Impaired dendritic cell functions disrupt antigen-specific adaptive immune responses in mice with nonalcoholic fatty liver disease
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
The magnitude of antigen-specific immunity was assessed in a murine model of nonalcoholic fatty liver diseases (NAFLD). Because antigen-specific immunity was diminished in NAFLD mice, the underlying mechanisms were evaluated through analysis of the functions of antigen-presenting dendritic cells (DC) and other immunocytes.
For 12 weeks, NAFLD mice received a high-fat (60%) and high-calorie (520 kcal/100 g) diet. C57BL/6 mice (controls) received a standard diet. NAFLD mice and control mice were immunized with hepatitis B vaccine containing hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg). Antibody to HBsAg (anti-HBs), HBsAg and HBcAg-specific cellular immune response and functions of whole spleen cells, T lymphocytes, B lymphocytes and spleen DCs of NAFLD and control mice were assessed in vitro.
Levels of anti-HBs and the magnitude of proliferation of HBsAg and HBcAg-specific lymphocytes were significantly lower in NAFLD mice than control mice (P < 0.05). The spleen cells of NAFLD mice produced significantly higher levels of inflammatory cytokines (P < 0.05) and exhibited significantly increased T cell proliferation compared with control mice (P < 0.05). However, the antigen processing and presenting capacities of spleen DCs were significantly decreased in NAFLD mice compared with control mice (P < 0.05). Palmitic acid, a saturated fatty acid, caused diminished antigen processing and presenting capacity of both murine and human DCs.
Nonalcoholic fatty liver disease mice exhibit decreased magnitudes of antigen-specific humoral and cellular immune responses. This effect is mainly, if not solely, due to impaired antigen processing and presentation capacities of DC.
- Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–7. CrossRef
- Tordjman J, Guerre-Millo M, Clément K. Adipose tissue inflammation and liver pathology in human obesity. Diabetes Metab. 2008;34:658–63. CrossRef
- Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114:842–5. CrossRef
- de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett. 2008;582:97–105. CrossRef
- Cawthorn WP, Sethi JK. TNF-alpha and adipocyte biology. FEBS Lett. 2008;582:117–31. CrossRef
- Li Z, Soloski MJ, Diehl AM. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease. Hepatology. 2005;42:880–5. CrossRef
- Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology. 2007;132:2169–80. CrossRef
- Tajiri K, Shimizu Y, Tsuneyama K, Sugiyama T. Role of liver-infiltrating CD3+ CD56+ natural killer T cells in the patogénesis of nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2009;21:673–80. CrossRef
- Ma X, Hua J, Mohamood AR, Hamad AR, Ravi R, Li Z. A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury. Hepatology. 2007;46:1519–29. CrossRef
- Diehl AM. Nonalcoholic steatosis and steatohepatitis IV. Nonalcoholic fatty liver disease abnormalities in macrophage function and cytokines. Am J Physiol Gastrointest Liver Physiol. 2002;282:G1–5.
- Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8(+) effector T cells contribute to macrophage requirement and adipose tissue inflammation in obesity. Nat Med. 2009;15:846–7. CrossRef
- Eliakim A, Schwindt C, Zaldivar F, Casali P, Cooper DM. Reduced tetanus antibody titers in overweight children. Autoimmunity. 2006;39:137–41. CrossRef
- Weber DJ, Rutala WA, Samsa GP, Bradshaw SE, Lemon SM. Impaired immunogenicity of hepatitis B vaccine in obese persons. N Engl J Med. 1986;314:1393.
- Sanyal AJ, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Stravitz RT, et al. Nonalcoholic fatty liver disease in patients with hepatitis C is associated with features of the metabolic syndrome. Am J Gastroenterol. 2003;98:2064–71. CrossRef
- Bondini S, Kallman J, Wheeler A, Prakash S, Gramlich T, Jondle DM, et al. Impact of non-alcoholic fatty liver disease on chronic hepatitis B. Liver Int. 2007;27:607–11. CrossRef
- Rehermann B. Chronic infections with hepatotropic viruses: mechanisms of impairment of cellular immune responses. Semin Liver Dis. 2007;27:152–60. CrossRef
- Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature. 2007;449:419–26. CrossRef
- Onji M, Akbar SM. Dendritic cells in clinics. 2nd ed. Tokyo: Springer; 2008.
- Fazle Akbar SM, Abe M, Yoshida O, Murakami H, Onji M. Dendritic cell-based therapy as a multidisciplinary approach to cancer treatment: present limitations and future scopes. Curr Med Chem. 2006;13:3113–9. CrossRef
- Niiya T, Akbar SM, Yoshida O, Miyake T, Matsuura B, Murakami H, et al. Impaired dendritic cell function resulting from chronic undernutrition disrupts the antigen-specific immune response in mice. J Nutr. 2007;137:671–5.
- Akbar SM, Onji M, Inaba K, Yamamura K-I, Ohta Y. Low responsiveness of hepatitis B virus transgenic mice in antibody response to T-cell-dependent antigen: defect in antigen presenting activity of dendritic cells. Immunology. 1993;78:468–73.
- Akbar SM, Inaba K, Onji M. Upregulation of MHC class II antigen on dendritic cells from hepatitis B virus transgenic mice by g-interferon: abrogation of immune response defect to a T-cell-dependent antigen. Immunology. 1996;87:519–27. CrossRef
- Akbar SM, Abe M, Masumoto T, Horiike N, Onji M. Mechanism of action of vaccine therapy in murine hepatitis B virus carriers: vaccine-induced activation of antigen presenting dendritic cells. J Hepatol. 1999;30:755–64. CrossRef
- Akbar SM, Furukawa S, Yoshida O, Hiasa Y, Horiike N, Onji M. Induction of anti-HBs in HB vaccine nonresponders in vivo by hepatitis B surface antigen-pulsed blood dendritic cells. J Hepatol. 2007;47:60–6. CrossRef
- Schaeffler A, Gross P, Buettner R, Bollheimer C, Buechler C, Neumeier M, et al. Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity. Immunology. 2009;126:233–45. CrossRef
- Håversen L, Danielsson KN, Fogelstrand L, Wiklund O. Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages. Atherosclerosis. 2009;202:382–93. CrossRef
- Yoshida O, Akbar F, Miyake T, Abe M, Matsuura B, Hiasa Y, et al. Impaired dendritic cell functions because of depletion of natural killer cells disrupt antigen-specific immune responses in mice: restoration of adaptive immunity in natural killer-depleted mice by antigen-pulsed dendritic cell. Clin Exp Immunol. 2008;152:174–81. CrossRef
- Coll T, Eyre E, Rodriguez-Calvo R, Palomer X, Sanchez RM, Merols M, et al. Oleate reverses palmitate-induced insulin resistance and inflammation in skeletal muscle. J Biol Chem. 2008;283:11107–16. CrossRef
- Guaraldi G, Squillace N, Stentarelli C, Orlando G, D’Amico R, Ligabue G, et al. Nonalcoholic fatty liver disease in HIV-infected patients referred to a metabolic clinic: prevalence, characteristics, and predictors. Clin Infect Dis. 2008;47:250–7. CrossRef
- Hill-Baskin AE, Markiewski MM, Buchner DA, Shao H, DeSantis D, Hsiao G, et al. Diet-induced hepatocellular carcinoma in genetically predisposed mice. Hum Mol Genet. 2009;18:2975–88. CrossRef
- Abe M, Akbar SM, Horiike N, Onji M. Inability of liver dendritic cells from mouse with experimental hepatitis to process and present specific antigens. Hepatol Res. 2003;26:61–7. CrossRef
- Pickup JC, Crook MA. Is type II diabetes mellitus a disease of the innate immune system? Diabetologia. 1998;41:1241–8. CrossRef
- Impaired dendritic cell functions disrupt antigen-specific adaptive immune responses in mice with nonalcoholic fatty liver disease
Journal of Gastroenterology
Volume 45, Issue 8 , pp 859-867
- Cover Date
- Print ISSN
- Online ISSN
- Springer Japan
- Additional Links
- Adaptive immunity
- Dendritic cell
- HB vaccine
- Industry Sectors
- Author Affiliations
- 1. Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan
- 2. Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan