Targeting Toll-like receptor signaling in plasmacytoid dendritic cells and autoreactive B cells as a therapy for lupus - PubMed (original) (raw)

Review

Targeting Toll-like receptor signaling in plasmacytoid dendritic cells and autoreactive B cells as a therapy for lupus

Petar S Lenert. Arthritis Res Ther. 2006.

Abstract

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.

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Figures

Figure 1

Figure 1

The innate model of lupus pathogenesis: central role of TLR-activated MZ-B cells and pDCs. Presented is a schematic overview of innate activation of MZ-B cells and pDCs with hypomethylated CpG-DNA or microbial DNA. Exposure to self CpG-DNA derived from apoptotic cells initially engages anti-dsDNA reactive low-affinity MZ-B cells. Endosomal delivery of CpG-DNA leads to TLR9-dependent and TLR9-independent activation of MZ-B cells, resulting in enhanced MHC class II, CD40, and CD86 upregulation and more efficient antigen processing/peptide presentation to histone-specific autoreactive T cells. Maturation of MZ-B cells drives secretion of anti-dsDNA antibodies, which then combine with freely circulating dsDNA to promote FcγR-dependent endogenous IFN-α secretion by pDCs (as well as activation of RF-specific B cells). IFN-α produced by pDCs, through a positive feedback loop, further enhances MZ-B cell activation and autoantibody secretion. IFN-α additionally diverts some autoreactive B cell precursors toward the follicular B cell pathway, activates T cells, and promotes development of myeloid dendritic cells (mDCs). Activated T cells direct isotype switching and affinity maturation in autoreactive B cells dependent on CD40/CD40L interaction and IFN-γ secretion. Independently of T cells, pDC-derived IFN-α can additionally help CpG-DNA activated B cells to express T-bet, a key transcription factor that induces isotype switch to complement fixing IgG2a in mice. Myeloid dendritic cell derived BAFF may further promote survival and differentiation of autoreactive B cells. Higher affinity microbial CpG-DNA released during infections directly triggers MZ-B cells and pDC activation, causing flares of lupus. ds, double stranded; IFN, interferon; MHC, major histocompatibility complex; MZ, marginal zone; pDC, plasmacytoid dendritic cell; TCR, T-cell receptor; TLR, Toll-like receptor.

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