The Role of Innate Cells Is Coupled to a Th1-Polarized Immune Response in Pediatric Nonalcoholic Steatohepatitis

• Published in: Journal of clinical immunology 2012-06, Vol.32 (3), p.611-621
• Main Authors: Ferreyra Solari, Nazarena E., Inzaugarat, María Eugenia, Baz, Placida, De Matteo, Elena, Lezama, Carol, Galoppo, Marcela, Galoppo, Cristina, Cherñavsky, Alejandra C.
• Format: Article
• Language: English
• Subjects: Adolescent; Biomedical and Life Sciences; Biomedicine; Biopsy; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD45RA antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell activation; Child; Cytokines; Fatty liver; Fatty Liver - immunology; Fatty Liver - pathology; Female; Flow cytometry; gamma -Interferon; Humans; Immune response; Immunology; Infectious Diseases; Inflammatory diseases; Interferon-gamma - genetics; Interferon-gamma - immunology; Interleukin 4; Interleukin-4 - genetics; Interleukin-4 - immunology; Internal Medicine; Leukocyte migration; Leukocytes (neutrophilic); Leukocytes (polymorphonuclear); Leukocytes, Mononuclear - immunology; Liver diseases; Lymphocytes; Male; Medical Microbiology; Metabolic disorders; Microenvironments; Monocytes; Neutrophils - immunology; Non-alcoholic Fatty Liver Disease; Pediatrics; Peripheral blood; Phorbol esters; Reactive oxygen species; Reactive Oxygen Species - immunology; Risk factors; RNA, Messenger - immunology
• ISSN: 0271-9142; 1573-2592
• DOI: 10.1007/s10875-011-9635-2

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. Aims 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. Conclusion 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.