Activation of Autoreactive B Cells by Endogenous TLR7 and TLR3 RNA Ligands

Abstract

Background: Low affinity autoreactive B cells are activated by co-engagement of the BCR and TLRs. Results: Endogenous RNAs that are associated with autoantigens are ligands for TLR7 and TLR3. Conclusion: Sequence and structure of RNA determines recognition by TLRs. Significance: B cells are activated by RNA delivered through the BCR, and the sequences of RNAs define their stimulatory capacity as TLR ligands.

A TLR9-dependent checkpoint governs B cell responses to DNA-containing antigens

“…Additionally, in vivo and in vitro data suggest that RNA-sensing receptors, such as TLR7, do not promote post-proliferative cell death, but instead foster plasma cell differentiation (75). Thus, activation via these pathways may require concomitant TLR9 signals to control the overall response (30,33,76). Indeed, in mouse models in which TLR7 plays a critical role, TLR9 haploinsufficiency exacerbates disease (15,16,(18)(19)(20).…”

“…AM14 mice were maintained at the University of Massachusetts. Tlr9 -/-mice were provided by P. (38,39,44,76,80). Briefly, B cells were stimulated with 10 micrograms/ml F(ab)′ 2 fragments of goat antiIgM (Jackson ImmunoResearch Laboratories); 1 μg/ml anti-CD40 (clone HM40-3; BD); and 1 μM CpG DNA (ODN 1826; InvivoGen).…”

Low TLR7 gene expression in atherosclerotic plaques is associated with major adverse cardio- and cerebrovascular events

“…The first TLR7-specific ligands to be identified were viral, single-stranded RNA, but several mammalian endogenous ligands have recently been identified, such as RNA from apoptotic cells, miRNA and extracellular RNA from necrotic cells. 23 In atherogenesis, RNA from apoptotic and necrotic cells and from tissue damage could be a plausible source of ligands. We were interested in determining whether the immunosuppressive response originates from T cells or macrophages.…”

TLR8 on dendritic cells and TLR9 on B cells restrain TLR7-mediated spontaneous autoimmunity in C57BL/6 mice

“…Human endosomal TLRs consist of TLR3, which senses viral double-stranded RNA (dsRNA) (7), TLR7 and TLR8, which recognize viral single-stranded RNA (8)(9)(10), and TLR9, which detects bacterial and viral unmethylated CpGcontaining DNA motifs (11). Interestingly, these endosomal TLRs are also able to detect self-nucleic acids (12)(13)(14). Although the endosomal localization isolate TLR3, TLR7, TLR8, and TLR9 away from self-nucleic acids in the extracellular space, still self-RNA or -DNA can become a potent trigger of cell activation when transported into TLR-containing endosomes, and such recognition can result in sterile inflammation and autoimmunity, including SLE (4,15,16).…”