Toll-like receptors in systemic lupus erythematosus; prospects for therapeutic intervention☆
Section snippets
Mechanisms for breaching self-tolerance to nucleic acids
The immunogenicity of self-DNA is minimized by CpG suppression, CpG methylation, and inhibitory motifs that act together with the inaccessibility to TLRs, which are sequestered within the endosomal compartment [2]. In SLE, the immunogenicity of nucleic acids nevertheless can be enhanced by several processes. The release of immunogenic nucleic acid into the environment results from cell death through necrosis. In fact, many factors such as UV light, mitochondrial hyperpolarization, and ATP
Anti-nuclear immune complex, interferon-α, and TLR activation contribute to a self-sustaining cycle of autoimmunity
How do self-DNA and self-RNA, released into the circulation, enter cells to activate TLR receptors? One possibility is suggested by the ‘dual receptor paradigm’ [2], [15]. By this concept, nucleic acid-containing immune complexes are engaged simultaneously by both a specific receptor on cell surfaces that recognizes immune complex, such as Fcγ receptors (FcγR) and a TLR. For instance, nucleic acids complexed with IgG autoantibody bind to FcγRIIa (CD32) on dendritic cells and then are
TLR-9 deficiency in vivo: friend or foe in SLE?
While there are reports that genetic deficiency of TLR-7 or its signaling adaptor, MyD88, confers protection from autoimmunity in lupus-prone mice [20], [21], the effect of TLR-9 deficiency on the lupus phenotype remains controversial [21], [22], [23], [24], [25], [26], [27], [28]. A study in partially backcrossed, TLR-9 deficient MRL-Faslpr lupus mice showed that while anti-dsDNA antibody titers were decreased, kidney disease and overall survival were unaffected [22]. In FcγRIIB-deficient,
Potential role for TLR-7 and TLR-9 in human SLE
Patients with SLE have increased blood levels of IFN-α, which correlates with disease activity [32]. Moreover, IFN-α therapy used to treat patients with malignancies or chronic viral infection is frequently associated with the development of lupus-like symptoms, including anti-DNA antibodies [33]. Several studies have demonstrated that anti-nucleic acid immune complexes, isolated from the sera of SLE patients, stimulate pDCs to produce IFN-α. Means et al. [34] have reported that DNA-containing
Conclusion
Over the last several years, new emphasis has been placed on the role of the innate immune system in SLE. Nucleic acids-containing immune complexes are now known to activate the innate immune response as well as adaptive response. In addition, it is appreciated that endogenous ligands may lead to TLR activation and promote the generation of autoantibodies against nuclear components. Evidence in support of a role for TLR-7 and TLR-9 in autoimmunity also has emerged from studies of human SLE.
Take-home messages
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Similar to the adaptive immune system, the innate immune system may contribute importantly to the immunopathogenesis of systemic lupus erythematosus (SLE).
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Nucleic acids are rendered immunogenic through hypomethylation, oxidation, and high content CpG.
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Both nucleic acids, RNA and DNA, interact with TLR-7 and TLR-9, respectively, to cause autoimmunity.
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TLR signaling in T cells leads to production of Th1 cytokines, and in B cells to cell proliferation, differentiation, and immunoglobulin switching.
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Supported by grants from the NIH, the Alliance for Lupus Research, and the American College of Rheumatology.