RESUMEN
BACKGROUND: Mucous membrane pemphigoid (MMP) is a chronic blistering skin disease frequently associated with circulating autoantibodies directed to a number of antigens including the NC16A region of BP180. NC16A domain-specific T cells have been identified in the blood of individuals with bullous pemphigoid (BP), pemphigoid gestationis and linear IgA disease, but there are no data investigating the potential role for such T cells in the pathogenesis of MMP. OBJECTIVES: To test the hypothesis that NC16A-specific T cells exist in the peripheral blood of individuals with MMP. METHODS: We isolated peripheral blood mononuclear cells from 10 patients with MMP, 17 with BP and 10 healthy controls and examined the immunogenicity of overlapping peptides spanning the NC16A domain using interferon (IFN)-gamma enzyme-linked immunospot assay. RESULTS: Significant IFN-gamma production was observed in response to the NC16A peptides in two of the patients with MMP and two of the patients with BP but in none of the normal controls. These data suggest that in a minority of individuals with MMP, NC16A domain-specific T cells circulate at sufficiently high frequency to be detectable directly ex vivo and to show rapid effector function. CONCLUSIONS: Overall, these findings are the first to examine the potential role for antigen-specific autoreactive T cells in the pathogenesis of MMP, and confirm that in some individuals the NC16A domain may be an important target antigen.
Asunto(s)
Autoantígenos/inmunología , Penfigoide Benigno de la Membrana Mucosa/inmunología , Subgrupos de Linfocitos T/inmunología , Ensayo de Inmunoadsorción Enzimática/métodos , Epítopos de Linfocito T/inmunología , Humanos , Epítopos Inmunodominantes/inmunología , Interferón gamma/biosíntesis , Colágenos no Fibrilares , Penfigoide Ampolloso/inmunología , Colágeno Tipo XVIIRESUMEN
The purpose of this study is to assess the role of tumour necrosis factor (TNF) polymorphisms in the risk of developing bladder cancer and effect on tumour stage, grade and progression. In all, seven single-nucleotide polymorphisms in TNF were studied in 196 bladder cancer patients and 208 controls using a PCR-SSP genotyping technique. It was seen that there was a significant association of two polymorphisms in TNF with bladder cancer: the TNF+488A allele was found in 28.1% of patients compared with 14.9% of controls (P=0.0012). In addition, TNF-859T was found in 26.0% of patients compared with 14.4% of the controls (P=0.0036). The two loci were in tight linkage disequilibrium, that is, almost all the individuals having TNF+488A also had TNF-859T. Patients with the TNF+488A or TNF-859T were more likely to present with a moderately differentiated tumour than those patients without the uncommon allele. In all, 16.7% of patients with TNF+488A and 29.9% of patients without TNF+488A presented with a G1 tumour (P=0.015). A total of 14% of patients with TNF-859T and 30.5% of patients without TNF-859T presented with a G1 tumour (P=0.0043). There was no significant effect on time to first recurrence, stage progression or grade progression. In conclusion, a significant association between TNF polymorphisms TNF+488A and TNF-859T and risk of bladder cancer was detected in this study. Both these polymorphisms were associated with grade of tumour at presentation although there was no significant effect on subsequent tumour behaviour.
Asunto(s)
Frecuencia de los Genes , Polimorfismo Genético , Factor de Necrosis Tumoral alfa/genética , Neoplasias de la Vejiga Urinaria/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Cartilla de ADN/química , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Reino Unido , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Bullous pemphigoid (BP) is an autoimmune disease mediated by autoantibodies against hemidesmosome components. This study used PCR-sequence-specific primers to genotype polymorphisms in HLA-DR and DQ in 25 BP patients and 57 normal controls from northern China. We found lower frequencies of DRB1*08 (DR8) and DRB1*08/DQB1*06 (DR8/DQ6) haplotypes in BP patients than in controls (4.08% vs. 15.19% and 1.54% vs. 13.82%, respectively; P < 0.05), suggesting a protective role for DR8 and DR8/DQ6 haplotypes in BP patients from northern China; there were no statistical differences among other alleles tested. This result is strikingly different from previous reports that DQB1*0301 is associated with BP in Caucasian patients and DRB1*1101, DQB1*0302, DRB1*04/DQA1*0301/DQB1*0302 and DRB1*1101/ DQA1*0505/DQB1*0302 with Japanese BP patients. Ethnic differences in the polymorphic composition of the HLA-DR and DQ genes may influence genetic susceptibility to BP.
Asunto(s)
Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Penfigoide Ampolloso/genética , Polimorfismo Genético , Estudios de Casos y Controles , China , Frecuencia de los Genes , Humanos , Reacción en Cadena de la Polimerasa/métodosRESUMEN
Exposure to UV radiation is a major risk factor for the development of malignant melanoma. DNA damage caused by UV radiation is thought to play a major role in carcinogenesis induction. Multiprotein pathways involved in repairing UV-DNA damage are the base excision, the nucleotide excision, and the homologous double-stranded DNA repair pathways. This study used a sequence-specific primer PCR (PCR-SSP) genotyping method to investigate the association between polymorphisms in DNA repair genes from these pathways with the development of malignant melanoma. The patient cohort was comprised of 125 individuals with malignant melanoma with lesions or staging suggesting a high risk of relapse or metastatic disease. The control population consisted of 211 individuals. We found the presence of a T allele in exon 7 (position 18067) of the XRCC3 gene was significantly associated with melanoma development (P = 0.004; odds ratio, 2.36; relative risk, 1.74). This gene codes for a protein involved in the homologous pathway of double-stranded DNA repair, thought to repair chromosomal fragmentation, translocations, and deletions. These results may provide further insights into the pathogenesis and the mechanism of UV-radiation induced carcinogenesis as well as having a role in prevention.
Asunto(s)
Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Melanoma/genética , Neoplasias Cutáneas/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Exones , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Reacción en Cadena de la Polimerasa , Polimorfismo GenéticoRESUMEN
Lichen sclerosus is among the most frequently seen paediatric vulval disorders. In adults a strong association between lichen sclerosus and autoimmune diseases, and also with HLA class II locus DQ7, has been well demonstrated in women and a weaker association in men. These associations have not previously been studied in children, although in other autoimmune diseases, the HLA associations have been strongest in children. We performed HLA tissue typing and looked for autoimmune associations in a group of 30 children with vulval lichen sclerosus. HLA DQ7 was present in 66% of female children with lichen sclerosus compared with 31% in controls. Previous studies reported DQ7 in 51% of adult female patients and 45% of male patients. Sixteen per cent of the children were homozygous for DQ7 as opposed to 5% of controls. In the childhood group, only 4% had another autoimmune disease, but 56% of their parents or grandparents did. Age differences make comparison difficult, but the family history of autoimmunity appears to be strong in the early-onset group, in addition to the stronger association with DQ7.
Asunto(s)
Autoinmunidad/fisiología , Antígenos HLA-DQ/sangre , Liquen Escleroso y Atrófico/genética , Liquen Escleroso y Atrófico/inmunología , Enfermedades de la Vulva/genética , Enfermedades de la Vulva/inmunología , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Femenino , Predisposición Genética a la Enfermedad , Antígenos HLA-DR/sangre , Humanos , Masculino , Reacción en Cadena de la PolimerasaRESUMEN
There is a need to evaluate the permeability of human ulcerated tissue and periulcer tissue in order to assess the possible treatment of such a localized pathological lesion with a topical therapy. In vitro percutaneous absorption studies were undertaken to evaluate an animal model that may mimic this clinical situation. Porcine skin from three anatomical sites, the ear, abdomen, and dorsum; ischaemic skin (porcine and guinea pig); porcine wounds; and human skin (including periulcer and ulcerated tissue) were investigated, utilizing both whole skin and dermal membranes. Dermal membranes were chosen as representative of ulcerated tissue, as there would be no epidermal barrier present, and the thickness of the dermal membrane was not expected to offer any diffusional resistance to topically applied active agents. A range of chemicals with differing physicochemical properties was investigated using a Franz type diffusion cell. For all tissues a permeability coefficient (kp with units of cm h-1) was measured, along with skin thickness and tissue partition coefficient measurements. Under these experimental conditions and for the range of compounds tested, the results suggest that porcine skin, whole skin, and dermal membranes should be considered as good representative in vitro models for the topical delivery of compounds to human skin and ulcerated tissue, respectively.