Journal article
Engagement of the B cell receptor for antigen differentially affects B cell responses to Toll-like receptor-7 agonists and antagonists in BXSB mice
Clinical and experimental immunology, Vol.163(3), pp.392-403
2011
DOI: 10.1111/j.1365-2249.2010.04307.x
PMCID: PMC3048624
PMID: 21235537
Abstract
Nucleic acid sensors of the Toll-like receptor (TLR) family play a well-established role in the pathogenesis of lupus. This is particularly true for a single-stranded RNA-sensing TLR-7 receptor, as lupus mice lacking TLR-7 show ameliorated disease. Cytosine-guanosine dinucleotide (CpG)-DNA-sensing TLR-9, conversely, has a complex regulatory role in systemic lupus erythematosus (SLE). Much less is known about whether signals through the B cell receptor for antigen (BCR) may affect the ability of B cells to respond to suboptimal TLR-7 agonists and antagonists. We studied this question in prediseased BXSB male and female B cells. We found that male B cells responded more vigorously to numerous TLR-7 ligands and this responsiveness was enhanced further upon co-engagement of the BCR. This synergy was seen primarily with the interleukin (IL)-6 secretion. A number of 32-mer inhibitory oligonucleotides (INH-ODNs) with a nuclease-resistant phosphorothioate backbone were capable of blocking TLR-7, but not BCR-induced B cell activation, with an inhibitory concentration (IC)(50) of approximately 100 nm. Surprisingly, while the presence of a single TGC motif at the 5' end of an ODN did not increase its inhibitory capacity, INH-ODNs containing multiple TGC motifs had greater inhibitory potency. When BCR and TLR-7 were co-engaged, INH-ODNs showed a differential effect on B cell activation. Whereas apoptosis protection and G1-M entry completely escaped suppression, IL-6 secretion remained sensitive to inhibition, although with a 10-fold lower potency. Our results suggest that while TLR-7 antagonists may be considered as lupus therapeutics, simultaneous co-engagement of the TLR-7 and BCR might favour autoreactive B cell survival. This hypothesis needs further experimental validation.
Details
- Title: Subtitle
- Engagement of the B cell receptor for antigen differentially affects B cell responses to Toll-like receptor-7 agonists and antagonists in BXSB mice
- Creators
- T LAYER - Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, United StatesA STEELE - Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, United StatesJ. A GOEKEN - Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, United StatesS FLEENOR - Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, United StatesP LENERT - Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, United States
- Resource Type
- Journal article
- Publication Details
- Clinical and experimental immunology, Vol.163(3), pp.392-403
- Publisher
- Blackwell
- DOI
- 10.1111/j.1365-2249.2010.04307.x
- PMID
- 21235537
- PMCID
- PMC3048624
- ISSN
- 0009-9104
- eISSN
- 1365-2249
- Language
- English
- Date published
- 2011
- Academic Unit
- Pathology; Immunology; Internal Medicine
- Record Identifier
- 9984094875102771
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