Abstract
Objective
To investigate whether Toll-like receptor (TLR) 7 and TLR9-mediated interferon α (IFN-α) production in plasmacytoid dendritic cells (pDCs) is compromised in patients with chronic hepatitis B virus (HBV) infection.
Materials and methods
Peripheral blood mononuclear cells (PBMCs) were prepared from 32 chronic HBV patients and 13 healthy volunteers, and treated with loxoribine or cytidine phosphate guanosine (CpG) oligodeoxynucleotides (ODN). Interferon α in the supernatant was measured by sandwich ELISA. PDC frequency and the expression levels of TLR7 and TLR9 in pDCs were quantified by flow cytometry. The serum viral load of HBV was quantified using a highly sensitive real-time PCR kit.
Results
Compared to cells from healthy control group, PBMCs and pDCs from the HBV group showed significantly decreased production of IFN-α in response to ligand for TLR7 (loxoribine) and TLR9 (CpG ODN, P < 0.05). Mechanistically, the number of pDCs in peripheral blood, and the expression of pDC-associated TLR7 and TLR9 were significantly lower in HBV group than in the healthy control group (P < 0.05). In addition, the number of pDCs and the expression of TLR9 on pDCs were correlated inversely with the serum load of HBV.
Conclusion
Impaired IFN-α production from pDC may contribute to the immunopathogenesis of chronic HBV infection, which may be the result of a reduced amount of pDCs as well as decreased expression of TLR7 and TLR9 on pDCs.
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References
Merican I, Guan R, Amarapuka D, Alexander MJ, Chutaputti A, Chien RN, et al. Chronic hepatitis B virus infection in Asian countries. J Gastroenterol Hepatol. 2000;15:1356–61.
Chang JJ, Lewin SR. Immunopathogenesis of hepatitis B virus infection. Immunol Cell Biol. 2007;85:16–23.
Banchereau J, Fay J, Pascual V, Palucka AK. Dendritic cells: controllers of the immune system and a new promise for immunotherapy. Novartis Found Symp 2003; 252:226-35. discussion 235-8, 257–67.
Chan CW, Crafton E, Fan HN, Flook J, Yoshimura K, Skarica M, et al. Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity. Nat Med. 2006;12:207–13.
Hasebe A, Akbar SM, Furukawa S, Horiike N, Onji M. Impaired functional capacities of liver dendritic cells from murine hepatitis B virus (HBV) carriers: relevance to low HBV-specific immune responses. Clin Exp Immunol. 2005;139:35–42.
van der Molen RG, Sprengers D, Binda RS, de Jong EC, Niesters HG, Kusters JG, et al. Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B. Hepatology. 2004;40:738–46.
Op den Brouw ML, Binda RS, van Roosmalen MH, Protzer U, Janssen HL, van der Molen RG, et al. Hepatitis B virus surface antigen impairs myeloid dendritic cell function: a possible immune escape mechanism of hepatitis B virus. Immunology. 2009;126:280–9.
Schlender J, Hornung V, Finke S, Gunthner-Biller M, Marozin S, Brzozka K, et al. Inhibition of toll-like receptor 7- and 9-mediated alpha/beta interferon production in human plasmacytoid dendritic cells by respiratory syncytial virus and measles virus. J Virol. 2005;79:5507–15.
Coccia EM, Severa M, Giacomini E, Monneron D, Remoli ME, Julkunen I, et al. Viral infection and Toll-like receptor agonists induce a differential expression of type I and lambda interferons in human plasmacytoid and monocyte-derived dendritic cells. Eur J Immunol. 2004;34:796–805.
Medzhitov R, Janeway C Jr. Innate immune recognition: mechanisms and pathways. Immunol Rev. 2000;173:89–97.
Werling D, Jungi TW. TOLL-like receptors linking innate and adaptive immune response. Vet Immunol Immunopathol. 2003;91:1–12.
Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R. Toll-like receptors control activation of adaptive immune responses. Nat Immunol. 2001;2:947–50.
Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:197–216.
Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004;5:987–95.
Xie Q, Shen HC, Jia NN, Wang H, Lin LY, An BY, et al. Patients with chronic hepatitis B infection display deficiency of plasmacytoid dendritic cells with reduced expression of TLR9. Microbes Infect. 2009;11:515–23.
Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004;39:1147–71.
Siegal FP, Fitzgerald-Bocarsly P, Holland BK, Shodell M. Interferon-alpha generation and immune reconstitution during antiretroviral therapy for human immunodeficiency virus infection. AIDS. 2001;15:1603–12.
Duan XZ, Zhuang H, Wang M, Li HW, Liu JC, Wang FS. Decreased numbers and impaired function of circulating dendritic cell subsets in patients with chronic hepatitis B infection (R2). J Gastroenterol Hepatol. 2005;20:234–42.
Renshaw M, Rockwell J, Engleman C, Gewirtz A, Katz J, Sambhara S. Cutting edge: impaired Toll-like receptor expression and function in aging. J Immunol. 2002;169:4697–701.
Colisson R, Barblu L, Gras C, Raynaud F, Hadj-Slimane R, Pique C, et al. Free HTLV-1 induces TLR7-dependent innate immune response and TRAIL relocalization in killer plasmacytoid dendritic cells. Blood. 2010;115:2177–85.
Dolganiuc A, Chang S, Kodys K, Mandrekar P, Bakis G, Cormier M, et al. Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection. J Immunol. 2006;177:6758–68.
Martinson JA, Montoya CJ, Usuga X, Ronquillo R, Landay AL, Desai SN. Chloroquine modulates HIV-1-induced plasmacytoid dendritic cell alpha interferon: implication for T-cell activation. Antimicrob Agents Chemother. 2010;54:871–81.
Untergasser A, Zedler U, Langenkamp A, Hosel M, Quasdorff M, Esser K, et al. Dendritic cells take up viral antigens but do not support the early steps of hepatitis B virus infection. Hepatology. 2006;43:539–47.
Yuen MF, Yuan HJ, Hui CK, Wong DK, Wong WM, Chan AO, et al. A large population study of spontaneous HBeAg seroconversion and acute exacerbation of chronic hepatitis B infection: implications for antiviral therapy. Gut. 2003;52:416–9.
Brook MG, Karayiannis P, Thomas HC. Which patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy? A statistical analysis of predictive factors. Hepatology. 1989;10:761–3.
Tavakoli S, Schwerin W, Rohwer A, Hoffmann S, Weyer S, Weth R, et al. Phenotype and function of monocyte derived dendritic cells in chronic hepatitis B virus infection. J Gen Virol. 2004;85:2829–36.
Acknowledgments
This work was supported by the grant (No. 2007CB512905) from the National Basic Research Program (to Z.C.), and the grant (No. 30801035) from the National Natural Science Foundation of China (to N.X.).
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Xu, N., Yao, HP., Lv, GC. et al. Downregulation of TLR7/9 leads to deficient production of IFN-α from plasmacytoid dendritic cells in chronic hepatitis B. Inflamm. Res. 61, 997–1004 (2012). https://doi.org/10.1007/s00011-012-0493-z
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DOI: https://doi.org/10.1007/s00011-012-0493-z