21235537

pubmed:Citation

3

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.

eng

IM

MEDLINE

1365-2249

© 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.

163

Y

pubmed-meshheading:21235537-Animals, pubmed-meshheading:21235537-Antibodies, Anti-Idiotypic, pubmed-meshheading:21235537-Apoptosis, pubmed-meshheading:21235537-B-Lymphocytes, pubmed-meshheading:21235537-Cell Proliferation, pubmed-meshheading:21235537-Drug Synergism, pubmed-meshheading:21235537-Female, pubmed-meshheading:21235537-Interleukin-6, pubmed-meshheading:21235537-Lupus Erythematosus, Systemic, pubmed-meshheading:21235537-Male, pubmed-meshheading:21235537-Membrane Glycoproteins, pubmed-meshheading:21235537-Mice, pubmed-meshheading:21235537-Mice, Inbred C57BL, pubmed-meshheading:21235537-Mice, Knockout, pubmed-meshheading:21235537-Mice, Transgenic, pubmed-meshheading:21235537-Oligodeoxyribonucleotides, pubmed-meshheading:21235537-Quinolines, pubmed-meshheading:21235537-Receptors, Antigen, B-Cell, pubmed-meshheading:21235537-Signal Transduction, pubmed-meshheading:21235537-Thiazoles, pubmed-meshheading:21235537-Toll-Like Receptor 7, pubmed-meshheading:21235537-Toll-Like Receptor 9

Engagement of the B cell receptor for antigen differentially affects B cell responses to Toll-like receptor-7 agonists and antagonists in BXSB mice.

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