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2.
PLoS One ; 14(7): e0210308, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31277078

RESUMO

Alopecia areata (AA) is a hair loss disorder resulting from an autoimmune reaction against hair follicles. T-helper 1 cells are a major contributor to this disorder, but little is known about the role of T-regulatory cells (Tregs) in AA. Here, we analysed the distribution of circulating Treg subsets in twenty AA patients with active hair loss and fifteen healthy subjects by flow cytometry. The Treg suppressor HLA-DR+ subpopulation was significantly reduced in the patients (P<0.001) and there were significantly fewer cells expressing CD39 among the CD4+CD25+Foxp3+ Treg subpopulation in patients (P = 0.001). FOXP3 CD39 Treg cells were also reduced in hair follicles; by 75% in non-lesional skin and 90% in lesional skin, when compared to control healthy skin. To further characterise Treg cells in AA; Tregs (CD4+CD25+FOXP3+) were investigated for their TCRß sequence. PCR products analysed by Next Generation Sequencing techniques, showed that all frequent public clonotypes in AA Tregs were also present in controls at relatively similar frequencies, excepting two public clonotypes: CATSRDEGGLDEKLFF (V15 D1 J1-4) and CASRDGTGPSNYGYTF (V2 D1 J1-2), which were exclusively present in controls. This suggests that these Treg clonotypes may have a protective effect and that they may be an exciting subject for future therapeutic applications.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30558329

RESUMO

BACKGROUND: Alopecia areata (AA) is associated with Interferon- γ (IFN-γ) mediated T-lymphocyte dysfunction and increased circulating Interleukine-17 (IL-17) levels. Epigallocatechin-3-gallate (EGCG) specifically inhibits IFN-γ pathways and unlike Janus Kinase 1 and 2 (JAK1/JAK2) inhibitors (tofacitinib, ruxolitinib), EGCG is safer, more cost-effective, and is a topically active agent. Our objective is to test the mode of action of EGCG in vitro and ex vivo using HaCat, Jurkat cell lines, and peripheral blood mononuclear cells (PBMCs) of AA patients and healthy controls (HCs), respectively. METHODS: distribution of T helper cells (Th1, Th17), and cytotoxic cells (CD8) in PBMCs isolated from 30 AA patients and 30 HCs was investigated by flowcytomterty. In vitro treatment of HaCat and Jurkat cells with 40 µm EGCG for 48 h was performed to measure the level of phosphorylation of signal transducer and activator of transcription protein STAT1, and replicated in ex vivo model using PBMCs of AA patients. RESULTS: Interestingly, 40 µm EGCG is capable of completely inhibiting phosphorylation of STAT1 after 48 h in HaCat and Jurkat cells and ex vivo in PBMCs of AA patients. Based on QPCR data, the action of EGCG on p-STAT1 seems to be mediated via downregulation of the expression of JAK2 but not JAK1 leading to the inhibition of human leukocyte antigens (HLA-DR and HLA-B) expression probably via IRF-1. On the other hand, AA patients have significantly increased levels of Th1, Th17, and CD8 cells and the production of IFN-γ and IL-17 by PBMCs in AA patients was significantly higher compared to HC; p = 0.008 and p = 0.006, respectively. Total numbers of CD8+ cells were not significantly different between treated and untreated samples. However, CD8+ cells with positive Natural killer group 2 member D (NKG2D) transmembrane receptor (CD8+ NKG2D+ subset) was significantly reduced when PBMCs were treated with 20 µm EGCG for 48 h. CONCLUSION: These results suggest that EGCG has a synergistic action that inhibits expression of HLA-DR and HLA-B molecules via the IFN-γ pathway to maintain immune privilege in HF; also it reduces CD8+ NKG2D+ subset.


Assuntos
Alopecia em Áreas/tratamento farmacológico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Catequina/análogos & derivados , Antígenos HLA-B/imunologia , Antígenos HLA-DR/imunologia , Transdução de Sinais/efeitos dos fármacos , Adulto , Alopecia em Áreas/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Catequina/farmacologia , Análise Custo-Benefício , Feminino , Humanos , Fator Regulador 1 de Interferon/metabolismo , Interferon gama/imunologia , Interferon gama/farmacologia , Janus Quinase 2/metabolismo , Fator de Transcrição STAT1/metabolismo
4.
Dermatol Res Pract ; 2018: 1284568, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30174688

RESUMO

We report a family from Tabuk, Saudi Arabia, previously screened for Acrodermatitis Enteropathica (AE), in which two siblings presented with typical features of acral dermatitis and a pustular eruption but differing severity. Affected members of our family carry a rare genetic variant, p.Gly512Trp in the SLC39A4 gene which encodes a zinc transporter; disease is thought to result from zinc deficiency. Similar mutations have been reported previously; however, the variable severity within cases carrying the p.Gly512Trp variant and in AE overall led us to hypothesise that additional genetic modifiers may be contributing to the disease phenotype. Therefore whole genome sequencing was carried out in five family members, for whom material was available to search for additional modifiers of AE; this included one individual with clinically diagnosed AE. We confirmed that the p.Gly512Trp change in SLC39A4 was the only candidate homozygous change which was sufficiently rare (ExAC allele frequency 1.178e-05) and predicted deleterious (CADD score 35) to be attributable as a fully penetrant cause of AE. To identify other genes which may carry relevant genetic variation, we reviewed the relevant literature and databases including Gene Ontology Consortium, GeneMANIA, GeneCards, and MalaCards to identify zinc transporter genes and possible interacting partners. The affected individual carried variants in RECQL4 and GPAA1 genes with ExAC allele frequency <0.01 and CADD score >10. p.Gly512Trp is highly likely to be the pathogenic variant in this family. This variant was previously detected in a Tunisian proband with perfect genotype-phenotype segregation suggestive of pathogenicity. Further research is required in this area due to small sample size, but attention should be given to RECQL4 and GPAA1 to understand their role in the skin disease.

5.
Front Immunol ; 9: 1380, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30002654

RESUMO

Autoimmune regulator (AIRE) regulates promiscuous expression of tissue-restricted antigens in medullary epithelial cells (mTEC) of the thymus. To understand the diverse effects of AIRE, it is crucial to elucidate the molecular mechanisms underlying the process of AIRE-regulated gene expression. In this study, we generated a recombinant AIRE expression variant of the TEC 1A3 human cell line, TEC 1A3 AIREhi, to determine genes targeted by AIRE, and using microarray analysis, we identified 482 genes showing significant differential expression (P < 0.05; false discovery rate <5%), with 353 upregulated and 129 downregulated by AIRE expression. Microarray data were validated by quantitative PCR, confirming the differential expression of 12 known AIRE-regulated genes. Comparison of AIRE-dependent differential expression in our cell line model with murine datasets identified 447 conserved genes with a number of transcription regulatory interactions, forming several key nodes, including STAT1, which had over 30 interactions with other AIRE-regulated genes. As STAT1 mutations cause dominant chronic mucocutaneous candidiasis and decreased STAT1 levels in monocytes of autoimmune polyglandular syndrome 1 (APS-1) patients, it was important to further characterize AIRE-STAT1 interactions. TEC 1A3AIREhi were treated with the STAT1 phosphorylation inhibitors fludarabine and LLL3 showed that phosphorylated STAT1 (p-STAT1) was not responsible for any of the observed differential expression. Moreover, treatment of TEC 1A3 AIREhi with STAT1 shRNA did not induce any significant variation in the expression of unphosphorylated STAT1 (U-STAT1) downstream genes, suggesting that these genes were directly regulated by AIRE but not via U-STAT1. The novel model system we have developed provides potential opportunities for further analysis of the pathogenesis of (APS-1) and the wider roles of the AIRE gene.

7.
Biomed Res Int ; 2016: 3460234, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27413743

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Ten of fifteen causative genes linked to familial forms of PD have been reported to cause autosomal recessive forms. Among them, mutations in the PTEN-induced kinase 1 (PINK1) gene were shown to be responsible for a phenotype characterized by early onset, good response to levodopa, and a benign course. Using chromosomal microarray analysis and Sanger sequencing, we identified a homozygous G/C substitution in a 58-year-old Moroccan man diagnosed with recessive inherited Parkinson's disease. This G-to-C transition occurred at position 1617 leading to an amino acid change L/F at position 539 located in highly conserved motif in the C terminal sequence of PINK1. Interestingly, the c.1617G>C substitution is absent in 192 ethnically matched control chromosomes. Our findings have shown that the p.L539F is a novel mutation located in the C terminal sequence of the PINK1 protein that could be pathogenic and responsible for a clinical phenotype resembling idiopathic Parkinson's disease with rapid progression and early cognitive impairment.


Assuntos
Mutação , Doença de Parkinson/genética , Proteínas Quinases/genética , Motivos de Aminoácidos , Cromossomos/ultraestrutura , Transtornos Cognitivos/genética , Biologia Computacional , Progressão da Doença , Éxons , Homozigoto , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Marrocos , Mutação de Sentido Incorreto , Análise de Sequência com Séries de Oligonucleotídeos , Doença de Parkinson/tratamento farmacológico , Linhagem , Fenótipo , Domínios Proteicos , Análise de Sequência de DNA
8.
PLoS One ; 10(5): e0127476, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25978041

RESUMO

BACKGROUND: The autoimmune regulator (AIRE) is expressed in the thymus, particularly in thymic medullary epithelial cells (mTECs), and is required for the ectopic expression of a diverse range of peripheral tissue antigens by mTECs, facilitating their ability to perform negative selection of auto-reactive immature T-cells. The expression profile of peripheral tissue antigens is affected not only by AIRE deficiency but also with variation of AIRE activity in the thymus. METHOD AND RESULTS: Therefore we screened 591bp upstream of the AIRE transcription start site including AIRE minimal promoter for single nucleotide polymorphism (SNPs) and identified two SNPs -655R (rs117557896) and -230Y (rs751032) respectively. To study the effect of these variations on AIRE promoter activity we generated a Flp-In host cell line which was stably transfected with a single copy of the reporter vector. Relative promoter activity was estimated by comparing the luciferase specific activity for lysates of the different reporter AIRE promoter-reporter gene constructs including AIRE-655G AIRE-230C, AIRE-655G AIRE-230T and AIRE-655A AIRE-230C. The analysis showed that the commonest haplotype AIRE-655G AIRE-230C has the highest luciferase specific activity (p<0.001). Whereas AIRE-655G AIRE-230T has a luciferase specific activity value that approaches null. Both AIRE promoter polymorphic sites have one allele that forms a CpG methylation site which we determined can be methylated in methylation assays using the M.SssI CpG methyltransferase. CONCLUSION: AIRE-230Y is in a conserved region of the promoter and is adjacent to a predicted WT1 transcription factor binding site, suggesting that AIRE-230Y affects AIRE expression by influencing the binding of biochemical factors to this region. Our findings show that AIRE-655GAIRE-230T haplotype could dramatically alter AIRE transcription and so have an effect on the process of negative selection and affect susceptibility to autoimmune conditions.


Assuntos
Polimorfismo de Nucleotídeo Único/genética , Timo/metabolismo , Fatores de Transcrição/genética , Transcrição Genética/genética , Alelos , Sequência de Bases , Linhagem Celular , Ilhas de CpG/genética , Metilação de DNA/genética , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/genética , Haplótipos/genética , Humanos , Dados de Sequência Molecular , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , Alinhamento de Sequência , Sítio de Iniciação de Transcrição/fisiologia
9.
Arch Dermatol Res ; 306(4): 413-8, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24352509

RESUMO

Female pattern hair loss (FPHL) is a common hair loss disorder in women and has a complex mode of inheritance. The etiopathogenesis of FPHL is largely unknown; however, it is hypothesized that FPHL and male pattern baldness [androgenetic alopecia (AGA)] share common genetic susceptibility alleles. Our recent findings indicate that the major AGA locus, an X-chromosome region containing the androgen receptor and the ectodysplasin A2 receptor (EDA2R) genes, may represent a common genetic factor underlying both early-onset FPHL and AGA. This gives further support for the widespread assumption of shared susceptibility loci for FPHL and AGA. However, we could not demonstrate association of further AGA risk loci, including 20p11, 1p36.22, 2q37.3, 7p21.1, 7q11.22, 17q21.31, and 18q21.1, with FPHL. Interestingly, a recent study identified four novel AGA risk loci in chromosomal regions 2q35, 3q25.1, 5q33.3, and 12p12.1. In particular, the 2q35 locus and its gene WNT10A point to an as-yet unknown involvement of the WNT signaling pathway in AGA. We hypothesized that the novel loci and thus also the WNT signaling may have a role in the etiopathogenesis of FPHL and therefore examined the role of these novel AGA risk loci in our FPHL samples comprising 440 German and 145 UK affected patients, 500 German unselected controls (blood donors), and 179 UK supercontrols. Patients and controls were genotyped for the top two single nucleotide polymorphisms at each of the four AGA loci. However, none of the genotyped variants displayed any significant association. In conclusion, the results of this study provide no support for the hypothesis that the novel AGA loci influence susceptibility to FPHL.


Assuntos
Alopecia/genética , Receptores Androgênicos/genética , Proteínas Wnt/genética , Receptor Xedar/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Via de Sinalização Wnt/genética
11.
Indian J Pediatr ; 80(8): 694-6, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23180398

RESUMO

The neuronal ceroid-lipofuscinosis (NCL) are a heterogeneous group of neurodegenerative diseases characterized by the lysosomal accumulation of ceroid and lipofuscin with mitochondrial ATP synthase subunit C in various tissues. Clinical features include progressive mental and motor deterioration, myoclonus, seizure, visual failure and premature death. Ten CLN genes have been identified, among them CLN6 genes for which 55 disease-causing mutations have already been reported. The authors describe here a large consanguineous Moroccan family with three affected patients due to the p.I154del mutation that has been exclusively reported in Portuguese patients. This is the first published report of a genetic study in a Moroccan family with NCL. A relatively inexpensive CLN6 mutation screening should be considered first in Morocco as an initial diagnosis step when the disease course is consistent with late infantile neuronal ceroid-lipofuscinosis.


Assuntos
Proteínas de Membrana/genética , Lipofuscinoses Ceroides Neuronais/genética , Consanguinidade , Humanos , Marrocos , Mutação , Linhagem
12.
Arch Dermatol Res ; 305(3): 249-53, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23124548

RESUMO

Female pattern hair loss (FPHL) is a common hair loss disorder in women with a complex mode of inheritance. Its etiopathogenesis is poorly understood. Widespread assumptions of overlapping susceptibility variants between FPHL and male pattern baldness (androgenetic alopecia) and a crucial role of androgens or distinct sexual steroid hormones in the development of FPHL could neither be clearly demonstrated nor completely excluded at the molecular level up to date. Interestingly, recent studies suggested an association of metabolic syndrome-including obesity, hyperlipidaemia, hypertension and diabetes mellitus type 2 or abnormally high fasting blood glucose-with FPHL. Of note, mutations in the melanocortin 4 receptor gene (MC4R) have been identified in patients with morbid obesity. Interestingly, this neuropeptide receptor has been detected amongst others in the dermal papilla of the hair follicle. As almost half of our FPHL patients of German origin present with adipositas and/or obesity, we hypothesized as to whether FPHL could be associated with variants of the MC4R gene. Thus, we genotyped a total of six variants from MC4R in our case-control sample comprising 245 UK patients of German and UK origin. However, based on our present study none of the genotyped MC4R variants displayed any significant association, neither in the overall UK and German samples nor in any subgroup analyses. In summary, these results do not point to an involvement of MC4R in FPHL.


Assuntos
Hipotricose/genética , Receptor Tipo 4 de Melanocortina/genética , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Obesidade/genética , Polimorfismo de Nucleotídeo Único
13.
Nat Genet ; 44(12): 1341-8, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23143594

RESUMO

To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Imunidade Inata/genética , Psoríase/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/imunologia , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Subunidade alfa 3 de Fator de Ligação ao Core/imunologia , Proteína DEAD-box 58 , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/imunologia , Grupo com Ancestrais do Continente Europeu/genética , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/imunologia , Estudo de Associação Genômica Ampla , Guanilato Ciclase/genética , Guanilato Ciclase/imunologia , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Psoríase/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Pele/imunologia , Linfócitos T/imunologia
14.
Exp Dermatol ; 21(5): 390-3, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22509838

RESUMO

Female pattern hair loss (FPHL) is a common disorder with a complex mode of inheritance. Although understanding of its etiopathogenesis is incomplete, an interaction between genetic and hormonal factors is assumed to be important. The involvement of an androgen-dependent pathway and sex steroid hormones is the most likely hypothesis. We therefore selected a total of 21 variants from the steroid-5-alpha-reductase isoforms SRD5A1 and SRD5A2, the sex steroid hormone receptors ESR1, ESR2 (oestrogen receptor) and PGR (progesterone receptor) and genotyped these in a case-control sample of 198 patients (145 UK; 53 German patients) and 329 controls (179 UK; 150 German). None of these variants showed any significant association, either in the overall UK and German samples or in the subgroup analyses. In summary, the present results, while based on a limited selection of gene variants, do not point to the involvement of SRD5A1, SRD5A2, ESR1, ESR2 or PGR in FPHL.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Alopecia/genética , Variação Genética/genética , Proteínas de Membrana/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/genética , Alelos , Alopecia/etnologia , Estudos de Casos e Controles , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Feminino , Alemanha , Humanos , Reino Unido
15.
J Hum Genet ; 56(6): 423-7, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21412248

RESUMO

Psoriasis is an inflammatory skin disorder that exhibits multifactorial mode of inheritance. In addition to the well-known susceptibility locus PSORS1 many other loci have been shown to be implicated in the genetic predisposition for disease. However, interactions between loci have not been thoroughly explored. Thus, we measured the effect of potential interaction between human leukocyte antigen (HLA)-C, CSTA and D1S236 at PSORS1, PSORS4 and PSORS5, respectively, in the development of psoriasis. Analysis of 130 Caucasian psoriatic families showed that the risk to an HLA-Cw6 +ve individual who carries two copies of the risk allele at both the CSTA and D1S2346 is 105 times the risk to an HLA-Cw6 +ve individual who does not carry any risk alleles at the CSTA or D1S2346. This is the first demonstration of an interaction between risk alleles in three susceptibility loci suggesting possible functional interaction between genes in these loci, which might explain the complexity of the pathogenesis of psoriasis.


Assuntos
Alelos , Cistatina A/genética , Predisposição Genética para Doença/genética , Antígenos HLA-C/genética , Proteínas/genética , Psoríase/genética , Adolescente , Adulto , Criança , Pré-Escolar , Epistasia Genética/genética , Frequência do Gene/genética , Genótipo , Humanos , Lactente , Recém-Nascido , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Proteínas/metabolismo , Risco , Adulto Jovem
17.
J Invest Dermatol ; 129(8): 1892-908, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19494826

RESUMO

Atopic dermatitis (AD) is a multifactorial, heterogenous disease that arises as a result of the interaction between both environmental and genetic factors. Changes in at least three groups of genes encoding structural proteins, epidermal proteases, and protease inhibitors predispose to a defective epidermal barrier and increase the risk of developing AD. Loss-of-function mutations found within the FLG gene encoding the structural protein, filaggrin, represent the most significant genetic factor predisposing to AD identified to date. Enhanced protease activity and decreased synthesis of the lipid lamellae lead to exacerbated breakdown of the epidermal barrier. Environmental factors, including the use of soap and detergents, exacerbate epidermal barrier breakdown, attributed to the elevation of stratum corneum pH. A sustained increase in pH enhances the activity of degradatory proteases and decreases the activity of the lipid synthesis enzymes. The strong association between both genetic barrier defects and environmental insults to the barrier with AD suggests that epidermal barrier dysfunction is a primary event in the development of this disease. Our understanding of gene-environment interactions should lead to a better use of some topical products, avoidance of others, and the increased use and development of products that can repair the skin barrier.


Assuntos
Dermatite Atópica/metabolismo , Epiderme/metabolismo , Corticosteroides/administração & dosagem , Animais , Dermatite Atópica/etiologia , Detergentes/farmacologia , Homeostase , Humanos , Concentração de Íons de Hidrogênio , Calicreínas/fisiologia , Mutação , Proteínas Secretadas Inibidoras de Proteinases/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Inibidor de Serinopeptidase do Tipo Kazal 5
18.
Eur J Hum Genet ; 16(8): 1002-9, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18364739

RESUMO

Family-based analysis has revealed several loci for psoriasis and the locus, PSORS5, on chromosome 3q21 has been found in two independent studies. In this region, cystatin A (CSTA) encodes a skin barrier cystein protease inhibitor found in human sweat and it is over-expressed in psoriatic skin. Three CSTA markers at positions -190 (g.-190T>C), +162 (c.162T>C) and +344 (c.344C>T) were analysed in 107 unrelated patients and 216 matched controls. There was a significant trend for association with CSTA c.162T>C and psoriasis (odds ratio (OR)=3.45, P<0.001). Analysis of constructed haplotypes showed a highly significant association between disease and CSTA -190T/+162C/+344C (CSTA TCC) (P=10(-6)). In independent study, a TDT analysis in 126 nuclear families confirmed the over-transmission of CSTA TCC (P=0.0001). The presence of statistical interaction between CSTA TCC haplotype and HLA-Cw6 at PSORS1 locus was detected by performing TDT analysis on CSTA haplotypes stratified by the presence or absence of the risk allele at HLA-Cw6 locus. To estimate the disease risk we employed conditional logistic regression on the family data. The CSTA TCC haplotype is only associated with psoriasis in those individuals carrying the risk allele at the HLA-Cw6 locus (OR=2.22, P=0.0004, 95% CI= 1.42, 3.49). These results represent a major step towards the dissection of genetic factors involved in the pathogenesis of psoriasis.


Assuntos
Cistatinas/genética , Antígenos HLA-C/genética , Psoríase/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 6/genética , Cistatina A , Cistatinas/metabolismo , Família , Feminino , Predisposição Genética para Doença , Genótipo , Antígenos HLA-C/metabolismo , Haplótipos , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Masculino , Psoríase/imunologia , Psoríase/metabolismo
19.
Hum Immunol ; 67(7): 535-9, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16829308

RESUMO

Alopecia areata is an acquired hair loss disorder resulting from an immunologically- mediated attack on hair follicles and autoimmunity may play a part in its pathogenesis. The non-synonymous C1858T substitution in the PTPN22 gene, which encodes lymphoid protein tyrosine phosphatase, has been shown to be associated with susceptibility to autoimmune disorders. In this study, the objective was to ascertain whether or not the disease-associated 1858T (W620) allele was associated with alopecia areata. For this, the allelic distribution of the PTPN22 C1858T alleles was determined in 196 English patients with alopecia areata and 507 healthy subjects in a case control study using a restriction fragment length polymorphism-polymerase chain reaction (PCR-RFLP) genotyping method. The results indicated that the frequency of the 1858T allele did not differ significantly between the alopecia areata patient group and the control cohort: of 392 alopecia areata alleles, 41 (10.5%) encoded the W620 variant compared to 86 of 1014 (8.5%) control alleles. However, in patients with severe disease, 25/168 (14.9%) alleles were 1858T and this frequency differed from that in the control group (P = 0.0127; OR, 95% CI = 1.89, 1.17 - 3.05). These results suggest that the non-synonymous C1858T substitution in the PTPN22 gene may have an influence on the severity of alopecia areata and provide further evidence for autoimmunity as an aetiological factor in this disorder.


Assuntos
Alopecia em Áreas/genética , Predisposição Genética para Doença , Proteínas Tirosina Fosfatases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Inglaterra , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Proteína Tirosina Fosfatase não Receptora Tipo 22
20.
J Allergy Clin Immunol ; 118(1): 3-21; quiz 22-3, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16815133

RESUMO

Atopic dermatitis (AD) is a multifactorial, chronic inflammatory skin disorder in which genetic mutations and cutaneous hyperreactivity to environmental stimuli play a causative role. Genetic mutations alone might not be enough to cause clinical manifestations of AD, and this review will propose a new perspective on the importance of epidermal barrier dysfunction in genetically predisposed individuals, predisposing them to the harmful effects of environmental agents. The skin barrier is known to be damaged in patients with AD, both in acute eczematous lesions and also in clinically unaffected skin. Skin barrier function can be impaired first by a genetic predisposition to produce increased levels of stratum corneum chymotryptic enzyme. This protease enzyme causes premature breakdown of corneodesmosomes, leading to impairment of the epidermal barrier. The addition of environmental interactions, such as washing with soap and detergents, or long-term application of topical corticosteroids can further increase production of stratum corneum chymotryptic enzyme and impair epidermal barrier function. The epidermal barrier can also be damaged by exogenous proteases from house dust mites and Staphylococcus aureus. One or more of these factors in combination might lead to a defective barrier, thereby increasing the risk of allergen penetration and succeeding inflammatory reaction, thus contributing to exacerbations of this disease.


Assuntos
Dermatite Atópica/metabolismo , Epiderme/metabolismo , Corticosteroides/farmacologia , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/fisiologia , Detergentes/farmacologia , Meio Ambiente , Humanos , Concentração de Íons de Hidrogênio , Calicreínas/genética , Calicreínas/fisiologia , Peptídeo Hidrolases/farmacologia , Proteínas Secretadas Inibidoras de Proteinases , Inibidor de Serinopeptidase do Tipo Kazal 5 , Staphylococcus aureus/enzimologia
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