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Published on: June 22, 2016
TLR9 activation is defective in common variable immune deficiency
Charlotte Cunningham-Rundles1, Lin Radigan, Adina K Knight
1Department of Medicine and the Immunobiology Center, Mount Sinai Medical Center, New York, NY 10029, USA. Charlotte.Cunningham-Rundles@MSSM.edu
Insights
Common variable immune deficiency (CVID) involves impaired B cell responses due to Toll-like receptor 9 (TLR9) defects. These defects hinder innate immune activation by CpG-DNA, affecting B cell function and plasmacytoid dendritic cell responses.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Common variable immune deficiency (CVID) is a primary immune disorder marked by low immunoglobulin levels and impaired B cell function.
- Genetic underpinnings for most CVID cases remain elusive, despite known defects in T, B, and dendritic cells.
Purpose of the Study:
- To investigate the role of Toll-like receptor 9 (TLR9) in B cell and plasmacytoid dendritic cell activation in CVID patients.
- To identify potential molecular defects in TLR9 signaling pathways contributing to CVID pathogenesis.
Main Methods:
- Analysis of B cell and plasmacytoid dendritic cell activation in response to CpG-DNA, a TLR9 ligand.
- Assessment of cell surface marker expression (e.g., CD86), cytokine production (IL-6, IL-10, IFN-alpha), and TLR9 expression (protein and mRNA) in CVID and healthy controls.
- Sequencing of TLR9 gene to identify mutations or polymorphisms.
Main Results:
- CVID B cells exhibited defective upregulation of CD86 and impaired production of IL-6 and IL-10 upon CpG-DNA stimulation.
- Reduced expression of TLR9 protein and mRNA was observed in CVID B cells.
- CpG-DNA-activated CVID plasmacytoid dendritic cells produced lower levels of IFN-alpha, despite normal intracellular TLR9 levels.
- No mutations or polymorphisms in the TLR9 gene were identified in CVID patients.
Conclusions:
- Broad defects in TLR9 activation pathways are present in CVID, impacting both B cells and plasmacytoid dendritic cells.
- These TLR9 defects likely contribute to impaired innate immune responses initiated by CpG-DNA, leading to compromised B cell function and potentially altered dendritic cell activity in CVID.
- The identified TLR9 activation defects offer potential therapeutic targets for managing CVID, independent of specific genetic mutations.
Abstract:
Common variable immune deficiency (CVID) is a primary immune deficiency characterized by low levels of serum immune globulins, lack of Ab, and reduced numbers of CD27+ memory B cells. Although T, B, and dendritic cell defects have been described, for the great majority, genetic causes have not been identified. In these experiments, we investigated B cell and plasmacytoid dendritic cell activation induced via TLR9, an intracellular recognition receptor that detects DNA-containing CpG motifs from viruses and bacteria. CpG-DNA activates normal B cells by the constitutively expressed TLR9, resulting in cytokine secretion, IgG class switch, immune globulin production, and potentially, the preservation of long-lived memory B cells. We found that CpG-DNA did not up-regulate expression of CD86 on CVID B cells, even when costimulated by the BCR, or induce production of IL-6 or IL-10 as it does for normal B cells. TLR9, found intracytoplasmically and on the surface of oligodeoxynucleotide-activated normal B cells, was deficient in CVID B cells, as was TLR9 mRNA. TLR9 B cell defects were not related to proportions of CD27+ memory B cells. CpG-activated CVID plasmacytoid dendritic cells did not produce IFN-alpha in normal amounts, even though these cells contained abundant intracytoplasmic TLR9. No mutations or polymorphisms of TLR9 were found. These data show that there are broad TLR9 activation defects in CVID which would prevent CpG-DNA-initiated innate immune responses; these defects may lead to impaired responses of plasmacytoid dendritic cells and loss of B cell function.
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