The role of innate cells is coupled to a Th1-polarized immune response in pediatric nonalcoholic steatohepatitis.
BACKGROUND
Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory liver disease influenced by risk factors for the metabolic syndrome. In adult patients, NASH is associated with an altered phenotype and functionality of peripheral immune cells, the recruitment of leukocytes and intrahepatic activation, and an exacerbated production of reactive oxygen species (ROS) and cytokines. It remains unclear if the previously described differences between pediatric and adult nonalcoholic fatty liver diseases also reflect differences in their pathogenesis.


OBJECTIVE
We aimed to investigate the phenotype and functionality of circulating immune cells and the potential contribution of liver infiltrating leukocytes to the immunological imbalance in pediatric NASH.


RESULTS
By a real-time PCR-based analysis of cytokines and immunohistochemical staining of liver biopsies, we demonstrated that the hepatic microenvironment is dominated by interferon-gamma (IFN-γ) but not interleukin-4 and is infiltrated by a higher number of CD8(+) cells in pediatric NASH. The number of infiltrating neutrophils positively correlated with ROS generation by peripheral polymorphonuclear cells. By a flow cytometric analysis of peripheral blood lymphocytes, a distinctive increase in CD8(+) CD45RO and CD8(+) CD45RA subpopulations and an increased production of IFN-γ by CD4(+) and CD8(+) cells were shown. The production of ROS following PMA stimulation was augmented in circulating neutrophils but not in monocytes.


CONCLUSIONS
In sum, the distinctive phenotype and functionality of infiltrating and circulating cells suggest that the role of innate cells is coupled to a Th1-polarized immune response in pediatric NASH.
Laboratorio de Inmunogenética, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Av. Córdoba 2351, 3er piso, CP1120, Buenos Aires, Argentina.
Nazarena E
NE
Ferreyra Solari
María Eugenia
ME
Inzaugarat
Placida
P
Baz
Elena
E
De Matteo
Carol
C
Lezama
Marcela
M
Galoppo
Cristina
C
Galoppo
Alejandra C
AC
Cherñavsky
D000293:Adolescent; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002648:Child; D005234:Fatty Liver / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D009504:Neutrophils / Q000276:immunology; D065626:Non-alcoholic Fatty Liver Disease; D012333:RNA, Messenger / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology
D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D015847:Interleukin-4; D007371:Interferon-gamma