Targeting Toll-like receptor signaling in plasmacytoid dendritic cells and autoreactive B cells as a therapy for lupus.
This review focuses on the role of Toll-like receptors (TLRs) in lupus and on possibilities to treat lupus using TLR modulating inhibitory oligodeoxynucleotides (INH-ODNs). TLRs bridge innate and adaptive immune responses and may play an important role in the pathogenesis of systemic lupus erythematosus. Of particular interest are TLR3, -7, -8, and -9, which are localized intracellularly. These TLRs recognize single-stranded or double-stranded RNA or hypomethylated CpG-DNA. Exposure to higher order CpG-DNA ligands or to immune complexed self-RNA triggers activation of autoreactive B cells and plasmacytoid dendritic cells. INH-ODNs were recently developed that block all downstream signaling events in TLR9-responsive cells. Some of these INH-ODNs can also target TLR7 signaling pathways. Based on their preferential cell reactivity, we classify INH-ODNs into class B and class R. Class B ('broadly reactive') INH-ODNs target a broad range of TLR-expressing cells. Class R ('restricted') INH-ODNs easily form DNA duplexes or higher order structures, and are preferentially recognized by autoreactive B cells and plasmacytoid dendritic cells, rather than by non-DNA specific follicular B cells. Both classes of INH-ODNs can block animal lupus. Hence, therapeutic application of these novel INH-ODNs in human lupus, particularly class R INH-ODNs, may result in more selective and disease-specific immunosuppression.
Lenert
Petar S
PS
Division of Rheumatology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA. petar-lenert@uiowa.edu
D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism*; D006801:Humans; D008177:Lupus Vulgaris / Q000188:drug therapy*; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D010950:Plasma Cells / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics* / Q000378:metabolism
D016376:Oligonucleotides, Antisense; D051193:Toll-Like Receptors