loxoribine and Common-Variable-Immunodeficiency

Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia, reduced numbers of peripheral blood isotype-switched memory B cells, and loss of plasma cells.. 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.. 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.. 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.. 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.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; B-Lymphocyte Subsets; Cell Differentiation; Cell Proliferation; Common Variable Immunodeficiency; Dendritic Cells; Female; Fibroblasts; Guanosine; Humans; Immunoglobulin Class Switching; Interferon-alpha; Interferon-beta; Interleukin-12; Interleukin-6; Leukocytes, Mononuclear; Ligands; Lymphocyte Activation; Male; Middle Aged; Poly I-C; Toll-Like Receptor 7; Toll-Like Receptor 9; Tumor Necrosis Factor-alpha; Young Adult