Journal ArticleDOI
Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages
Kohki Kawane,Mayumi Ohtani,Keiko Miwa,Takuji Kizawa,Yoshiyuki Kanbara,Yoshichika Yoshioka,Hideki Yoshikawa,Shigekazu Nagata +7 more
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TLDR
It is shown that if macrophages cannot degrade mammalian DNA from erythroid precursors and apoptotic cells, they produce TNF-α, which activates synovial cells to produce various cytokines, leading to the development of chronic polyarthritis.Abstract:
A large amount of chromosomal DNA is degraded during programmed cell death and definitive erythropoiesis DNase II is an enzyme that digests the chromosomal DNA of apoptotic cells and nuclei expelled from erythroid precursor cells after macrophages have engulfed them Here we show that DNase II-/-IFN-IR-/- mice and mice with an induced deletion of the DNase II gene develop a chronic polyarthritis resembling human rheumatoid arthritis A set of cytokine genes was strongly activated in the affected joints of these mice, and their serum contained high levels of anti-cyclic citrullinated peptide antibody, rheumatoid factor and matrix metalloproteinase-3 Early in the pathogenesis, expression of the gene encoding tumour necrosis factor (TNF)-alpha was upregulated in the bone marrow, and administration of anti-TNF-alpha antibody prevented the development of arthritis These results indicate that if macrophages cannot degrade mammalian DNA from erythroid precursors and apoptotic cells, they produce TNF-alpha, which activates synovial cells to produce various cytokines, leading to the development of chronic polyarthritisread more
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The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors
Taro Kawai,Shizuo Akira +1 more
TL;DR: Recent advances that have been made by research into the role of TLR biology in host defense and disease are described.
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Protective and pathogenic functions of macrophage subsets
Peter J. Murray,Thomas A. Wynn +1 more
TL;DR: The four stages of orderly inflammation mediated by macrophages are discussed: recruitment to tissues; differentiation and activation in situ; conversion to suppressive cells; and restoration of tissue homeostasis.
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The roles of TLRs, RLRs and NLRs in pathogen recognition
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TL;DR: Recent insights into pathogen sensing by PRRs are summarized and specific signaling pathways that lead to expression of genes that tailor immune responses to particular microbes are summarized.
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STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors
Seng Ryong Woo,Mercedes Beatriz Fuertes,Leticia Corrales,Stefani Spranger,Michael J. Furdyna,Michael Y. K. Leung,Ryan Duggan,Ying Wang,Glen N. Barber,Katherine A. Fitzgerald,Maria-Luisa Alegre,Thomas F. Gajewski +11 more
TL;DR: It is found that spontaneous CD8(+) T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway.
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Intracellular Toll-like Receptors
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TL;DR: The latest findings on the intracellular Toll-like receptors are reviewed, with special emphasis on ligand uptake, receptor trafficking, signaling, and regulation.
References
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Role of cytokines in rheumatoid arthritis
TL;DR: Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.
Journal ArticleDOI
Inducible gene targeting in mice
TL;DR: A method of gene targeting that allows the inducible inactivation of a target gene in mice is presented, which uses an interferon-responsive promoter to control the expression of Cre recombinase.
Journal ArticleDOI
Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors
Elizabeth A. Leadbetter,Ian R. Rifkin,Andreas Hohlbaum,Britte C. Beaudette,Mark J. Shlomchik,Ann Marshak-Rothstein +5 more
TL;DR: It is shown that effective activation of RF+ B cells is mediated by IgG2a–chromatin immune complexes and requires the synergistic engagement of the antigen receptor and a member of the MyD88-dependent Toll-like receptor (TLR) family.
Journal ArticleDOI
Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis.
J. Keffer,Lesley Probert,H. Cazlaris,Spiros Georgopoulos,E. Kaslaris,D. Kioussis,George Kollias +6 more
TL;DR: A direct involvement of TNF in the pathogenesis of arthritis is indicated and transgenic mice which predictably develop arthritis represent a novel genetic model by which the pathogenic and treatment of this disease in humans may be further investigated.
Journal ArticleDOI
Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies.
G.A. Schellekens,B.A. de Jong,F.H.J. van den Hoogen,L. B. A. Van De Putte,W. J. Van Venrooij +4 more
TL;DR: It is shown that autoantibodies reactive with synthetic peptides containing the unusual amino acid citrulline, a posttranslationally modified arginine residue, are specifically present in the sera of RA patients, and the presence of these antibodies early in disease, even before other disease manifestations occur, are indicative for a possible role of citrulling epitopes in the pathogenesis of RA.