Nucleic acid-stimulated antigen-presenting cells trigger T cells to induce disease in a rat transfer model of inflammatory arthritis

Hoffmann, Markus; Skriner, Karl; Herman, Sonja; Baumann, Christoph; Steiner, Carl-Walter; Ospelt, Caroline; Meyer, Brigitte; Gleiß, Andreas; Pfatschbacher, J; Niederreiter, Birgit; Tuncel, Jonatan; Zanoni, Gerald; Steiner, Guenter

doi:10.1016/j.jaut.2011.02.007

Cited by 39 publications

(41 citation statements)

References 59 publications

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“…Confirming these observations, treatment with endosomal inhibitor and/or RNase/DNase ameliorate rat pristine-induced arthritis through blocking TLR7 and TLR9 ligation. 34 Interestingly, we found that TLR7 endogenous ligands were undetectable in RA plasma and were only expressed in RA SF. This may be due to ssRNA released from the necrotic SF cells which remains stagnated until removed by arthrocentesis, while in RA plasma ssRNA from necrotic cells is removed in the blood filtration process, hence, making it more difficult to maintain ssRNA levels.…”

Section: Discussionmentioning

confidence: 77%

Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNFα in monocytes

Chamberlain

Kim

Vila

et al. 2013

Annals of the Rheumatic Diseases

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Objective The aim of the study was to characterize the expression, regulation and pathogenic role of TLR7 and TLR8 in rheumatoid arthritis (RA). Methods Expression of TLR7 and TLR8 was demonstrated in RA, osteoarthritis (OA) and normal (NL) synovial tissues (ST) employing immunohistochemistry. We next examined the mechanism by which TLR7 and TLR8 ligation mediates proinflammatory response by Western blot analysis and ELISA. Expression of TLR7 and TLR8 in RA monocytes was correlated to disease activity score (DAS28) and TNF-α levels. Further the effect of TLR7 ligation in RA monocytes was determined on synovial fluid (SF) mediated TNF-α transcription. Results TLR7/TLR8 are predominately expressed in RA ST lining and sublining macrophages. We show that NF-κB and/or PI3K pathways are essential for TLR7/TLR8 induction of proinflammatory factors in RA peripheral blood (PB) differentiated macrophages. Expression of TLR7 in RA monocytes shows a strong correlation with DAS28 and TNF-α levels. In contrast, expression of TLR8 in these cells does not correlate with DAS28, TLR7 or TNF-α levels. We further demonstrate that RNA from RA SF but not RA or NL plasma could modulate TNF-α transcription from RA monocytes that can be downregulated by antagonizing TLR7 ligation or degradation of single stand (ss) RNA. Thus, ssRNA present in RA SF may function as a potential endogenous ligand for TLR7. Conclusions These results suggest that expression of TLR7 but not TLR8 may be a predictor for RA disease activity and anti-TNF-α responsiveness, and targeting TLR7 may suppress chronic progression of RA.

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Section: Discussionmentioning

confidence: 77%

Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNFα in monocytes

Chamberlain

Kim

Vila

et al. 2013

Annals of the Rheumatic Diseases

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“…Pristane-primed T cells have been shown to respond in vitro to challenge with hnRNP-A2 (42). However, whether hnRNP-A2 acts only as a T cell Ag is unclear because this nucleic acid-bound protein also can stimulate T cells through activation of TLRs in Mf (16). We also found several Ii-derived peptides among the peptides that were eluted from RT1-B of DA, DA.1FR9, and DA.1UR10.…”

Section: Discussionmentioning

confidence: 81%

“…Additionally, rats with PIA are positive for rheumatoid factor, and the clinical disease is preceded by a marked increase of acute-phase proteins in the blood (14,15). CD4 T cells from rats with PIA induce arthritis when transferred to MHC-syngenic recipients (11,16), and the onset and severity of the disease are influenced by genes within or close to the MHC locus (13,17). However, so far there has been no evidence that polymorphisms in the MHC-II genes, or in any other genes in the MHC region, affect the development of PIA.…”

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confidence: 99%

Positional Identification ofRT1-B(HLA-DQ) as Susceptibility Locus for Autoimmune Arthritis

Haag

Tuncel

Thordardottir

et al. 2015

The Journal of Immunology

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Rheumatoid arthritis (RA) is associated with amino acid variants in multiple MHC molecules. The association to MHC class II (MHC-II) has been studied in several animal models of RA. In most cases these models depend on T cells restricted to a single immunodominant peptide of the immunizing Ag, which does not resemble the autoreactive T cells in RA. An exception is pristane-induced arthritis (PIA) in the rat where polyclonal T cells induce chronic arthritis after being primed against endogenous Ags. In this study, we used a mixed genetic and functional approach to show that RT1-Ba and RT1-Bb (RT1-B locus), the rat orthologs of HLA-DQA and HLA-DQB, determine the onset and severity of PIA. We isolated a 0.2-Mb interval within the MHC-II locus of three MHC-congenic strains, of which two were protected from severe PIA. Comparison of sequence and expression variation, as well as in vivo blocking of RT1-B and RT1-D (HLA-DR), showed that arthritis in these strains is regulated by coding polymorphisms in the RT1-B genes. Motif prediction based on MHC-II eluted peptides and structural homology modeling suggested that variants in the RT1-B P1 pocket, which likely affect the editing capacity by RT1-DM, are important for the development of PIA.

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“…Finally, it has recently been shown that heterogeneous nuclear ribonucleoprotein (hbRNP), an RNA and DNA-binding protein that is a target of most nuclear antigen-specific T and B cells in systemic autoimmune diseases but also in human rheumatoid arthritis and in pristine-induced arthritis in rats, triggers TLR7-and TLR9-mediated activation of arthritogenic APCs, which activate pathogenic T cells 60 .…”

Section: The Link Between Pamps and Autoimmunitymentioning

confidence: 99%

TLR-dependent T cell activation in autoimmunity

2011

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Autoimmune disease can develop as a result of a breakdown in immunological tolerance, leading to the activation of self-reactive T cells. There is an established link between infection and human autoimmune diseases. Furthermore, experimental autoimmune diseases can be induced by immunization with autoantigens that are administered together with complete Freund's adjuvant containing killed Mycobacteria tuberculosis, which in some cases can be replaced with individual pathogen-associated molecular patterns (PAMPs). Exogenous PAMPs and endogenous danger signals from necrotic cells bind to pathogen recognition receptors, including Toll-like receptors, and activate signaling pathways in innate immune cells and on T cells, leading to inflammatory cytokine production and T cell activation, and this is now considered to be a major factor in the development of autoimmunity.

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Nucleic acid-stimulated antigen-presenting cells trigger T cells to induce disease in a rat transfer model of inflammatory arthritis

Cited by 39 publications

References 59 publications

Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNFα in monocytes

Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNFα in monocytes

Positional Identification ofRT1-B(HLA-DQ) as Susceptibility Locus for Autoimmune Arthritis

TLR-dependent T cell activation in autoimmunity

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