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

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Abstract

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.

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References

  1. Paschos P, Paletas K. Non alcoholic fatty liver disease and metabolic syndrome. Hippokratia. 2009;13:9–19.

    PubMed  CAS  Google Scholar 

  2. Vuppalanchi R, Chalasani N. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: past, present and future directions. J Gastrointestin Liver Dis. 2010;19:415–23.

    Google Scholar 

  3. Brunt EM. Pathology of nonalcoholic steatohepatitis. Hepatol Res. 2005;33:68–71.

    Article  PubMed  CAS  Google Scholar 

  4. Brunt EM. Histopathology of non-alcoholic fatty liver disease. Clin Liver Dis. 2005;13:533–44.

    Article  Google Scholar 

  5. Day C, James OFW. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114:842–5.

    Article  PubMed  CAS  Google Scholar 

  6. Basaranoglu M, Kayacetin S, Yilmaz N, Kayacetin E, Tarcin O, Sonsuz A. Understanding mechanisms of the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol. 2010;16:2223–6.

    Article  PubMed  Google Scholar 

  7. Fassio E, Alvarez E, Dominguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology. 2004;40:820–6.

    PubMed  Google Scholar 

  8. Jasen PML. Nonalcoholic steatohepatitis. J Med. 2004;62:217–24.

    Google Scholar 

  9. Pascale A, Pais R, Ratziu V. An overview of nonalcoholic steatohepatitis: past, present and future directions. J Gastrointestin Liver Dis. 2010;19:415–23.

    PubMed  Google Scholar 

  10. Tominaga K, Fujimoto E, Suzuki K, Hayashi M, Ichikawa M, Inaba Y. Prevalence of non-alcoholic fatty liver disease in children and relationship to metabolic syndrome, insulin resistance, and waist circumference. Environ Health Prev Med. 2009;14:142–9.

    Article  PubMed  CAS  Google Scholar 

  11. Argo CK, Caldwell SH. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis. 2009;13:511–31.

    Article  PubMed  Google Scholar 

  12. Frith J, Jones D, Newton J. Chronic liver disease in an ageing population. Age Ageing. 2009;38:11–8.

    Article  PubMed  Google Scholar 

  13. Singh R, Bullard J, Kalra M, Assefa S, Kaul AK, Vonfeldt K, et al. Status of bacterial colonization, Toll like receptor expression and nuclear factor-kappa B activation in normal and diseased human livers. Clin Immunol. 2011;138:41–9.

    Article  PubMed  CAS  Google Scholar 

  14. Jaeschke H, Gores GJ, Cederbaum AI, Hinson JÁ, Pessayre D, Lemasters JJ. Mechanisms of hepatotoxicity. Toxicol Sci. 2002;65:166–76.

    Article  PubMed  CAS  Google Scholar 

  15. Buffy G. Kupffer cells in non-alcoholic steatohepatitis: the emerging view. J Hepatol. 2009;51:212–23.

    Article  Google Scholar 

  16. Seki S, Kitada T, Yamada T, Sakaguchi H, Nakatani K, Wakasa K. In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases. J Hepatol. 2002;37:56–62.

    Article  PubMed  CAS  Google Scholar 

  17. Abdelmalek MF, Diehl AM. Mechanisms underlying nonalcoholic steatohepatitis. Drug Discov Today: Dis Mech. 2006;3:479–88.

    Article  Google Scholar 

  18. Schwimmer JB, Behling C, Newbury R, Deutsch R, Nievergelt C, Schork NJ, Lavine JE. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005;42:641–9.

    Article  PubMed  Google Scholar 

  19. Rensen SS, Slaats S, Nijhuis J, Jans A, Bieghs V, Driessen A, Malle E, Greve JW, Buurman WA. Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis. Am J Pathol. 2009;175:1473–82.

    Article  PubMed  CAS  Google Scholar 

  20. Adler M, Taylor S, Okebugwu K, Yee H, Fielding C, Fielding G, Poles M. Intrahepatic natural killer T cell populations are increased in human hepatic steatosis. World J Gastroenterol. 2011;17:1725–31.

    Article  PubMed  CAS  Google Scholar 

  21. Li QF, Li YP, Cheng PS. Peripheral T-lymphocyte subsets changes in patients with endocrine and metabolic diseases. Zhonghua Nei Ke Za Zhi. 1989;28:410–2.

    PubMed  CAS  Google Scholar 

  22. Romo EM, Muñoz-Robles JA, Castillo-Rama M, Meneu JC, Moreno-Elola A, Perez-Saborido B, et al. Peripheral blood lymphocyte populations in end-stage liver diseases. J Clin Gastroenterol. 2007;41(7):713–21.

    Article  PubMed  Google Scholar 

  23. Inzaugarat ME, Ferreyra Solari NE, Billordo LA, Abecasis R, Gadano AC, Cherñavsky AC. Altered phenotype and functionality of circulating immune cells characterize adult patients with nonalcoholic steatohepatitis. J Clin Immunol. 2011;31:1120–30.

    Article  PubMed  Google Scholar 

  24. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.

    Article  PubMed  Google Scholar 

  25. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–74.

    Article  PubMed  CAS  Google Scholar 

  26. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ. 2000;320:1–6.

    Article  Google Scholar 

  27. De Basio MB, Periolo N, Avagnina A, Garcia de Davila MT, Ciocca M, Goñi J, de Mateeo E, Galoppo C, Cañero-Velasco MC, Fainboim H, Muñoz AE, Fainboim L, Cherñavsky AC. Liver infiltrating mononuclear cells in children with type 1 autoimmune hepatitis. J Clin Pathol. 2006;59:417–23.

    Article  Google Scholar 

  28. Lalor PL, Shields P, et al. Recruitment of lymphocytes to the human liver. Immunol Cell Biol. 2002;80:52–64.

    Article  PubMed  CAS  Google Scholar 

  29. Lemmers A, Moreno C, Gustot T, et al. The interleukin-17 pathway is involved in human alcoholic liver disease. Hepatology. 2009;49:646–57.

    Article  PubMed  CAS  Google Scholar 

  30. Berard M, Tough DF. Qualitative differences between naïve and memory T cells. Immunology. 2002;106:127–38.

    Article  PubMed  CAS  Google Scholar 

  31. Linton JP, Haynes L, Tsui L, Zhang X, Swain S. From naive to effector—alterations with aging. Immunol Rev. 1997;160:9–18.

    Article  PubMed  CAS  Google Scholar 

  32. Kimmig S, Przybylski GK, Schmidt CA, Laurisch K, Mowes B, Radbruch A, Thiel A. Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood. J Exp Med. 2002;195:789–94.

    Article  PubMed  CAS  Google Scholar 

  33. Richards SJ, Jones RA, Roberts BE, Patel D, Scott CS. Relationships between 2H4 (CD45RA) and UCHLl (CD45RO) expression by normal blood CD4+ CD8−, CD4− CD8+, CD4− CD8dim+, CD3+ CD4−CD8− and CD3− CD4−CD8− lymphocytes. Clin Exp Immunol. 1990;81:149–55.

    Article  PubMed  CAS  Google Scholar 

  34. Socha P, Michalkiewicz J, Stachowski J, Pawlowska J, Jankowska I, Barth C, Socha J, Madalinski K. Deficiency of the expression of CD45RA isoform of CD45 common leukocyte antigen in CD4+ T lymphocytes in children with infantile cholestasis. Immunol Let. 2001;78:179–84.

    Article  Google Scholar 

  35. Summers KL, O’Donnell JL, Hart DNJ. Co-expression of the CD45RA and CD45RO antigens on T lymphocytes in chronic arthritis. Clin Exp Immunol. 1994;97:39–44.

    Article  PubMed  CAS  Google Scholar 

  36. Hu X, Gu Y, Wang Y, Cong Y, Qu X, Xu C. Increased CD4+ and CD8+ effector memory T cells in patients with aplastic anemia. Annu Rev Immunol. 2004;22:745–63.

    Article  Google Scholar 

  37. Messi M, Giacchetto I, Nagata K, Lanzavecchia A, Natoli G, Saluusto F. Memory and flexibility of cytokine gene expression as separable properties of human T(H)1 and T(H)2 lymphocytes. Nat Immunol. 2003;4:78–86.

    Article  PubMed  CAS  Google Scholar 

  38. Weng HL, Cai WM, Liu RH. Animal experiment and clinical study of effect of gamma-interferon on hepatic fibrosis. World J Gastroenterol. 2001;7:42–8.

    PubMed  CAS  Google Scholar 

  39. Knight B, Lim R, Yeoh GC, Olynyk JK. Interferon-γ exacerbates liver damage, the hepatic progenitor cell response and fibrosis in a mouse model of chronic liver injury. J Hepatol. 2007;47:826–33.

    Article  PubMed  CAS  Google Scholar 

  40. Videm V, Strand E. Changes in neutrophil surface-receptor expression after stimulation with FMLP endotoxin, interleukin-8 and activated complement compared to degranulation. Scand J Immunol. 2004;59:25–33.

    Article  PubMed  CAS  Google Scholar 

  41. Zarkesh-Esfahani H, Pockley AG, Wu Z, Hellewell PG, Weetman AP, Ross RJ. Leptin indirectly activates human neutrophils via induction of TNF-alpha. J Immunol. 2004;172:1809–14.

    PubMed  CAS  Google Scholar 

  42. Fitzpatrick E, Mitry RR, Quaglia A, Hussain MJ, DeBruyne R, Dhawan A. Serum levels of CK18 M30 and leptin are useful predictors of steatohepatitis and fibrosis in paediatric NAFLD. J Pediatr Gastroenterol Nutr. 2010;51:500–6.

    Article  PubMed  CAS  Google Scholar 

  43. Santos-Alvarez J, Goberna R, Sanchez-Margalet V. Human leptin stimulates proliferation and activation of human circulating monocytes. Cell Immunol. 1999;194:6–11.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. 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. Ferreyra Solari, María Eugenia Inzaugarat, Placida Baz & Alejandra C. Cherñavsky

  2. Servicio de Patología, Hospital de Niños “Dr. R. Gutierrez”, Universidad de Buenos Aires, Buenos Aires, Argentina

    Elena De Matteo

  3. Unidad de Hepatología, Hospital de Niños “Dr. Ricardo Gutiérrez”, Universidad de Buenos Aires, Buenos Aires, Argentina

    Carol Lezama, Marcela Galoppo & Cristina Galoppo

Authors
  1. Nazarena E. Ferreyra Solari
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  2. María Eugenia Inzaugarat
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  3. Placida Baz
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  4. Elena De Matteo
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  8. Alejandra C. Cherñavsky
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Corresponding author

Correspondence to Alejandra C. Cherñavsky.

Additional information

Nazarena E Ferreyra Solari and María Eugenia Inzaugarat contributed equally to this work.

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Ferreyra Solari, N.E., Inzaugarat, M.E., Baz, P. et al. The Role of Innate Cells Is Coupled to a Th1-Polarized Immune Response in Pediatric Nonalcoholic Steatohepatitis. J Clin Immunol 32, 611–621 (2012). https://doi.org/10.1007/s10875-011-9635-2

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  • DOI: https://doi.org/10.1007/s10875-011-9635-2

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