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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
Journal of Immunology (Baltimore, Md. : 1950)
|January 21, 2006
Summary
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.