title: Plasmacytoid dendritic cells mediate synergistic effects of HIV and lipopolysaccharide on CD27+ IgD- memory B cell apoptosis.
abstract: The effects of heightened microbial translocation on B cells during HIV infection are unknown. We examined the in vitro effects of HIV and lipopolysaccharide (LPS) on apoptosis of CD27+ IgD- memory B (mB) cells from healthy controls. In vivo analysis was conducted on a cohort of 82 HIV+ donors and 60 healthy controls. In vitro exposure of peripheral blood mononuclear cells (PBMCs) to LPS and HIV led to mB cell death via the Fas/Fas ligand (FasL) pathway. Plasmacytoid dendritic cells (pDCs) produced FasL in response to HIV via binding to CD4 and chemokine coreceptors. HIV and LPS increased Fas expression on mB cells in PBMCs, which was dependent on the presence of pDCs and monocytes. Furthermore, mB cells purified from PBMCs and pretreated with both HIV and LPS were more sensitive to apoptosis when cocultured with HIV-treated pDCs. Blocking the interferon receptor (IFNR) prevented HIV-stimulated FasL production in pDCs, HIV-plus-LPS-induced Fas expression, and apoptosis of mB cells. In vivo or ex vivo, HIV+ donors have higher levels of plasma LPS, Fas expression on mB cells, and mB cell apoptosis than controls. Correspondingly, in HIV+ donors, but not in controls, a positive correlation was found between plasma FasL and HIV RNA levels and between Fas expression on mB cells and plasma LPS levels. This work reveals a novel mechanism of mB cell apoptosis mediated by LPS and HIV through the Fas/FasL pathway, with key involvement of pDCs and type I IFN, suggesting a role for microbial translocation in HIV pathogenesis.
  
  
  OBJECTIVE
  This study demonstrates that lipopolysaccharide (LPS) and type I interferon (IFN) play an important role in memory B cell apoptosis in HIV infection. It reveals a previously unrecognized role of microbial translocation in HIV pathogenesis.
authors: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors: Lumin
authors: L
authors: Zhang
authors: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors: Zhenwu
authors: Z
authors: Luo
authors: Division of Infectious Diseases and HIV Medicine, Case Western Reserve University, University Hospitals/Case Medical Center, Cleveland, Ohio, USA.
authors: Scott F
authors: SF
authors: Sieg
authors: School of Health and Rehabilitation Sciences, Division of Medical Laboratory Science, The Ohio State University, Columbus, Ohio, USA.
authors: Nicholas T
authors: NT
authors: Funderburg
authors: Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts, USA.
authors: Xiaocong
authors: X
authors: Yu
authors: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Pingfu
authors: P
authors: Fu
authors: Center for Infectious Diseases, Beijing You-An Hospital, Capital Medical University, Beijing, China.
authors: Hao
authors: H
authors: Wu
authors: Center for Infectious Diseases, Beijing You-An Hospital, Capital Medical University, Beijing, China.
authors: Yanmei
authors: Y
authors: Jiao
authors: Division of Infectious Diseases and HIV Medicine, Case Western Reserve University, University Hospitals/Case Medical Center, Cleveland, Ohio, USA.
authors: Yong
authors: Y
authors: Gao
authors: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Neil S
authors: NS
authors: Greenspan
authors: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Clifford V
authors: CV
authors: Harding
authors: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
authors: J Michael
authors: JM
authors: Kilby
authors: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors: Zihai
authors: Z
authors: Li
authors: Division of Infectious Diseases and HIV Medicine, Case Western Reserve University, University Hospitals/Case Medical Center, Cleveland, Ohio, USA.
authors: Michael M
authors: MM
authors: Lederman
authors: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA jianw@musc.edu.
authors: Wei
authors: W
authors: Jiang
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D001419:Bacteria / Q000737:chemistry / Q000276:immunology; D018988:Bacterial Translocation; D002469:Cell Separation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D015497:HIV-1 / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007072:Immunoglobulin D / Q000235:genetics; D007156:Immunologic Memory; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology* / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
chemical_list: C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007072:Immunoglobulin D; D007370:Interferon Type I; D008070:Lipopolysaccharides; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D019014:fas Receptor