RESUMEN
BACKGROUND & AIMS: The genetic background of alcoholic liver diseases and their complications are increasingly recognized. A common polymorphism in the neurocan (NCAN) gene, which is known to be expressed in neuronal tissue, has been identified as a risk factor for non-alcoholic fatty liver disease (NAFLD). We investigated if this polymorphism may also be related to alcoholic liver disease (ALD) and hepatocellular carcinoma (HCC). METHODS: We analysed the distribution of the NCAN rs2228603 genotypes in 356 patients with alcoholic liver cirrhosis, 126 patients with alcoholic HCC, 382 persons with alcohol abuse without liver damage, 362 healthy controls and in 171 patients with hepatitis C virus (HCV) associated HCC. Furthermore, a validation cohort of 229 patients with alcoholic cirrhosis (83 with HCC) was analysed. The genotypes were determined by LightSNiP assays. The expression of NCAN was studied by RT-PCR and immunofluorescence microscopy. RESULTS: The frequency of the NCAN rs2228603 T allele was significantly increased in patients with HCC due to ALD (15.1%) compared to alcoholic cirrhosis without HCC (9.3%), alcoholic controls (7.2%), healthy controls (7.9%), and HCV associated HCC (9.1%). This finding was confirmed in the validation cohort (15.7% vs. 6.8%, OR=2.53; 95%CI: 1.36-4.68; p=0.0025) and by multivariate analysis (OR=1.840; 95%CI: 1.22-2.78; p=0.004 for carriage of the rs2228603 T allele). In addition, we identified and localised NCAN expression in human liver. CONCLUSIONS: NCAN is not only expressed in neuronal tissue, but also in the liver. Its rs2228603 polymorphism is a risk factor for HCC in ALD, but not in HCV infection.
Asunto(s)
Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/genética , Proteoglicanos Tipo Condroitín Sulfato/genética , Lectinas Tipo C/genética , Hepatopatías Alcohólicas/complicaciones , Hepatopatías Alcohólicas/genética , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/genética , Proteínas del Tejido Nervioso/genética , Adulto , Anciano , Anciano de 80 o más Años , Alcoholismo/genética , Estudios de Casos y Controles , Línea Celular , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Células Hep G2 , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/genética , Hepatocitos/metabolismo , Humanos , Cirrosis Hepática Alcohólica/genética , Masculino , Persona de Mediana Edad , Neurocano , Polimorfismo de Nucleótido Simple , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Riesgo , Adulto JovenRESUMEN
OBJECTIVE: Autoimmune hepatitis and primary sclerosing cholangitis are chronic inflammatory disorders of unknown aetiology, frequently associated with the presence of perinuclear antineutrophil cytoplasmic antibodies (p-ANCAs) directed against an unknown antigen of myeloid cells. METHODS AND RESULTS: Here, it is reported that p-ANCAs in autoimmune liver disorders react with beta-tubulin isotype 5 (TBB-5) as autoantigen as well as with its evolutionary bacterial precursor protein FtsZ. Both proteins were confirmed as antigens of p-ANCAs in autoimmune liver disorders by demonstrating reactivity of ANCA-positive sera with recombinant TBB-5 (72-88%) and FtsZ (64-82%) on immunoblots and antigen-specific abrogation of ANCA immunofluorescence when sera had been preabsorbed with tubulin and FtsZ. Using sera from interleukin 10-deficient mice (Il10(-)/(-)), an animal model of inflammatory bowel disease, it was also demonstrated that antibodies against TBB-5 are generated in response to intestinal microorganisms. However, unlike autoimmune liver disorders, human antibodies to FtsZ in the absence of TBB-5 antibodies were also a frequent finding in non-autoimmune liver diseases (up to 95%). Reactivity to TBB-5 without the presence of FtsZ antibodies was found in very few cases (<1%) in autoimmune liver disorders. CONCLUSIONS: Thus, p-ANCAs in autoimmune liver diseases are directed against human TBB-5 cross-reacting with the bacterial protein FtsZ, probably reflecting an abnormal immune response to intestinal microorganisms in susceptible, possibly genetically predisposed individuals.
Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Proteínas Bacterianas/inmunología , Colangitis Esclerosante/inmunología , Proteínas del Citoesqueleto/inmunología , Hepatitis Autoinmune/inmunología , Tubulina (Proteína)/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Reacciones Antígeno-Anticuerpo/inmunología , Autoantígenos/análisis , Autoantígenos/inmunología , Enfermedades Autoinmunes/inmunología , Reacciones Cruzadas , Electroforesis en Gel de Poliacrilamida/métodos , Femenino , Humanos , Masculino , Microscopía Fluorescente , Persona de Mediana Edad , Mapeo Peptídico/métodos , Proteínas Recombinantes/inmunología , Adulto JovenRESUMEN
NK cells, a heterogeneous sub-population of lymphocytes, are critically involved in the regulation of both innate and adaptive immune responses in humans. Besides their participation in the control of tumors and viral infections, they also regulate inflammatory processes, mediating both beneficial and detrimental effects. To effectively fulfil their role in immune surveillance, proper trafficking of NK cells is essential. However, the mechanisms and factors governing NK cell recruitment are only poorly dissected. Here, we describe the functional role of tetraspanins, a family of evolutionary conserved cell-surface proteins, in modulating migration and transmigration of human NK cells. We demonstrate expression of various tetraspanins on NK cells. Furthermore, we show that stimulation of the NK cell-expressed tetraspanin CD81 induces phosphorylation of ezrin/radixin/moesin proteins and leads to NK cell polarization thereby facilitating NK cell migration toward various chemokines/cytokines. Finally, we provide evidence for a role of CD81 in promoting adhesion of NK cells to components of the extracellular matrix, a prerequisite for extravasation of lymphocytes in inflamed tissues. Thus, our data suggest that the tetraspanin CD81 is importantly involved in the regulation of NK cell recruitment.
Asunto(s)
Antígenos CD/metabolismo , Movimiento Celular , Células Asesinas Naturales/metabolismo , Proteínas de la Membrana/metabolismo , Western Blotting , Adhesión Celular , Polaridad Celular , Quimiocina CCL5/metabolismo , Quimiocina CCL5/farmacología , Quimiotaxis/efectos de los fármacos , Proteínas del Citoesqueleto/metabolismo , Citometría de Flujo , Humanos , Células Asesinas Naturales/citología , Proteínas de Microfilamentos/metabolismo , Fosforilación , Glicoproteínas de Membrana Plaquetaria/metabolismo , Unión Proteica , Proteína Quinasa C/metabolismo , Tetraspanina 28 , Tetraspanina 30 , Quinasas Asociadas a rho/metabolismoRESUMEN
DC-SIGNR is a C-type lectin that functions as a transreceptor for HIV-1. The exon 4 of the DC-SIGNR gene comprises a variable number of 69-bp tandem repeats, encoding for parts of the extracellular protein domain. Here, we analyzed the relevance of this gene polymorphism for the interindividual transmission of HIV-1 and the progression to AIDS. A cross-sectional comparison between HIV-1-infected patients (n = 391) and healthy volunteers (n = 134) did not reveal significant differences with regard to the DC-SIGNR allele distribution. Moreover, DC-SIGNR allele frequencies were similar in slowly progressing HIV patients (n = 31) and patients who rapidly progressed to AIDS (n = 46). Additionally, in a cohort of 149 newly HIV-infected patients, no relationship was found between HIV set point viremia and DC-SIGNR genotypes. Thus, the DC-SIGNR tandem-repeat polymorphism in exon 4 does not have a significant impact on the host's susceptibility to HIV and the clinical progression to AIDS.