RESUMEN
To investigate the immunopathogenic mechanisms of type I autoimmune hepatitis in children, we analyzed by quantitative or semiquantitative reverse transcription-polymerase chain reaction the expression of cytokines interferon (IFN)-gamma, interleukin (IL)-12p40, IL-18, IL-4, IL-10, and IL-12R beta 2. In addition, liver and peripheral blood was collected to investigate the expression of the natural killer T (NKT) cell marker V alpha 24. The presence of NKT cells in hepatic lesions were also identified by immunohistochemistry. The analysis was performed on liver biopsies from 25 children with type I autoimmune hepatitis. As disease controls, we included six children with hepatitis C virus-related chronic hepatitis and nine control livers. The expression of IFN-gamma and IL-12p40 was not detected in controls but was clearly upregulated in pathologic biopsies. In addition, these samples showed an increased expression of IL-18 (p = 0.0003), IL-4 (p = 0.0055), and IL-12R beta 2 (p = 0.007). Western blot analysis confirmed the expression of IL-12p40 and IL-18. However, for IL-18, we detected only the immature biologically inactive polypeptide. The V alpha 24 transcripts were found increased in the liver (p = 0.0007) where V alpha 24(+) cells were also localized, but decreased in peripheral blood mononuclear cells (p = 0.041). In addition to a type I immune response, NKT cells might play a substantial role in the pathogenesis of type I autoimmune hepatitis in children.
Asunto(s)
Citocinas/genética , Expresión Génica , Hepatitis Autoinmune/patología , Interleucina-4/genética , Células TH1/inmunología , Adolescente , Autoanticuerpos/sangre , Biopsia con Aguja , Análisis Químico de la Sangre , Western Blotting , Niño , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Hepatitis Autoinmune/genética , Hepatitis Autoinmune/inmunología , Humanos , Inmunohistoquímica , Interferón gamma/genética , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Subunidad p40 de la Interleucina-12 , Interleucina-18/genética , Interleucina-18/metabolismo , Interleucina-4/inmunología , Interleucina-4/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/patología , Leucocitos Mononucleares/química , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Masculino , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/análisis , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Receptores de Interleucina-12 , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Células TH1/metabolismoRESUMEN
Elevated levels of interleukin 10 (IL-10) were previously described for chronically hepatitis C virus (HCV)-infected patients. We determined by a sequence-specific oligonucleotide probing technique the IL-10 promoter genotypes in 286 Argentinean HCV patients grouped according to disease outcome. The GG genotype (position -1082) is known to be associated with high IL-10 production, GA is considered an intermediate producer, and AA is associated with low IL-10 production. We found an increase in frequency of the GG genotype in female patients who do not eliminate the virus (RNA(+)). In these patients, the GG frequency was 0.19, versus 0.10 in controls (P = 0.03). This association became more significant in those RNA(+) female patients with elevated hepatic transaminases (GG frequency of 0.25; P = 0.0013). Additionally, this genotype frequency was higher in noncirrhotic female patients than in controls (GG frequency for noncirrhotic female patients was 0.31; P = 0.009). In RNA(-) patients, the GA frequency was elevated compared with that in controls (GA frequency of 0.76 in RNA(-) patients versus 0.48 in controls; P = 0.01), that in all HCV patients (GA frequency of 0.43; P = 0.001), and that in RNA(+) patients (GA frequency of 0.40; P = 0.0005). We conclude that a gender effect is observed with women carrying the GG high IL-10 producer genotype. The higher levels of IL-10 present in those individuals are associated with a higher risk of an inefficient clearance of the HCV and the development of a chronic HCV infection together with a lower risk of progression to cirrhosis in female patients.