title: Toll-like receptor 7 and 9 defects in common variable immunodeficiency.
abstract: BACKGROUND
  Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia, reduced numbers of peripheral blood isotype-switched memory B cells, and loss of plasma cells.
  
  
  OBJECTIVE
  Because Toll-like receptor (TLR) activation of B cells can initiate and potentially sustain normal B cell functions, we examined functional outcomes of TLR7 and TLR9 signaling in CVID B cells.
  
  
  METHODS
  TLR7-mediated, TLR7/8-mediated, and TLR9-mediated cell proliferation, isotype switch, and immunoglobulin production by control and CVID B cells or isolated naive and memory B cell subsets were examined. We quantitated TNF-alpha, IL-6, and IL-12 production in response to TLR1-9 ligands and measured IFN-alpha production by TLR7-stimulated PBMCs and isolated plasmacytoid dendritic cells (pDCs). IFN-beta mRNA expression by TLR3-stimulated fibroblasts was assessed.
  
  
  RESULTS
  Unlike CD27(+) B cells of controls, TLR7-activated, TLR7/8-activated, or TLR9-activated CVID B cells or isolated CD27(+) B cells did not proliferate, upregulate CD27, or shed surface IgD. TLR-stimulated CVID B cells failed to upregulate activation-induced cytosine deaminase mRNA or produce IgG and IgA. TLR7-stimulated PBMCs and pDCs produced little or no IFN-alpha. Reconstituting IFN-alpha in TLR7-stimulated CVID B-cell cultures facilitated proliferation, CD27 upregulation, and isotype switch. These TLR defects are restricted because CVID PBMCs stimulated with TLR ligands produced normal amounts of TNF-alpha, IL-6, and IL-12; TLR3-mediated expression of IFN-beta by CVID fibroblasts was normal.
  
  
  CONCLUSIONS
  Defective TLR7 and TLR9 signaling in CVID B cells and pDCs, coupled with deficient IFN-alpha, impairs CVID B cell functions and prevents TLR-mediated augmentation of humoral immunity in vivo.
authors: Department of Medicine, Mount Sinai Medical Center, New York, NY 10029, USA.
authors: Joyce E
authors: JE
authors: Yu
authors: Adina K
authors: AK
authors: Knight
authors: Lin
authors: L
authors: Radigan
authors: Thomas U
authors: TU
authors: Marron
authors: Li
authors: L
authors: Zhang
authors: Silvia
authors: S
authors: Sanchez-Ramón
authors: Charlotte
authors: C
authors: Cunningham-Rundles
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D017074:Common Variable Immunodeficiency / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000276:immunology; D016898:Interferon-alpha / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D016899:Interferon-beta / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011070:Poly I-C / Q000494:pharmacology; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D055815:Young Adult
chemical_list: D016898:Interferon-alpha; D015850:Interleukin-6; D008024:Ligands; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D006151:Guanosine; D018664:Interleukin-12; D016899:Interferon-beta; C068562:loxoribine; D011070:Poly I-C