and hence might be responsible for the progression of active vitiligo.

Topics: Adult; Epidermis; Female; Gene Expression Regulation; Humans; Interleukin-17; Interleukin-1beta; Male; Microphthalmia-Associated Transcription Factor; RNA, Messenger; Transforming Growth Factor beta; Vitiligo

NFATs and FOXP3 are linked with impaired regulatory T-cells (Tregs) in generalized vitiligo (GV). To elucidate calcium mediated NFATc1 signalling pathway and its effect on Treg suppressive capacity in GV. Calcium levels, calcineurin, NFATc1 and GSK-3β activity and cell proliferation were assessed in 52 GV patients and 50 controls by calcium assay kit, calcineurin phosphatase assay kit, TransAM NFATc1 kit, GSK-3β ELISA and BrdU cell proliferation assay. Transcripts (CNB, CAM, GSK3B, DYRK1A and calcium channel genes) and protein (IFN-γ, IL-10 and TGF-β) expressions were assessed by qPCR and ELISA, respectively. Reduced plasma and intracellular Tregs calcium levels and ORAI1 transcripts suggested altered calcium homeostasis in GV Tregs (p = 0.00387, p = 0.0048, p < 0.0001), which led to decreased calcineurin and NFATc1 activity in GV Tregs (p = 0.0299, p < 0.0001). CNB and CAM transcripts were reduced in GV Tregs (p < 0.0001, p = 0.0004). GSK-3β activity, GSK3B and DYRK1A transcripts significantly increased in GV Tregs (p = 0.0134, p < 0.0001 and p < 0.0001). Plasma (p = 0.0225, p = 0.032) and intracellular Treg (p = 0.0035, p = 0.005) calcium levels, calcineurin (p = 0.001) and NFATc1 (p = 0.001, p < 0.0001) activity and ORAI1 (p = 0.0093, p < 0.0001), CAM and CNB (p = 0.0214) transcripts significantly decreased in active vitiligo (AV) and severe GV (sGV) Tregs. Calcium treatment significantly increased intracellular calcium and ORAI1 transcripts in GV Tregs (p = 0.0042, p = 0.0035). Moreover, calcium treatment enhanced calcineurin and NFATc1 activity in GV Tregs (p = 0.0128, p < 0.0001). Remarkably, calcium treatment increased Treg mediated suppression of CD4

Topics: Bromodeoxyuridine; Calcineurin; Calcium; Calcium Channels; CD8-Positive T-Lymphocytes; Forkhead Transcription Factors; Glycogen Synthase Kinase 3 beta; Humans; Interleukin-10; NFATC Transcription Factors; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Vitiligo

Regulatory T cells (Tregs) are involved in the suppression of activated T cells in generalized vitiligo (GV). The study was aimed to investigate Tregs functional defects in Treg:CD8

Topics: Adolescent; Adult; Age of Onset; Case-Control Studies; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Proliferation; Cells, Cultured; Child; Coculture Techniques; Cytokines; Female; Forkhead Transcription Factors; Humans; Interferon-gamma; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Male; Middle Aged; NFATC Transcription Factors; Severity of Illness Index; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Vitiligo; Young Adult

Chemicals like Monobenzyl Ether of Hydroquinone (MBEH) and 4-Tertiary Butyl Phenol (4-TBP) have been widely recognized to induce clinical lesions that resemble vitiligo, but exact molecular pathway through which these chemicals initiate vitiligo is still far from clear.. Since vitiligo is widely considered as an autoimmune disease, this study was an attempt to understand miR-2909 RNomics in vitiligo pathogenesis using MBEH treated primary melanocytes as an archetype cellular model because MBEH causes pathological features indistinguishable from clinical vitiligo.. Primary melanocytes were treated with MBEH and 4-TBP and the role of miR-2909 RNomics at transcriptional and translational level was explored through qRT-PCR, western blot analysis, flow cytometry, immunocytochemistry, immunohistochemistry and in silico binding affinities. 4 mm punch biopsies were also obtained from lesional sites of vitiligo patients to validate the results observed in cell culture experiments.. MBEH induced miR-2909 RNomics led to downregulation of MITF, TYR, TYRP1, and TYRP2 leading to decreased melanin synthesis which in turn is a characteristic trait of vitiligo. On the other hand, 4-TBP increased TGF-β which also has the intrinsic capacity to downregulate MITF leading to decreased melanin synthesis and thereby initiation of vitiligo.. Based upon our results we propose a molecular pathway which has the inherent capacity to resolve the mechanism through which these chemicals may induce vitiligo. This mechanism was also found to be involved in the lesional biopsies of vitiligo patients. These results could be exploited in better understanding the pathogenesis as well as in treatment of vitiligo.

Topics: Biopsy; Cells, Cultured; Down-Regulation; Gene Expression Profiling; Gene Expression Regulation; Humans; Hydroquinones; Melanins; Melanocytes; MicroRNAs; Phenols; Primary Cell Culture; Roxithromycin; Skin; Skin Pigmentation; Transforming Growth Factor beta; Vitiligo

In vitiligo, cutaneous depigmentation is accompanied by increased T cell cytolytic activity targeting melanocytes, indicating that autoimmune tolerance is disrupted. The inhibited amount and function of Tregs have been indicated to be involved in the autoimmune intolerance in vitiligo, however, with the conclusion still controversial and the involved mechanism unknown. In this study, we explored the molecular and cellular alterations accounting for the impaired Treg response in vitiligo. Our results showed that the amount of Tregs was drastically reduced in peripheral blood of active vitiligo patients. Furthermore, the immunoregulatory function of Tregs was attenuated, with lower expression of CTLA4, IL-10 and TGF-β. Moreover, the expression of HO-1, a functional modulator of Tregs, was decreased in vitiligo Tregs, and the concentrations of HO-1 metabolites, including bilirubin, CoHb and iron, were correspondingly decreased in serum of vitiligo patients. In addition, we treated the Tregs from vitiligo patients with Hemin, an agonist of HO-1, and found that enhanced HO-1 expression restored the function of Tregs by up-regulating IL-10 expression. Our study demonstrates the essential role of HO-1 in the impaired Treg response in vitiligo and indicates the potential of HO-1 as a therapeutic target in vitiligo management.

Topics: Adolescent; Adult; Aged; Bilirubin; Carboxyhemoglobin; CTLA-4 Antigen; Disease Progression; Female; Gene Expression Regulation; Heme Oxygenase-1; Hemin; Humans; Immune Tolerance; Interleukin-10; Iron; Lymphocyte Count; Male; Melanocytes; Middle Aged; Primary Cell Culture; Severity of Illness Index; Signal Transduction; Skin; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Vitiligo

In the etiopathogenesis of vitiligo, the role of suppressor cytokines, such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), associated with regulatory T-cells (Treg) is not completely known. In this study, the role of Treg-cell functions in the skin of patients with nonsegmental vitiligo was investigated. Lesional and nonlesional skin samples from 30 adult volunteers ranging in age from 18 to 36 years with nonsegmental vitiligo were compared with normal skin area excision specimens of 30 benign melanocytic nevus cases as controls. All samples were evaluated staining for forkhead box P3 (Foxp3), TGF-β, and IL-10 using the standardized streptavidin-biotin immunoperoxidase immunohistochemistry method. Foxp3 expression was lower in lesional vitiligo skin specimens compared to controls; it was also lower in lesional vitiligo specimens than nonlesional vitiligo specimens. IL-10 levels were lower in lesional vitiligo specimens compared to the controls, whereas IL-10 expression was significantly lower in lesional specimens compared with nonlesional specimens. TGF-β expression was higher in both lesional and nonlesional skin specimens of patients with vitiligo compared to controls. TGF-β expression was lower in lesional skin specimens than nonlesional skin specimens. In addition, there was no significant correlation between Foxp3 expression with TGF-β and IL-10 expressions in lesional skin specimens in the vitiligo group. In this study, results supporting the contribution of Treg cells and IL-10 deficiency to the autoimmune process were obtained. Therefore, future studies are necessary to demonstrate the definitive role of Treg-cell functions in the etiopathogenesis of vitiligo.

Topics: Adolescent; Adult; Autoimmune Diseases; Case-Control Studies; Female; Forkhead Transcription Factors; Humans; Interleukin-10; Male; Middle Aged; Skin; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Vitiligo; Young Adult

Vitiligo is an autoimmune depigmentation disease, and defects in regulatory T cells (Tregs) have been proposed in the pathogenesis of generalized vitiligo (GV). However, the role of programmed cell death (PD)1(+) Tregs has not been studied.. To investigate the status of Tregs, PD1(+) Tregs and associated parameters in active GV (aGV) during the first episode of disease attack and to establish the clinical correlation.. The percentages of circulating Tregs, PD1(+) Tregs and CD3(+) CD4(+) PD1(+) T cells were evaluated in 50 patients with aGV and 51 controls. Expression levels of FOXP3, TGFB1, CTLA4 and genes for chemokine receptors (CCR4, CCR7) and their ligands (CCL21, CCL22) were quantified in peripheral blood and in lesional, perilesional, nonlesional and normal skin sections. The corresponding proteins were immunolocalized in tissue of aGV.. The percentage of Tregs was decreased (P = 0·001) and that of PD1(+) Tregs increased (P = 0·001) in peripheral blood of patients with aGV compared with controls. The abundance of TGFB1 and CCL21 mRNA was significantly decreased in the peripheral blood of patients with aGV. Significant differences in forkhead box P3, transforming growth factor-β and CCL21 protein expression were found in skin sections.. Deficiency in Treg frequency and decreased expression of Treg-associated parameters (TGFB and CCL21) suggested a possible defect in Tregs that may alter their suppression function and skin homing in aGV. The increased PD1(+) Tregs suggests that the PD1/PD ligand pathway may be involved in aGV and may have a role in Treg exhaustion. Further study is required to delineate the effect of PD1 in regulating Treg function in aGV.

Topics: Adult; Chemokine CCL21; Chemokine CCL22; Female; Flow Cytometry; Forkhead Transcription Factors; Humans; Male; Microscopy, Confocal; Programmed Cell Death 1 Receptor; Reverse Transcriptase Polymerase Chain Reaction; Skin; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Vitiligo

Although non-segmental vitiligo (NSV) results from the autoimmune destruction of melanocytes, the detailed immune mechanisms have not yet been fully elucidated. Th17 cells have been identified to be implicated in human autoimmune diseases. In this study, the frequencies of peripheral blood Th17 cells and serum levels of IL-17A and Th17 cell-related cytokines were examined in 45 patients with active NSV compared to 45 race-, gender-, and age-matched healthy controls. Our results showed increased circulating Th17 cell frequencies and elevated serum IL-17A, TGF-β1, and IL-21 levels in patients with NSV. Meanwhile, the increased Th17 cell frequencies are positively correlated with serum TGF-β1 level, and the body surface area of lesions is positively correlated with elevated TGF-β1 and IL-21 levels and Th17 cell frequencies. Furthermore, positive correlation was identified between Th17 and Th1 cell frequencies in patients with NSV. These results further indicate the potential involvement of Th17 cells and the collaborative contribution of Th17 and Th1 in NSV development, and suggest that the elevated serum TGF-β1 and IL-21 levels could contribute to enhanced Th17 cell differentiation in NSV.

Topics: CD8-Positive T-Lymphocytes; Flow Cytometry; Humans; Interleukin-17; Interleukins; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta; Vitiligo

Topics: Biomarkers; Case-Control Studies; Humans; Interleukin-17; Interleukin-2; Interleukin-4; T-Lymphocytes; Transforming Growth Factor beta; Vitiligo

Topics: Adult; Aged; Aged, 80 and over; Cell Proliferation; Female; Gene Expression Regulation; Humans; Interleukin-6; Keratinocytes; Langerhans Cells; Male; Middle Aged; Phosphorylation; Skin; STAT3 Transcription Factor; Th17 Cells; Transforming Growth Factor beta; Vitiligo