白癜风并发自身免疫性甲状腺疾病的研究现状

白癜风常并发其他自身免疫性疾病,如自身免疫性甲状腺疾病(autoimmunne thyroid disease,AITD)、类风湿关节炎、1型糖尿病、恶性贫血、系统性红斑狼疮(systemic lupus erthematosus,SLE)、艾迪生病、斑秃等,其中以AITD最多见,包括Graves病、慢性淋巴细胞性甲状腺炎(桥本病)、亚急性甲状腺炎、甲状腺相关性眼病等,但有关白癜风并发AITD确切机制研究甚少。鉴于白癜风是一种多因素、多基因遗传性疾病,发病机制复杂,与遗传和各种非遗传因素相关,多数认为是由基因、环境和免疫系统的相互作用,导致共同的终末通路,即氧化应激-自身免疫介导的黑素细胞缺失,特别是非节段型白癜风(non-segmental vitiligo,NSV)。该文从白癜风的基因、自身免疫和氧化应激3个关联机制上综述、阐述其与AITD的关系。     

Association of UVRAG polymorphisms with susceptibility to non‐segmental vitiligo in a Korean sample

Please cite this paper as: Association of UVRAG polymorphisms with susceptibility to non‐segmental vitiligo in a Korean sample. Experimental Dermatology 2010; 19 : e323–e325. Abstract: Autoimmune, self‐destructive, oxidative stress and genetic theories have been proposed for the pathogenesis of vitiligo. Autophagy is essential for cellular homeostasis and is implicated in many pathophysiological conditions such as cancer, response to oxidative stress and autoimmunity. The ultraviolet (UV) radiation resistance‐associated gene (UVRAG) activates the Beclin1‐PI(3)KC3 complex, promoting autophagy. To evaluate whether UVRAG polymorphisms are associated with non‐segmental vitiligo (NSV) patients in a Korean sample, we conducted a case–control association study of 225 NSV patients and 439 matched healthy controls. A total of five single nucleotide polymorphisms (SNPs) of UVRAG were selected for analysis. Among these, two SNPs (rs1458836, rs7933235) showed significant genotypic differences between the NSV patient group and the control group. These two SNPs were located within a strong linkage disequilibrium (LD) block. In addition, the haplotype of the UVRAG polymorphism was associated with NSV. This study suggests a possible association between UVRAG and NSV susceptibility.     

白癜风神经内分泌免疫发病机制研究新进展

目的白癜风是一种常见的获得性色素脱失性疾病,临床以皮肤黏膜出现边界清楚的瓷白色白斑为主要特征。尽管白癜风相关的研究取得了长足的进展,但白癜风发病具体机制仍未完全阐明。研究表明,白癜风与遗传、氧化应激、免疫等多种因素密切相关,但其具体的作用机制仍需进一步研究。近期,关于神经免疫系统相互作用导致免疫紊乱的致病机制逐渐受到重视。在心身应激等情况下,皮肤外周神经末梢神经肽的异常释放可以导致皮肤免疫微环境的紊乱,进一步损伤黑素细胞。神经肽参与白癜风发生发展的相关研究越来越多,基于神经肽调节的思路也为白癜风的治疗开辟了新的方向。     

Association of TXNDC5 gene polymorphisms and susceptibility to nonsegmental vitiligo in the Korean population

Background Vitiligo is a pigmentary skin disorder characterized by a chronic and progressive loss of melanocytes. Although the aetiology of vitiligo is currently unknown, several theories have been proposed to explain the pathogenesis of this disease, including autoimmune, neural, self‐destruction, oxidative stress, and genetic theories. Thioredoxin domain containing 5 (TXNDC5) is a newly identified member of the thioredoxin family. TXNDC5 has a protein disulphide isomerase‐like domain which plays an important role in protein folding and chaperone activity, against endoplasmic reticulum (ER) stress induced by oxidative stress within the ER. Objectives To determine whether variation in the TXNDC5 gene contributes to the risk of developing nonsegmental vitiligo (NSV) in the Korean population. Methods We conducted a case–control association study of 230 patients with NSV and 417 matched, unaffected controls. Seven single nucleotide polymorphisms (SNPs) in the TXNDC5 gene were selected for study. Results Of the selected SNPs, three exonic SNPs (rs1043784, rs7764128 and rs8643) were statistically associated with NSV. Among them, rs1043784 remained a statistically significant association following Bonferroni correction. These three SNPs were located within a block of linkage disequilibrium; the haplotypes AGG and GAA, consisting of rs1043784, rs7764128 and rs8643, demonstrated a significant association with NSV. Conclusions These results suggest that TXNDC5 gene polymorphisms are associated with the development of NSV in the Korean population.     

Commentary from the Editorial Board to Vitiligo: interplay between oxidative stress and immune system (Laddha et al.)

Vitiligo pathogenesis is very puzzling, and novel mechanisms possibly involved in the development of this disorder are frequently explored. Recently, some authors proposed an interplay between oxidative stress and immune system at the basis of melanocyte loss. According to the experimental evidence, they suggest that exposition to environmental agents might lead to an association between vitiligo and other autoimmune diseases. Accordingly, it is proposed that increased reactive oxygen species due to environmental agents could induce a modification of both melanocytic structures and other tissue proteins, or might disregulate the immune system, influencing the appearance of vitiligo and autoimmune comorbidities.     

The role of oxidants and antioxidants in generalized vitiligo

Oxidative stress may be induced by increasing the generation of reactive oxygen species (ROS) and other free radicals. The generation of ROS is known to be associated with a decrease in antioxidant levels. In the present study, the role of oxidative stress was assessed in the pathogenesis of generalized vitiligo. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and glutathione (GSH) levels in erythrocytes and serum malondialdehyde (MDA) and nitric oxide (NO) levels were investigated in 24 patients with generalized vitiligo and 20 healthy controls. Our results indicated that significantly increased levels of erythrocyte SOD, serum MDA, and NO were associated with a marked reduction of erythrocyte GSH-Px and GSH activities in patients with generalized vitiligo (p<0.05). Our observations suggest that the presence of an imbalance in the oxidant-antioxidant system might play a role in the pathogenesis of vitiligo. Our results further support the concept that free radical-mediated damage may be the initial pathogenic event in melanocyte degeneration in generalized vitiligo.     

Role of oxidative stress and autoimmunity in onset and progression of vitiligo

Vitiligo is an acquired depigmentation disorder characterized by the loss of functional melanocytes from the epidermis. Two major theories of vitiligo pathogenesis include autoimmunity and oxidative stress‐mediated toxicity in melanocytes. The present study aimed to evaluate both the hypotheses in vitiligo patients and to investigate their role in the disease onset and progression. Antimelanocyte antibody levels and lipid peroxidation (LPO) levels were evaluated in 427 patients and 440 controls; antithyroid peroxidase (TPO) antibody levels were estimated in 102 patients and 72 controls. Patients showed a significant increase in LPO and antimelanocyte antibody levels compared to controls. Antimelanocyte antibody and LPO levels were higher in active vitiligo compared to stable. Only 9.8% of patients showed the presence of anti‐TPO antibodies in their circulation. Oxidative stress may be the initial triggering event to precipitate vitiligo in Gujarat population, which is exacerbated by contributing autoimmune factors together with oxidative stress.     

白癜风发病过程研究进展

白癜风是皮肤科常见的色素脱失性疾病,其发病机制目前尚不明确,主要有遗传、氧化应激、黑素细胞丢失、免疫等学说,其发病可能经历了始动阶段、效应阶段及致病阶段,本文对其进行了综述。     

Glutathione S‐transferase M1 and T1 genetic polymorphism in Egyptian patients with nonsegmental vitiligo

Oxidative stress and accumulation of free radicals might play a role in the pathogenesis of vitiligo. Glutathione S‐transferase (GST) is a multigene family of enzymes that detoxify oxidative stress products. In this study, genotyping by multiplex PCR of GSTM1 and GSTT1 in 101 women with nonsegmental vitiligo vulgaris and 101 age‐matched healthy female volunteers showed that only the GSTM1 null genotype (P = 0.04) was significantly overexpressed in patients with vitiligo. Analysis of the combined effect of GSTM1 and GSTT1 genotyping identified a significant association of risk for vitiligo with the GSTT1/GSTM1 double‐null type only (P = 0.01; OR = 2.69; 95% CI 1.12–6.46). Age of onset of vitiligo was significantly earlier in patients with the T1 null genotype (P < 0.01) and those with the T1?/M1+ and T1?/M1? combined genotypes (P < 0.01 and P = 0.01, respectively). In conclusion, the GSTM1 gene and the GSTM1/GSTT1 double‐null genotype may be a risk factor for vitiligo in Egyptian patients. Inability to cope with oxidative stresses because of GST deficiency may cause early disease onset.     

白癜风易感基因研究进展

白癜风是一种获得性皮肤黏膜色素脱失性疾病,其发病机制未明,遗传因素在白癜风的发病中起重要作用,本文按照基因功能分类对白癜风易感基因的研究进展进行了总结,如免疫调节相关类基因、黑素细胞相关类基因、细胞凋亡相关类基因、氧化应激相关类基因,希望能对了解其病因病机有所助益。     

Circulatory levels of antioxidants and lipid peroxidation in Indian patients with generalized and localized vitiligo

Vitiligo is an acquired skin disease, characterized by white areas on the skin due to loss of functional melanocytes. The pathogenesis of the disease is still unclear. Published data show the involvement of oxidative stress in the pathophysiology of vitiligo. A total of 30 vitiligo patients and 30 healthy controls were included in this study. We estimated serum levels of malondialdehyde (MDA), vitamins E and C, total antioxidant activity and whole blood levels of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in vitiligo patients and controls. We found significantly higher levels of MDA and significantly lower levels of SOD, GPx, vitamins C and E and total antioxidant activity in vitiligo patients compared with controls. This study is a maiden attempt to report on antioxidant parameters of both generalized/localized-type Indian vitiligo patients. Our results confirmed that oxidative stress may play an important role in the pathogenesis of vitiligo and cause melanocyte damage in vitiligo.     

Association between an HLA-G 14 bp insertion/deletion polymorphism and non-segmental vitiligo in the Korean population

Vitiligo is a pigmentary skin disorder characterized by the chronic and progressive loss of melanocytes. Although the etiology of vitiligo is still unknown, several theories have been proposed to explain the pathogenesis of vitiligo including autoimmune, neural, self-destruction, oxidative stress, and genetic theories. Human leukocyte antigen (HLA)-G is a nonclassic, major histocompatibility complex class I molecule that plays an important role in suppression of the immune response. Several recent studies have provided evidence that a 14 bp insertion (INS)/deletion (DEL) polymorphism in the HLA-G gene might be associated with autoimmune disease. Our aim in this study was to determine whether the 14 bp INS/DEL polymorphism in the HLA-G gene contributes to the risk of developing non-segmental vitiligo (NSV) in the Korean population. We conducted a case–control association study of 192 NSV patients and 491 matched, unaffected controls. The HLA-G 14bp INS/DEL polymorphism was analyzed by gene scan after amplification using the polymerase chain reaction. Genotype frequencies for the 14bpINS/DEL were different between the vitiligo group and Korean control group. The proportion of subjects with a homozygote 14bpINS/14bpINS genotype was significantly higher in the vitiligo group compared with the control group (7.1 vs. 3.5 %, OR 2.25, 95 % CI 1.06–4.76, p = 0.039 in the recessive model). Our results suggest that the HLA-G 14bpINS/DEL polymorphism is associated with the development of NSV in the Korean population.     

Possible contribution of GSTP1 and other xenobiotic metabolizing genes to vitiligo susceptibility

Vitiligo is an acquired pigmentary disorder with several proposed pathogenesis mechanisms and complex multifactorial genetic predisposition. We analyzed 65 polymorphisms in genes potentially relevant to vitiligo pathogenesis mechanism to reveal novel and confirm reported genetic risk factors in general Russian population. We found that polymorphism rs1138272 (TC + CC) in GSTP1 gene encoding enzyme involved in xenobiotic metabolism is associated with vitiligo (Bonferroni adjusted P value 0.0015) with extraordinary high odds ratio 13.03, and haplotype analysis confirmed association of GSTP1 gene with vitiligo risk. Moreover, analysis of variations in several genes encoding enzymes of xenobiotic metabolism showed that higher risk of vitiligo is associated with higher number of risk alleles. This finding reveals possible contribution of genetic background to observed imbalance of oxidative stress control in vitiligo through cumulative effect of multiple genetic variations in xenobiotic metabolizing genes, supporting the concept of multigenic nature of vitiligo with multiple low-risk alleles cumulatively contributing to vitiligo risk.     

In vivo and in vitro evidence for epidermal H2O2‐mediated oxidative stress in piebaldism

Please cite this paper as: In vivo and in vitro evidence for epidermal H₂O₂‐mediated oxidative stress in piebaldism. Experimental Dermatology 2010; 19 : 883–887. Abstract: Piebaldism is characterised by the absence of pigment in patches on the skin, usually present at birth. Mutations in the kit gene are documented. Clinically this disorder can mimic vitiligo. Here, we show for the first time the presence of oxidised pteridine‐induced fluorescence in association with H₂O₂‐mediated stress in piebald patches employing Wood’s light and in vivo FT‐Raman spectroscopy. In situ immunofluorescence data revealed low catalase and methionine sulphoxide reductase A (MSRA) levels whereas thioredoxin reductase and methionine sulphoxide reductase B (MSRB) are not affected. We also show low superoxide dismutase levels in these patients. The presence of thioredoxin reductase provides capacity to reduce H₂O₂, a mechanism which is absent in vitiligo. Importantly, this enzyme reduces biopterin back to the functioning cofactor 6‐tetrahydrobiopterin. The absence of MSRA indicates deficient methionine sulphoxide repair in the cytosol, meanwhile the presence of MSRB is helpful to protect the nucleus. Taken together, we have identified H₂O₂‐mediated stress in piebald skin with distinct differences to vitiligo.     

Update on the pathogenesis of vitiligo

Vitiligo is a complex disease whose pathogenesis results from the interaction of genetic components, metabolic factors linked to cellular oxidative stress, melanocyte adhesion to the epithelium, and immunity (innate and adaptive), which culminate in aggression against melanocytes. In vitiligo, melanocytes are more sensitive to oxidative damage, leading to the increased expression of proinflammatory proteins such as HSP70. The lower expression of epithelial adhesion molecules, such as DDR1 and E-cadherin, facilitates damage to melanocytes and exposure of antigens that favor autoimmunity. Activation of the type 1-IFN pathway perpetuates the direct action of CD8+ cells against melanocytes, facilitated by regulatory T-cell dysfunction. The identification of several genes involved in these processes sets the stage for disease development and maintenance. However, the relationship of vitiligo with environmental factors, psychological stress, comorbidities, and the elements that define individual susceptibility to the disease are a challenge to the integration of theories related to its pathogenesis.     

Increased advanced oxidation protein products in Behçet's disease: a new activity marker?

Background Behçet's disease (BD) is a chronic inflammatory disease with unknown pathogenesis. As various functions of neutrophils in peripheral blood, such as chemotaxis, phagocytosis and generation of reactive oxygen species (ROS) increase in BD, ROS‐mediated oxidative stress related to neutrophil activation may have an important role in the pathogenesis of BD. Objectives To investigate the importance of neutrophil activation as the main source of oxidative stress through protein oxidation in the pathogenesis of BD, and also to investigate whether one of the products of protein oxidation, advanced oxidation protein products (AOPP), may be used as an activity marker for BD. Methods Patients with BD (n = 49), at active and inactive stages, with or without evidence of uveitis, and healthy volunteers (n = 40) were entered into the study. A full blood count, peripheral blood smears, routine biochemical analyses, C‐reactive protein (CRP) and erythrocyte sedimentation rate (ESR) measurements were performed in all patients preceding the study. Plasma myeloperoxidase (MPO) activity, representing neutrophil activation, and biomarkers of oxidative stress reflecting protein oxidation, such as levels of AOPP and thiol, were measured spectrophotometrically. Statistical comparisons were made using Mann–Whitney U‐tests, Student's t‐tests, anova /post‐anova tests and correlation analyses. Results In all patients, the results of full blood count, peripheral blood smears and routine biochemical analyses were in the normal range, but mean values of CRP and ESR were higher than laboratory reference values. Plasma MPO activity and AOPP levels were found to be higher and thiol values lower in the total patient group and individual subgroups than in controls. Patients with active BD had significantly higher MPO and AOPP levels and lower thiol levels than patients with inactive BD. There was no difference between uveitis‐positive and uveitis‐negative subgroups in MPO and thiol levels, but AOPP levels were lower in the latter group. Patients with active BD ± uveitis were shown to have increased MPO and AOPP but decreased thiol levels in comparison with the inactive BD, uveitis‐negative subgroup. There were strong positive correlations between ESR and CRP, ESR and MPO, ESR and thiol, ESR and AOPP, CRP and MPO, CRP and AOPP, MPO and AOPP, and thiol and AOPP levels in patients with BD. Conclusions Based on this first study, in which MPO‐mediated AOPP formation has been demonstrated, it may be suggested that activated neutrophils may play an important role in the pathogenesis of BD and that chlorinated oxidants of neutrophil origin may lead to oxidative stress, notably protein oxidation. Therefore, AOPP may be a useful marker for monitoring the progress and the severity of the disease activity.     

The role of oxidants and antioxidants in generalized vitiligo at tissue level

BACKGROUND: The role of oxidative stress has not been fully understood in the aetiopathogenesis of vitiligo in different studies. AIM: We aimed to investigate the role of the oxidative stress in the pathogenesis of vitiligo. METHODS: In this study, we examined levels of superoxide dismutase, glutathione peroxidase, malondialdehyde and nitric oxide in tissue of 25 patients with generalized vitiligo and 25 healthy controls. RESULTS: Our results revealed that levels of superoxide dismutase, glutathione peroxidase and malondialdehyde in tissue were significantly increased in patients with generalized vitiligo (P < 0.05). However, there was no statistically significantly difference between two groups at tissue level of nitric oxide (P > 0.05). CONCLUSION: Our results demonstrate the presence of an imbalance in the oxidant-antioxidant system in vitiligo at tissue level and provide further support for a free radical-mediated damage as an initial pathogenic event in melanocyte degeneration in vitiligo.     

白癜风动物模型研究进展

白癜风的病因和发病机制尚未完全阐明,遗传、自身免疫、氧化应激和环境等多种因素参与了白癜风的发病, 建立适宜的白癜风动物模型可为研究其发病机制和开发新疗法奠定基础。相较自发性白癜风模型,诱导性模型能更好的模拟白癜风发病的病理过程及影响因素。本文着重综述了诱导性白癜风动物模型的最新进展。