Direct enumeration and functional assessment of circulating dendritic cells in patients with liver disease

Chronic liver disease has been shown to be associated with diminished humoral and cellular immune function. Although antigen‐presenting cells (APC) that initiate immune responses include various cells (B cells, endothelial cells, macrophages, etc.), the dendritic cell (DC) is a professional APC that activates naive T cells most efficiently. To examine the frequency and function of DCs in chronic liver disease, we studied circulating DCs from a cohort of 112 subjects (23 normal subjects, 29 subjects who had spontaneously recovered from hepatitis C virus [HCV] infection, 30 chronically infected HCV patients, and 30 patients with liver disease unrelated to HCV infection). Our analyses revealed significant reduction in both circulating myeloid (mDC) and plasmacytoid dendritic cells (pDC) in patients with liver disease. In contrast, examination of subjects with spontaneously resolved HCV infection revealed no significant difference in either circulating mDCs or pDCs. We found an inverse correlation with serum alanine aminotransferase (ALT) levels and both mDCs and pDCs frequency. In a subset of patients for whom intrahepatic cells were available, paired analysis revealed enrichment for DCs within the intrahepatic compartment. Interferon alfa (IFN‐α) production in response to influenza A and poly (I:C) correlated with the frequency of circulating DCs, although IFN‐α production was comparable on a per‐DC basis in patients with liver disease. In conclusion, patients with liver disease exhibit a reduction in circulating DCs. Considering that DCs are essential for initiation and regulation of innate and adaptive immunity, these findings have implications for both viral persistence and liver disease. (HEPATOLOGY 2004;40:335–345.)

[1]  H. S. Warren,et al.  Toll-like receptors. , 2005, Critical care medicine.

[2]  M. Mohty,et al.  Dendritic cells: interfaces with immunobiology and medicine. A report from the Keystone Symposia Meeting held in Keystone, 3–8 March 2003 , 2003, Leukemia.

[3]  V. de Lédinghen,et al.  Evidence of viral replication in circulating dendritic cells during hepatitis C virus infection. , 2003, The Journal of infectious diseases.

[4]  D. Lewinsohn,et al.  Novel CD4+ and CD8+ T‐cell determinants within the NS3 protein in subjects with spontaneously resolved HCV infection , 2003, Hepatology.

[5]  K. Legge,et al.  Accelerated migration of respiratory dendritic cells to the regional lymph nodes is limited to the early phase of pulmonary infection. , 2003, Immunity.

[6]  D. Stolz,et al.  Reduction in the circulating pDC1/pDC2 ratio and impaired function of ex vivo-generated DC1 in chronic hepatitis B infection. , 2002, Clinical immunology.

[7]  P. Godowski,et al.  Tissue Expression of Human Toll-Like Receptors and Differential Regulation of Toll-Like Receptor mRNAs in Leukocytes in Response to Microbes, Their Products, and Cytokines , 2002, The Journal of Immunology.

[8]  M. Colonna,et al.  Interferon-producing cells: on the front line in immune responses against pathogens. , 2002, Current opinion in immunology.

[9]  J. Prieto,et al.  Abnormal Priming of CD4+ T Cells by Dendritic Cells Expressing Hepatitis C Virus Core and E1 Proteins , 2002, Journal of Virology.

[10]  Michael Loran Dustin,et al.  The immunological synapse , 2002, Arthritis research.

[11]  R. Standish,et al.  Scoring of chronic hepatitis. , 2002, Clinics in liver disease.

[12]  G. Trinchieri,et al.  Persistent Decreases in Blood Plasmacytoid Dendritic Cell Number and Function Despite Effective Highly Active Antiretroviral Therapy and Increased Blood Myeloid Dendritic Cells in HIV-Infected Individuals1 , 2002, The Journal of Immunology.

[13]  Y. Fukuhara,et al.  Involvement of TIRAP/MAL in signaling for the activation of interferon regulatory factor 3 by lipopolysaccharide , 2002, FEBS letters.

[14]  Yong‐jun Liu,et al.  Mouse and human dendritic cell subtypes , 2002, Nature Reviews Immunology.

[15]  P. Godowski,et al.  Tissue Expression of Human Toll-Like Receptors and Differential Regulation of Toll-Like Receptor mRNAs in Leukocytes in Response to Microbes, Their Products, and Cytokines , 2002, The Journal of Immunology.

[16]  R. Flavell,et al.  Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 , 2001, Nature.

[17]  B. Gazzard,et al.  Loss of blood CD11c(+) myeloid and CD11c(-) plasmacytoid dendritic cells in patients with HIV-1 infection correlates with HIV-1 RNA virus load. , 2001, Blood.

[18]  J. Gilmour,et al.  Plasmacytoid Dendritic Cells Are Highly Susceptible to Human Immunodeficiency Virus Type 1 Infection and Release Infectious Virus , 2001, Journal of Virology.

[19]  V. Soumelis,et al.  Dendritic cell lineage, plasticity and cross-regulation , 2001, Nature Immunology.

[20]  E. Keeffe,et al.  Impaired dendritic cell maturation in patients with chronic, but not resolved, hepatitis C virus infection. , 2001, Blood.

[21]  N. Kadowaki,et al.  Distinct CpG DNA and Polyinosinic-Polycytidylic Acid Double-Stranded RNA, Respectively, Stimulate CD11c− Type 2 Dendritic Cell Precursors and CD11c+ Dendritic Cells to Produce Type I IFN1 , 2001, The Journal of Immunology.

[22]  F. Zoulim,et al.  Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection. , 2001, Gastroenterology.

[23]  S. Dower,et al.  Regulation of Toll-Like Receptors in Human Monocytes and Dendritic Cells1 , 2001, The Journal of Immunology.

[24]  D. Doherty,et al.  Isolation of lymphocytes from normal adult human liver suitable for phenotypic and functional characterization. , 2000, Journal of immunological methods.

[25]  J. Banchereau,et al.  Flt3-Ligand and Granulocyte Colony-Stimulating Factor Mobilize Distinct Human Dendritic Cell Subsets In Vivo1 , 2000, The Journal of Immunology.

[26]  S. Heimfeld,et al.  Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells. , 2000, Blood.

[27]  A. Sing,et al.  Bacterial Induction of Beta Interferon in Mice Is a Function of the Lipopolysaccharide Component , 2000, Infection and Immunity.

[28]  A. Lanzavecchia,et al.  Inhibition of dendritic cell maturation by herpes simplex virus , 1999, European journal of immunology.

[29]  A. Sher,et al.  The role of dendritic cells in the induction and regulation of immunity to microbial infection. , 1999, Current opinion in immunology.

[30]  D. Jarrossay,et al.  Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon , 1999, Nature Medicine.

[31]  R. Verdijk,et al.  Polyriboinosinic polyribocytidylic acid (poly(I:C)) induces stable maturation of functionally active human dendritic cells. , 1999, Journal of immunology.

[32]  N. Kadowaki,et al.  The nature of the principal type 1 interferon-producing cells in human blood. , 1999, Science.

[33]  J. Atzpodien,et al.  Images in clinical medicine. Immunologic crosstalk. , 1999, The New England journal of medicine.

[34]  N. Hayashi,et al.  Impaired allostimulatory capacity of peripheral blood dendritic cells recovered from hepatitis C virus-infected individuals. , 1999, Journal of immunology.

[35]  Hanno Langen,et al.  Maturation, Activation, and Protection of Dendritic Cells Induced by Double-stranded RNA , 1999, The Journal of experimental medicine.

[36]  N. Kadowaki,et al.  Reciprocal control of T helper cell and dendritic cell differentiation. , 1999, Science.

[37]  Y. Hiasa,et al.  Low stimulatory capacity of lymphoid dendritic cells expressing hepatitis C virus genes. , 1998, Biochemical and biophysical research communications.

[38]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[39]  M. Albert,et al.  Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs , 1998, Nature.

[40]  J. Banchereau,et al.  Measles Virus Infects Human Dendritic Cells and Blocks Their Allostimulatory Properties for CD4+ T Cells , 1997, The Journal of experimental medicine.

[41]  J. Banchereau,et al.  The Enigmatic Plasmacytoid T Cells Develop into Dendritic Cells with Interleukin (IL)-3 and CD40-Ligand , 1997, The Journal of experimental medicine.

[42]  J A Hokanson,et al.  Theoretical basis for sampling statistics useful for detecting and isolating rare cells using flow cytometry and cell sorting. , 1997, Cytometry.

[43]  William M. Lee,et al.  Use of aminotransferase, hepatitis C antibody, and hepatitis C polymerase chain reaction RNA assays to establish the diagnosis of hepatitis C virus infection in a diagnostic virology laboratory , 1992, Journal of clinical microbiology.

[44]  C. M. Leevy,et al.  Immunological Aspects of Liver Disease , 1970, The Medical clinics of North America.

[45]  F. Chisari,et al.  Noncytolytic control of viral infections by the innate and adaptive immune response. , 2001, Annual review of immunology.

[46]  S. Patterson,et al.  Infection of dendritic cells with HIV1: virus load regulates stimulation and suppression of T-cell activity. , 1993, Research in virology.

[47]  F. Paronetto.  Immunologic aspects of liver disease. , 1973, Postgraduate medicine.