Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus

Kono, Dwight H.; Haraldsson, M. Katarina; Lawson, Brian R.; Pollard, K. Michael; Koh, Yi Ting; Du, Xin; Arnold, Carrie; Baccalà, Roberto; Silverman, Gregg J.; Beutler, Bruce; Theofilopoulos, Argyrios N.

doi:10.1073/pnas.0905441106

Cited by 140 publications

(122 citation statements)

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“…Similarly, antigenic cargo containing nucleic acids was found to promote B-cell proliferation in a TLR9-or TLR7-dependent manner, with this effect enhanced by type I IFN signaling (9,12,13). The contribution of nucleic acid-sensing TLRs to systemic autoimmunity was further corroborated by studies in lupus-predisposed mice lacking or overexpressing TLR7 and/or TLR9 (14)(15)(16)(17)(18)(19)(20), and in Unc93b1 (3d) mutant mice in which signaling by endosomal TLRs is extinguished (21).…”

supporting

confidence: 53%

“…CD8α + cDCs have several functional properties of potential relevance to autoimmunity, including ingestion of materials from dying cells, antigen cross-presentation, and production of IL-12, a cytokine involved in Th1 differentiation (49). Regardless, however, these cells are unlikely to promote disease, because they do not express TLR7, the engagement of which appears to be a major pathogenic contributor in several lupus-predisposed mouse strains (14,15,21), and do not produce significant amounts of type I IFNs in response to ligands or viruses that engage endosomal TLRs or cytosolic sensors for nucleic acids (50)(51)(52)(53)(54). Similarly, the partial defects in TLR7 and TLR9 responses by the IRF8-deficient CD4 + and CD4 -CD8α -cDCs are likely insufficient to explain disease reduction, given that these subsets have been reported to produce meager amounts of type I IFNs when stimulated with endosomal TLR ligands, including lupus-associated nucleic acid-containing immune complexes (53).…”

Section: Discussionmentioning

confidence: 99%

“…These findings support the critical role of type I IFN production by pDCs in systemic autoimmunity. Disease reduction in Slc15a4 mutant C57BL/6-Fas lpr mice, as well as in Unc93b1 mutant C57BL/6-Fas lpr mice (21), is at variance with the reported disease enhancement in IFNAR-deficient MRL-Fas lpr mice (58). There is no clear explanation for this variance, but possibilities include genetic contributions beyond the Fas defect, exemplified by differences in disease severity between these strains (59), and complete absence of signaling in Ifnar1-deleted mice versus pDC-specific absence of type I IFN production in Slc15a4 mutant mice.…”

Section: Discussionmentioning

confidence: 99%

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Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Baccalà¹,

Gonzalez-Quintial²,

Blasius

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In vitro evidence suggests that plasmacytoid dendritic cells (pDCs) are intimately involved in the pathogenesis of lupus. However, it remains to be determined whether these cells are required in vivo for disease development, and whether their contribution is restricted to hyperproduction of type I IFNs. To address these issues, we created lupus-predisposed mice lacking the IFN regulatory factor 8 (IRF8) or carrying a mutation that impairs the peptide/histidine transporter solute carrier family 15, member 4 (SLC15A4). IRF8-deficient NZB mice, lacking pDCs, showed almost complete absence of anti-nuclear, anti-chromatin, and anti-erythrocyte autoantibodies, along with reduced kidney disease. These effects were observed despite normal B-cell responses to Toll-like receptor (TLR) 7 and TLR9 stimuli and intact humoral responses to conventional T-dependent and -independent antigens. Moreover, Slc15a4 mutant C57BL/6-Fas lpr mice, in which pDCs are present but unable to produce type I IFNs in response to endosomal TLR ligands, also showed an absence of autoantibodies, reduced lymphadenopathy and splenomegaly, and extended survival. Taken together, our results demonstrate that pDCs and the production of type I IFNs by these cells are critical contributors to the pathogenesis of lupus-like autoimmunity in these models. Thus, IRF8 and SLC15A4 may provide important targets for therapeutic intervention in human lupus.E xtensive evidence suggests that type I IFNs are major pathogenic effectors in lupus-associated systemic autoimmunity. A well-documented pattern of expression of type I IFN-inducible genes occurs in peripheral blood mononuclear cells of patients with systemic lupus erythematosus (SLE) (1-3), and reduced disease is observed in some lupus-predisposed mice that either lack the common receptor (IFNAR) for these cytokines (4, 5) or have been treated with IFNAR-blocking antibody (6). Consequently, attention has focused on defining the cell subsets and signaling processes involved in type I IFN production, the mechanisms by which these mediators accelerate disease, and approaches to interfere with these pathogenic events.Early in vitro studies showed that type I IFN production can be induced in normal blood leukocytes by SLE autoantibodies complexed with nucleic acid-containing apoptotic/necrotic cell material, and further work demonstrated that this activity is sensitive to RNase and DNase digestion (7,8). These results were integrated in a more comprehensive scheme following the demonstration that type I IFN induction by these complexes is mediated by the engagement of endosomal Toll-like receptors (TLRs) (9-11). Similarly, antigenic cargo containing nucleic acids was found to promote B-cell proliferation in a TLR9-or TLR7-dependent manner, with this effect enhanced by type I IFN signaling (9, 12, 13). The contribution of nucleic acid-sensing TLRs to systemic autoimmunity was further corroborated by studies in lupus-predisposed mice lacking or overexpressing TLR7 and/or TLR9 (14-20), and in Unc93b1 (3d) mutant mice i...

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supporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Baccalà¹,

Gonzalez-Quintial²,

Blasius

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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123

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“…MyD88-deficiency abrogates most attributes of lupus in several lupus-prone mouse strains (19,(27)(28)(29). Moreover, deficiency for Unc93B1, a multipass transmembrane protein that controls trafficking of TLRs from the endoplasmic reticulum to endolysosomes and is required for nucleic acid-sensing TLR function (30), also abrogates many clinical parameters of disease in mouse lupus strains, suggesting that endosomal TLRs are critical in this disease (31). Interestingly, TLR9 competes with TLR7 for Unc93B1-dependent trafficking and predominates over TLR7 (32).…”

mentioning

confidence: 99%

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

Desnues

Macedo

Roussel‐Queval

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

111

105

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Systemic lupus erythematosus (SLE) is a complex autoimmune disease with diverse clinical presentations characterized by the presence of autoantibodies to nuclear components. Toll-like receptor (TLR)7, TLR8, and TLR9 sense microbial or endogenous nucleic acids and are implicated in the development of SLE. In mice TLR7-deficiency ameliorates SLE, but TLR8-or TLR9-deficiency exacerbates the disease because of increased TLR7 response. Thus, both TLR8 and TLR9 control TLR7 function, but whether TLR8 and TLR9 act in parallel or in series in the same or different cell types in controlling TLR7-mediated lupus remains unknown. Here, we reveal that double TLR8/9-deficient (TLR8/9 −/− ) mice on the C57BL/6 background showed increased abnormalities characteristic of SLE, including splenomegaly, autoantibody production, frequencies of marginal zone and B1 B cells, and renal pathology compared with single TLR8 −/− or TLR9 −/− mice. On the cellular level, TLR8 −/− and TLR8/ 9 −/− dendritic cells were hyperesponsive to TLR7 ligand R848, but TLR9 −/− cells responded normally. Moreover, B cells from TLR9 −/− and TLR8/9 −/− mice were hyperesponsive to R848, but TLR8 −/− B cells were not. These results reveal that TLR8 and TLR9 have an additive effect on controlling TLR7 function and TLR7-mediated lupus; however, they act on different cell types. TLR8 controls TLR7 function on dendritic cells, and TLR9 restrains TLR7 response on B cells. knockout mice | innate immunity | endosomal TLRs

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“…However, sialylation of C. jejuni LOS induces a strong type I IFN response, which may increase BCR signaling in B cells (47) that have a low affinity for self-glycolipids, resulting in full-blown B cell activation and proliferation. In this respect, the endosomal TLR pathway could be regarded as the Achilles' heel by producing type I IFN that promotes B cell autoimmunity, a concept previously proposed for lupus (48,49). In addition, the brief persistence of the ganglioside-mimicking epitope in LOS and the resulting temporary activation of DCs might explain the transitory nature of the Ab response in GBS.…”

Section: Discussionmentioning

confidence: 99%

Sialylation of Campylobacter jejuni Endotoxin Promotes Dendritic Cell–Mediated B Cell Responses through CD14-Dependent Production of IFN-β and TNF-α

Huizinga

Rijs

Bajramović

et al. 2013

The Journal of Immunology

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Campylobacter jejuni is the most common bacterial cause of human gastroenteritis and often precedes development of Guillain–Barré syndrome (GBS), a life-threatening paralytic disease. The incorporation of the carbohydrate sialic acid into C. jejuni lipooligosaccharides (LOS) is associated with increased severity of gastroenteritis and with induction of GBS; however, the underlying mechanisms remain completely unknown. In this study, we demonstrate that sialic acids in C. jejuni endotoxin enhance the rapid production of IFN-β and TNF-α by human dendritic cells (DCs). Using neutralizing Abs and receptors it was shown that these DC-derived cytokines promote the proliferation of human mucosal B cells in a T cell–independent manner. The production of both IFN-β and TNF-α by DCs in response to LOS requires CD14, and the amplified response of DCs to sialylated C. jejuni LOS is CD14 dependent. Together, these results indicate that sialylation of C. jejuni LOS increases DC activation and promotes subsequent B cell responses through CD14-driven production of IFN-β and TNF-α. This enhanced DC/B cell response may explain the increased pathogenicity of sialylated C. jejuni and may be key to the initiation of B cell–mediated autoimmunity in GBS.

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Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus

Cited by 140 publications

References 50 publications

Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

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

Sialylation of Campylobacter jejuni Endotoxin Promotes Dendritic Cell–Mediated B Cell Responses through CD14-Dependent Production of IFN-β and TNF-α

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