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Toll-like receptor 7 and 9 defects in common variable immunodeficiency.
J Allergy Clin Immunol 2009; 124(2):349-56, 356.e1-3JA

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.

CONCLUSION

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+Show Affiliations

Department of Medicine, Mount Sinai Medical Center, New York, NY 10029, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

19592080

Citation

Yu, Joyce E., et al. "Toll-like Receptor 7 and 9 Defects in Common Variable Immunodeficiency." The Journal of Allergy and Clinical Immunology, vol. 124, no. 2, 2009, pp. 349-56, 356.e1-3.
Yu JE, Knight AK, Radigan L, et al. Toll-like receptor 7 and 9 defects in common variable immunodeficiency. J Allergy Clin Immunol. 2009;124(2):349-56, 356.e1-3.
Yu, J. E., Knight, A. K., Radigan, L., Marron, T. U., Zhang, L., Sanchez-Ramón, S., & Cunningham-Rundles, C. (2009). Toll-like receptor 7 and 9 defects in common variable immunodeficiency. The Journal of Allergy and Clinical Immunology, 124(2), pp. 349-56, 356.e1-3. doi:10.1016/j.jaci.2009.05.019.
Yu JE, et al. Toll-like Receptor 7 and 9 Defects in Common Variable Immunodeficiency. J Allergy Clin Immunol. 2009;124(2):349-56, 356.e1-3. PubMed PMID: 19592080.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Toll-like receptor 7 and 9 defects in common variable immunodeficiency. AU - Yu,Joyce E, AU - Knight,Adina K, AU - Radigan,Lin, AU - Marron,Thomas U, AU - Zhang,Li, AU - Sanchez-Ramón,Silvia, AU - Cunningham-Rundles,Charlotte, Y1 - 2009/07/09/ PY - 2009/02/27/received PY - 2009/05/10/revised PY - 2009/05/12/accepted PY - 2009/7/14/entrez PY - 2009/7/14/pubmed PY - 2009/9/9/medline SP - 349-56, 356.e1-3 JF - The Journal of allergy and clinical immunology JO - J. Allergy Clin. Immunol. VL - 124 IS - 2 N2 - 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. CONCLUSION: 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. SN - 1097-6825 UR - https://www.unboundmedicine.com/medline/citation/19592080/Toll_like_receptor_7_and_9_defects_in_common_variable_immunodeficiency_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-6749(09)00810-0 DB - PRIME DP - Unbound Medicine ER -