RESUMO
Vitiligo is a hypomelanotic skin disease and considered to be of autoimmune origin due to breaching of immunological self-tolerance, resulting in inappropriate immune responses against melanocytes. The development of vitiligo includes a strong heritable component. Different strategies ranging from linkage studies to genome-wide association studies are used to explore the genetic factors responsible for the disease. Several vitiligo loci containing the respective genes have been identified which contribute to vitiligo and genetic variants for some of the genes are still unknown. These genes include mainly the proteins that play a role in immune regulation and a few other genes important for apoptosis and regulation of melanocyte functions. Despite the available data on genetic variants and risk alleles which influence the biological processes, only few immunological pathways have been found responsible for all ranges of severity and clinical manifestations of vitiligo. However, studies have concluded that vitiligo is of autoimmune origin and manifests due to complex interactions in immune components and their inappropriate response toward melanocytes. The genes involved in the immune regulation and processing the melanocytes antigen and its presentation can serve as effective immune-therapeutics that can target specific immunological pathways involved in vitiligo. This chapter highlights those immune-regulatory genes involved in vitiligo susceptibility and loci identified to date and their implications in vitiligo pathogenesis.
Assuntos
Vitiligo , Ligação Genética , Estudo de Associação Genômica Ampla , Humanos , Imunogenética , Melanócitos/patologia , Vitiligo/genéticaRESUMO
Tumor necrosis factor-α (TNF-α) is a major mediator of inflammation and its increased levels have been analyzed in vitiligo patients. Vitiligo is a depigmentary skin disarray caused due to disapperance of functional melanocytes. The aim of the study was to investigate the role of TNF-α in melanocyte biology, analyzing candidate molecules of melanocytes and immune homeostasis. Our results showed increased TNF-α transcripts in vitiligenous lesional and non-lesional skin. Melanocytes upon exogenous stimulation with TNF-α exhibited a significant reduction in cell viability with elevated cellular and mitochondrial ROS and compromised complex I activity. Moreover, we observed a reduction in melanin content via shedding of dendrites, down-regulation of MITF-M, TYR and up-regulation of TNFR1, IL6, ICAM1 expression, whereas TNFR2 levels remain unaltered. TNF-α exposure stimulated cell apoptosis at 48 h and autophagy at 12 h, elevating ATG12 and BECN1 transcripts. Our novel findings establish the functional link between autophagy and melanocyte destruction. Overall, our study suggests a key function of TNF-α in melanocyte homeostasis and autoimmune vitiligo pathogenesis.
Assuntos
Melaninas/metabolismo , Melanócitos/metabolismo , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Vitiligo/metabolismo , Apoptose/fisiologia , Proteína 12 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/metabolismo , Regulação para Baixo/fisiologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-6/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Pele/metabolismo , Regulação para Cima/fisiologiaRESUMO
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.
Assuntos
Autoimunidade/imunologia , Iodeto Peroxidase/química , Peroxidação de Lipídeos , Melanócitos/citologia , Estresse Oxidativo , Vitiligo/imunologia , Adolescente , Adulto , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Índia , Iodeto Peroxidase/imunologia , Masculino , Melanócitos/imunologia , Vitiligo/etnologia , Vitiligo/patologia , Adulto JovemRESUMO
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), while generalized vitiligo(GV) is an autoimmune disease that causes the loss of functional melanocytes, resulting in white patches all over the body. Human Leukocyte Antigen (HLA) plays a crucial role in immune response to pathogens. Studies assessing the link between GV and COVID-19 are lacking; therefore, our current study was aimed to establish the association between GV and HLAB27 by genotyping the HLAB27 allele in 150 GV patients and 150 controls from South Gujarat population through polymerase chain reaction-sequence-specific primers (PCR-SSP) method. Additionally, we assessed the correlation of GV with COVID-19 and the influence of HLAB27 on COVID-19 development. Interestingly, our study suggested that the HLAB27 allele was prevalent in GV patients as compared to controls (52% vs 35.33%; p = 0.0051). Moreover, the occurrence of COVID-19 was significantly lower in GV patients than in controls (10% vs 32.66%; p < 0.0001). Disease activity-based analysis suggested that COVID-19 occurrence was significantly lower in active vitiligo (AV) patients as compared to stable vitiligo (SV) patients(6.87% vs 31.57%; p = 0.0045). Furthermore, COVID-19 development was significantly reduced in HLAB27 positive individuals as compared to HLAB27 negative individuals (p = 0.0025). Overall, our study suggests, for the first time, that HLAB27 allele might be a genetic risk factor for GV susceptibility, and an ongoing immune response in GV patients, more specifically in AV patients, might protect against COVID-19 infection in South Gujarat population. Additionally, our study highlighted the likely role of HLAB27 in protection against COVID-19 development.
RESUMO
Vitiligo is a multifactorial polygenic disorder with a complex pathogenesis, linked with both genetic and non-genetic factors. The precise modus operandi for vitiligo pathogenesis has remained elusive. Theories regarding loss of melanocytes are based on autoimmune, cytotoxic, oxidant-antioxidant and neural mechanisms. Reactive oxygen species (ROS) in excess have been documented in active vitiligo skin. Numerous proteins in addition to tyrosinase are affected. It is possible that oxidative stress is one among the main principal causes of vitiligo. However, there also exists ample evidence for altered immunological processes in vitiligo, particularly in chronic and progressive conditions. Both innate and adaptive arms of the immune system appear to be involved as a primary event or as a secondary promotive consequence. There is speculation on the interplay, if any, between ROS and the immune system in the pathogenesis of vitiligo. The article focuses on the scientific evidences linking oxidative stress and immune system to vitiligo pathogenesis giving credence to a convergent terminal pathway of oxidative stress-autoimmunity-mediated melanocyte loss.
Assuntos
Estresse Oxidativo/imunologia , Vitiligo/etiologia , Apoptose/imunologia , Autoimunidade , Citocinas/metabolismo , Predisposição Genética para Doença , Humanos , Melanócitos/imunologia , Melanócitos/metabolismo , Melanócitos/patologia , Modelos Biológicos , Vitiligo/imunologia , Vitiligo/metabolismoRESUMO
Agents which can either trigger proliferation of ß-cells or induce neogenesis of ß-cells from precursors would be of pivotal role in reversing diabetic manifestations. We examined the role of flavonoid rich fraction (FRF) of Oreocnide integrifolia leaves using a mice model of experimental regeneration. BALB/c mice were subjected to ~70% pancreatectomy (Px) and supplemented with FRF for 7, 14, and 21 days after pancreatectomy. Px animals displayed increased blood glucose levels and decreased insulin titres which were ameliorated by FRF supplementation. FRF-treated mice demonstrated prominent newly formed islets budding off from ducts and depicting increased BrdU incorporation. Additionally, transcripts levels of Ins1/2, Reg-3α/γ, Ngn-3, and Pdx-1 were upregulated during the initial 1 week. The present study provides evidence of a nutraceutical contributing to islet neogenesis from ductal cells as the mode of ß-cell regeneration and a potential therapeutic for clinical trials in management of diabetic manifestations.
Assuntos
Glutationa Peroxidase/genética , Vitiligo/genética , Substituição de Aminoácidos , Estudos de Casos e Controles , Eritrócitos/enzimologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Peroxidação de Lipídeos , Masculino , Simulação de Dinâmica Molecular , Glutationa Peroxidase GPX1RESUMO
BACKGROUND: Insulin deficiency is the prime basis of all diabetic manifestations and agents that can bring about insulin secretion would be of pivotal significance for cure of diabetes. To test this hypothesis, we carried out bioactivity guided fractionation of Oreocnide integrifolia (Urticaceae); a folklore plant consumed for ameliorating diabetic symptoms using experimental models. METHODS: We carried out bioassay guided fractionation using RINmF and C2C12 cell line for glucose stimulated insulin secretion (GSIS) and glucose uptake potential of fractions. Further, the bioactive fraction was challenged for its GSIS in cultured mouse islets with basal (4.5 mM) and stimulated (16.7 mM) levels of glucose concentrations. The Flavonoid rich fraction (FRF) was exposed to 2 mM streptozotocin stress and the anti-ROS/RNS potential was evaluated. Additionally, the bioactive fraction was assessed for its antidiabetic and anti-apoptotic property in-vivo using multidose streptozotocin induced diabetes in BALB/c mice. RESULTS: The results suggested FRF to be the most active fraction as assessed by GSIS in RINm5F cells and its ability for glucose uptake in C2C12 cells. FRF displayed significant potential in terms of increasing intracellular calcium and cAMP levels even in presence of a phosphodiesterase inhibitor, IBMX in cultured pancreatic islets. FRF depicted a dose-dependent reversal of all the cytotoxic manifestations except peroxynitrite and NO formation when subjected in-vitro along with STZ. Further scrutinization of FRF for its in-vivo antidiabetic property demonstrated improved glycemic indices and decreased pancreatic ß-cell apoptosis. CONCLUSIONS: Overall, the flavonoid mixture has shown to have significant insulin secretogogue, insulinomimetic and cytoprotective effects and can be evaluated for clinical trials as a therapeutant in the management of diabetic manifestations.
Assuntos
Antioxidantes/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Flavonoides/administração & dosagem , Glucose/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/metabolismo , Extratos Vegetais/administração & dosagem , Urticaceae/química , Animais , Antioxidantes/farmacologia , Linhagem Celular , Diabetes Mellitus Experimental/metabolismo , Flavonoides/farmacologia , Humanos , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/farmacologia , EstreptozocinaRESUMO
The study was aimed to analyze expression of nuclear factor of activated T cells (NFATs), forkhead box P3 (FOXP3), and their associated genes (sCTLA4, flCTLA4, IL10, TGFB, IL2, IL4, CD25) in regulatory T cells (Tregs) of 48 generalized vitiligo (GV) patients and 45 unaffected controls. The transcripts of NFATC1 to NFATC4, FOXP3, IL10, flCTLA4 (p < .0001), NFAT5 (p = .0003), sCTLA4 (p = .001), and FOXP3 protein in Tregs and plasma IL-10 levels were reduced significantly (p < .0001) in GV Tregs compared to controls. The FOXP3 promoter polymorphisms [rs3761548(C > A), rs3761547(A > G), and rs2232365(A > G)] revealed significantly decreased FOXP3 protein levels in patients' Tregs with susceptible AA, GG, and GG genotypes (p < .0001, p = .028, p = .022, respectively). The active vitiligo Tregs showed reduced levels of NFATC3, NFATC4, NFAT5, FOXP3, TGFB, and flCTLA4 transcripts (p = .0005, p = .0003, p = .0002, p = .020, p < .0001, p = .006, respectively) and FOXP3 and TGF-ß proteins (p = .0394 and p = .0013) compared to stable vitiligo. Early-onset patients (1-20 years) demonstrated decreased IL-10, sCTLA-4, flCTLA-4, TGFB, and FOXP3 transcripts and FOXP3 protein as compared to late-onset patients (41-60 years) (p = .001, p = .003, p = .009, p = .005, p = .038, p = .0226, respectively). Overall, our results for the first time suggest a likely role of NFATs and FOXP3 together with Treg immune-suppressive genes in GV pathogenesis and disease progression, warranting additional investigations.
Assuntos
Fatores de Transcrição Forkhead/metabolismo , Terapia de Imunossupressão , Fatores de Transcrição NFATC/metabolismo , Linfócitos T Reguladores/imunologia , Vitiligo/genética , Vitiligo/imunologia , Adulto , Idade de Início , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética , Humanos , Masculino , Modelos Biológicos , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Adulto JovemRESUMO
BACKGROUND: Autoimmunity has been implicated in the destruction of melanocytes from vitiligo skin. Major histocompatibility complex (MHC) class-II linked genes proteasome subunit beta 8 (PSMB8) and transporter associated with antigen processing 1 (TAP1), involved in antigen processing and presentation have been reported to be associated with several autoimmune diseases including vitiligo. OBJECTIVES: To explore PSMB8 rs2071464 and TAP1 rs1135216 single nucleotide polymorphisms and to estimate the expression of PSMB8 and TAP1 in patients with vitiligo and unaffected controls from Gujarat. METHODS: PSMB8 rs2071464 polymorphism was genotyped using polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) and TAP1 rs1135216 polymorphism was genotyped by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in 378 patients with vitiligo and 509 controls. Transcript levels of PSMB8 and TAP1 were measured in the PBMCs of 91 patients and 96 controls by using qPCR. Protein levels of PSMB8 were also determined by Western blot analysis. RESULTS: The frequency of 'TT' genotype of PSMB8 polymorphism was significantly lowered in patients with generalized and active vitiligo (p = 0.019 and p = 0.005) as compared to controls suggesting its association with the activity of the disease. However, TAP1 polymorphism was not associated with vitiligo susceptibility. A significant decrease in expression of PSMB8 at both transcript level (p = 0.002) as well as protein level (p = 0.0460) was observed in vitiligo patients as compared to controls. No significant difference was observed between patients and controls for TAP1 transcripts (p = 0.553). Interestingly, individuals with the susceptible CC genotype of PSMB8 polymorphism showed significantly reduced PSMB8 transcript level as compared to that of CT and TT genotypes (p = 0.009 and p = 0.003 respectively). CONCLUSIONS: PSMB8 rs2071464 was associated with generalized and active vitiligo from Gujarat whereas TAP1 rs1135216 showed no association. The down-regulation of PSMB8 in patients with risk genotype 'CC' advocates the vital role of PSMB8 in the autoimmune basis of vitiligo.
Assuntos
Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Vitiligo/metabolismo , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Western Blotting , Estudos de Casos e Controles , Biologia Computacional , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição/genética , Polimorfismo de Nucleotídeo Único/genética , Complexo de Endopeptidases do Proteassoma/genética , Vitiligo/genéticaRESUMO
Regulatory T cells (Tregs) are comprised of a heterogeneous population of cells that play a vital role in suppressing inflammation and maintaining immune tolerance. Given the crucial role of Tregs in maintaining immune homeostasis, it is probably not surprising that many microbial species and their metabolites have the potential to induce Tregs. There is now great interest in the therapeutic potential of probiotics and prebiotics based strategies for a range of autoimmune disorders. This review will summarise recent findings concerning the role of probiotics and prebiotics in induction of Tregs to ameliorate the autoimmune conditions. In addition, the article is focused to explain the different mechanisms of Treg induction and function by these probiotics and prebiotics, based on the available studies till date. The article further proposes that induction of Tregs by probiotics and prebiotics could lead to the development of new therapeutic approach towards curbing the autoimmune response and as an alternative to detrimental immunosuppressive drugs.
Assuntos
Autoimunidade/imunologia , Prebióticos , Probióticos , Linfócitos T Reguladores/imunologia , Humanos , Tolerância Imunológica , Ativação LinfocitáriaRESUMO
BACKGROUND: Neuropeptide Y (NPY) is known to play a role in the regulation of satiety, energy balance, body weight, and insulin release. Interleukin-1beta (IL1B) has been associated with loss of beta-cell mass in type-II diabetes (TIID). OBJECTIVES: The present study attempts to investigate the association of NPY exon2 +1128 T/C (Leu7Pro; rs16139), NPY promoter -399 T/C (rs16147) and IL1B -511 C/T (rs16944) polymorphisms with TIID and their correlation with plasma lipid levels, BMI, and IL1B transcript levels. METHODS: PCR-RFLP was used for genotyping these polymorphisms in a case-control study involving 558 TIID patients and 1085 healthy age-matched controls from Gujarat. Linkage disequilibrium and haplotype analysis of the NPY polymorphic sites were performed to assess their association with TIID. IL1B transcript levels in PBMCs were also assessed in 108 controls and 101 patients using real-time PCR. RESULTS: Our results show significant association of both structural and promoter polymorphisms of NPY (p<0.0001 and p<0.0001 respectively) in patients with TIID. However, the IL1B C/T polymorphism did not show any association (p = 0.3797) with TIID patients. Haplotype analysis revealed more frequent association of CC and CT haplotypes (p = 3.34 x 10-5, p = 6.04 x 10-9) in diabetics compared to controls and increased the risk of diabetes by 3.02 and 2.088 respectively. Transcript levels of IL1B were significantly higher (p<0.0001) in patients as compared to controls. Genotype-phenotype correlation of IL1B polymorphism did not show any association with its higher transcript levels. In addition, NPY +1128 T/C polymorphism was found to be associated with increased plasma LDL levels (p = 0.01). CONCLUSION: The present study provides an evidence for a strong correlation between structural and promoter polymorphisms of NPY gene and upregulation of IL1B transcript levels with susceptibility to TIID and altering the lipid metabolism in Gujarat population.
Assuntos
Diabetes Mellitus Tipo 2/genética , Estudos de Associação Genética , Interleucina-1beta/genética , Lipídeos/sangue , Neuropeptídeo Y/genética , Adulto , Alelos , Glicemia/análise , Índice de Massa Corporal , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/patologia , Éxons , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Interleucina-1beta/metabolismo , Desequilíbrio de Ligação , Lipoproteínas LDL/sangue , Masculino , Pessoa de Meia-Idade , Neuropeptídeo Y/metabolismo , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Risco , Triglicerídeos/sangueRESUMO
Vitiligo is a hypomelanotic autoimmune skin disease arising from a breakdown in immunological self-tolerance, which leads to aberrant immune responses against melanocytes. Regulatory T cells (Tregs) are crucial to the development of self-tolerance and so are major foci in the study of autoimmune pathogenesis of vitiligo. This review will summarise recent findings concerning the role of Tregs in the pathogenesis of vitiligo. In addition, as antigen-specific Tregs are a potential route for the reinstatement of immune tolerance, new strategies that expand or induce de novo generation of Tregs and which are currently being investigated as therapies for other autoimmune diseases, will be discussed. These approaches will highlight the opportunities for Treg cell-based therapeutics in vitiligo.
Assuntos
Linfócitos T Reguladores/imunologia , Vitiligo/imunologia , Vitiligo/terapia , Animais , Humanos , Melanócitos/citologia , Tolerância a Antígenos Próprios , Vitiligo/patologiaRESUMO
BACKGROUND: Vitiligo is a depigmenting disorder resulting from loss of functional melanocytes in the skin. NPY plays an important role in induction of immune response by acting on a variety of immune cells. NPY synthesis and release is governed by IL1B. Moreover, genetic variability in IL1B is reported to be associated with elevated NPY levels. OBJECTIVES: Aim of the present study was to explore NPY promoter -399T/C (rs16147) and exon2 +1128T/C (rs16139) polymorphisms as well as IL1B promoter -511C/T (rs16944) polymorphism and to correlate IL1B transcript levels with vitiligo. METHODS: PCR-RFLP method was used to genotype NPY -399T/C SNP in 454 patients and 1226 controls; +1128T/C SNP in 575 patients and 1279 controls and IL1B -511C/T SNP in 448 patients and 785 controls from Gujarat. IL1B transcript levels in blood were also assessed in 105 controls and 95 patients using real-time PCR. RESULTS: Genotype and allele frequencies for NPY -399T/C, +1128T/C and IL1B -511C/T SNPs differed significantly (p<0.0001, p<0.0001; pâ=â0.0161, pâ=â0.0035 and p<0.0001, p<0.0001) between patients and controls. 'TC' haplotype containing minor alleles of NPY polymorphisms was significantly higher in patients and increased the risk of vitiligo by 2.3 fold (p<0.0001). Transcript levels of IL1B were significantly higher, in patients compared to controls (pâ=â0.0029), in patients with active than stable vitiligo (pâ=â0.015), also in female patients than male patients (pâ=â0.026). Genotype-phenotype correlation showed moderate association of IL1B -511C/T polymorphism with higher IL1B transcript levels. Trend analysis revealed significant difference between patients and controls for IL1B transcript levels with respect to different genotypes. CONCLUSION: Our results suggest that NPY -399T/C, +1128T/C and IL1B -511C/T polymorphisms are associated with vitiligo and IL1B -511C/T SNP influences its transcript levels leading to increased risk for vitiligo in Gujarat population. Up-regulation of IL1B transcript in patients advocates its possible role in autoimmune pathogenesis of vitiligo.
Assuntos
Predisposição Genética para Doença , Interleucina-1beta/genética , Neuropeptídeo Y/genética , Polimorfismo de Nucleotídeo Único , Vitiligo/genética , Éxons , Feminino , Frequência do Gene , Humanos , Índia , Desequilíbrio de Ligação , Masculino , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Fatores SexuaisRESUMO
BACKGROUND: MYG1 (Melanocyte proliferating gene 1 or C12orf10) -119C/G promoter and Arg4Gln structural polymorphisms have a functional impact on its regulation. The promoter polymorphism was shown to be associated with vitiligo in Caucasian population. OBJECTIVE: The present study explores MYG1 polymorphisms and correlates them with MYG1 mRNA expression, disease onset and progression in vitiligo patients. METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used for genotyping of MYG1 -119C/G promoter (rs1465073) and 11-12AA/GC structural polymorphisms (rs1534284-rs1534283; Arg4Gln) in 846 vitiligo patients and 726 age-matched unaffected controls. MYG1 mRNA levels were assessed in whole blood of 166 patients and 175 controls by Real-time PCR. RESULTS: The MYG1 -119C/G promoter polymorphism was found to be in significant association with vitiligo being 'G' allele prevalent in patients. However, 11-12AA/GC structural polymorphism was prevalently monogenic in patients and controls with only MYG1 GC (4Arg) allele being present. Significant increase in MYG1 mRNA expression was observed in vitiligo patients compared to controls. The MYG1 mRNA expression was increased in patients with active and generalized vitiligo as compared to stable and localized vitiligo. MYG1 mRNA expression was increased in patients with susceptible -119 GG genotype compared to controls. Also, patients with susceptible -119 GG genotype had early age of onset of vitiligo. Moreover, patients with age groups 1-20 years and 21-40 years showed increased expression of MYG1 mRNA compared to those of controls. Female patients showed significant increase in MYG1 mRNA and early age of onset of vitiligo compared to male patients. CONCLUSION: The present study suggests that MYG1 -119C/G promoter polymorphism may be a genetic risk factor for susceptibility and progression of vitiligo. The up-regulation of MYG1 transcript in patients with susceptible -119GG genotype advocates the crucial role of MYG1 in autoimmune pathogenesis of vitiligo.
Assuntos
Regiões Promotoras Genéticas , Proteínas/genética , Vitiligo/genética , Adolescente , Adulto , Idade de Início , Estudos de Casos e Controles , Criança , Pré-Escolar , Progressão da Doença , Exonucleases , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Polimorfismo de Fragmento de Restrição , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima , Adulto JovemRESUMO
Genetic polymorphisms in TNFB are involved in the regulation of its expression and are found to be associated with various autoimmune diseases. The aim of the present study was to determine whether TNFB +252A/G (rs909253) and exon 3 C/A (rs1041981) polymorphisms are associated with vitiligo susceptibility, and expression of TNFB and ICAM1 affects the disease onset and progression. We have earlier reported the role of TNFA in autoimmune pathogenesis of vitiligo, and we now show the involvement of TNFB in vitiligo pathogenesis. The two polymorphisms investigated in the TNFB were in strong linkage disequilibrium and significantly associated with vitiligo. TNFB and ICAM1 transcripts were significantly increased in patients compared to controls. Active vitiligo patients showed significant increase in TNFB transcripts compared to stable vitiligo. The genotype-phenotype analysis revealed that TNFB expression levels were higher in patients with GG and AA genotypes as compared to controls. Patients with the early age of onset and female patients showed higher TNFB and ICAM1 expression. Overall, our findings suggest that the increased TNFB transcript levels in vitiligo patients could result, at least in part, from variations at the genetic level which in turn leads to increased ICAM1 expression. For the first time, we show that TNFB +252A/G and exon 3 C/A polymorphisms are associated with vitiligo susceptibility and influence the TNFB and ICAM1 expression. Moreover, the study also emphasizes influence of TNFB and ICAM1 on the disease progression, onset and gender bias for developing vitiligo.
Assuntos
Regulação da Expressão Gênica , Predisposição Genética para Doença/genética , Linfotoxina-alfa/genética , Polimorfismo de Nucleotídeo Único , Vitiligo/genética , Adulto , Estudos de Casos e Controles , Progressão da Doença , Éxons/genética , Feminino , Humanos , Molécula 1 de Adesão Intercelular/genética , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Adulto JovemRESUMO
The aim of present study was to evaluate CD4(+) /CD8(+) ratio and CD4(+) CD25(hi) FoxP3(+) Tregs in GV patients with reference to their effect on disease onset and progression. Flow cytometry was used for determination of CD4(+) /CD8(+) ratio and Tregs in 82 patients and 50 controls. CD8(+) T-cell counts were significantly higher in GV patients as compared with controls (p = 0.003). Active GV patients showed higher CD8(+) T-cell counts compared with stable GV patients (p = 0.001). The CD4(+) /CD8(+) ratio decreased significantly in patients as compared with controls (p = 0.001). Moreover, the ratio in active GV patients significantly lowered as compared with stable GV patients (p = 0.002). Significant decrease in Treg cell percentage and counts in GV patients was observed compared with controls (p = 0.009, p = 0.008) with significant reduction in FoxP3 expression (p = 0.024). Treg cell percentage and counts were significantly decreased in active GV patients compared with stable GV patients (p = 0.007, p = 0.002). Our results suggest that an imbalance of CD4(+) /CD8(+) ratio and natural Tregs in frequency and function might be involved in the T-cell mediated pathogenesis of GV and its progression.
Assuntos
Relação CD4-CD8 , Linfócitos T Reguladores/citologia , Vitiligo/sangue , Vitiligo/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoimunidade , Progressão da Doença , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunoterapia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Masculino , Melanócitos/citologia , Pessoa de Meia-Idade , Pigmentação , Adulto JovemRESUMO
Interferon-gamma (IFN-γ) is a paracrine inhibitor of melanocytes and genetic variability due to intron 1 polymorphisms in IFNG has been reported to be associated with increased risk for several autoimmune diseases. The aim of present study was to determine whether intron 1 +874A/T (rs2430561) and CA microsatellite (rs3138557) polymorphisms in IFNG are associated with generalized vitiligo (GV) susceptibility and expression of IFNG and intercellular adhesion molecule-1 (ICAM1) affects the disease onset and progression. Here we report that IFNG CA microsatellite but not +874A/T may be a genetic risk factor for GV; however, +874T allele plays a crucial role in increased expression of IFNG mRNA and protein levels which could affect the onset and progression of the disease. Active GV patients showed increased IFNG levels compared to stable GV patients. The genotype-phenotype analysis revealed that IFNG expression levels were higher in patients with +874 TT genotypes and 12 CA repeats. Patients with the early age of onset showed higher IFNG expression and female GV patients showed higher IFNG and ICAM1 expression implicating gender biasness and involvement of IFN-γ in early onset of the disease. Moreover, the increased IFN-γ levels in patients lead to increased ICAM1 expression, which could be a probable link between cytokines and T-cell involvement in pathogenesis of GV.
Assuntos
Variação Genética/genética , Molécula 1 de Adesão Intercelular/genética , Interferon gama/genética , Vitiligo/genética , Progressão da Doença , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , Caracteres Sexuais , Vitiligo/patologiaRESUMO
Oxidative stress has been implicated as the initial triggering event in vitiligo pathogenesis leading to melanocyte destruction. Here, we report a significant increase in oxidative stress in vitiligo patients as evidenced by high lipid peroxidation levels suggesting an imbalance in the antioxidant enzyme system as reported in our previous studies. This study examined the role of the enzymatic antioxidant SOD, which converts the pro-oxidant superoxide into H2O2, in vitiligo pathogenesis. The activity of three isoforms of SOD, i.e., SOD1, SOD2, and SOD3, was significantly higher in vitiligo patients. To identify the underlying mechanism for the increase in activities of SOD isoforms, we explored the SOD1, SOD2, and SOD3 genes for their genetic variations and transcript levels. The SOD2 Thr58Ile (rs35289490) and Leu84Phe (rs11575993) polymorphisms were significantly associated with vitiligo patients, and the Val16Ala (rs4880) polymorphism was associated with active vitiligo patients. Interestingly, SOD2 activity was contributed by these polymorphisms along with its increase in transcript levels in patients. SOD3 activity was associated with the Arg213Gly (rs8192291) polymorphism. The SOD3 transcript levels were also increased in patients, which might contribute to the increased SOD3 activity. However, we could not establish the genotype-phenotype correlation for SOD1 as we could not detect any novel or reported SNPs in SOD1. In addition, both transcript and protein levels of SOD1 were unchanged between patients and controls, though SOD1 activity was increased in patients. Activities of SOD isoforms also correlated with progression of the disease as the activity was higher in active cases of vitiligo compared to stable cases. Here, we report that SOD2 and SOD3 polymorphisms may be genetic risk factors for susceptibility and progression of vitiligo and hence the genetic makeup of an individual may form a basis for the effective treatment of the disease. Overall, our results suggest that increased activity of SOD isoforms under the influence of genetic factors may lead to accumulation of H2O2 in cytoplasmic, mitochondrial, and extracellular compartments resulting in oxidative damage to the melanocytes.