Toll-like receptor 7 and 9 defects in common variable immunodeficiency - 20/08/11
Reprint requests: Charlotte Cunningham-Rundles, MD, PhD, Departments of Medicine and Pediatrics, Immunology Institute, Mount Sinai School of Medicine, 1425 Madison Ave, New York, NY 10029.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-⍺, IL-6, and IL-12 production in response to TLR1-9 ligands and measured IFN-⍺ production by TLR7-stimulated PBMCs and isolated plasmacytoid dendritic cells (pDCs). IFN-β 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-⍺. Reconstituting IFN-⍺ 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-⍺, IL-6, and IL-12; TLR3-mediated expression of IFN-β by CVID fibroblasts was normal.
Conclusion |
Defective TLR7 and TLR9 signaling in CVID B cells and pDCs, coupled with deficient IFN-⍺, impairs CVID B cell functions and prevents TLR-mediated augmentation of humoral immunity in vivo.
Le texte complet de cet article est disponible en PDF.Key words : Common variable immunodeficiency, Toll-like receptor, memory B cell, plasmacytoid dendritic cell, isotype switch, IFN-⍺
Abbreviations used : AID, BCR, CpG-ODN, CVID, MyD88, pDC, Poly(I:C), TLR, TRIF
Plan
| Supported by the National Institutes of Health grants AI-101093, AI-467320, and AI-48693 and National Institute of Allergy and Infectious Diseases contract 03-22 (C.C.-R.). |
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| Disclosure of potential conflict of interest: C. Cunningham-Rundles is a medical advisor for Talecris and Baxter and receives grant support from the National Institutes of Health. A. K. Knight receives research support from Genentech, AstraZeneca, Novartis, Wyeth, Schering-Plough, UCB Inc, and GlaxoSmithKline. The rest of the authors have declared that they have no conflict of interest. |
Vol 124 - N° 2
P. 349 - août 2009 Retour au numéro
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