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Anti-cytokine autoantibodies: Epiphenomenon or critical modulators of cytokine action 总被引:3,自引:0,他引:3
Low amounts of high-affinity autoantibodies to various cytokines have been detected in sera from healthy donors. Their levels,
although highly variable, are increased in the circulation of patients subjected to cytokine therapy or suffering from a variety
of immunoinflammatory diseases. It has been suggested that these autoantibodies play a regulatory role in the intensity and
duration of an immune response. The antibodies may prevent the binding of a cytokine to its specific cell surface receptor
thereby neutralizing its biological activityin vivo. They may also act as carrier proteins preventing the rapid elimination of a cytokine from the circulation and thus increase
its bioactivity. Additionally or alternatively, autoantibodies may modulate cytokine-induced intracellular signal transduction
pathways or trigger complement-mediated cytotoxicity towards cells carrying membrane-bound cytokines. The autoantibodies may
exert their regulatory role in compliance with other factors that control cytokine activity, including soluble cytokine receptors,
cell surface decoy receptors, and receptor antagonists. Although not favored by many investigators, a less sophisticated role
for naturally occurring anti-cytokine autoantibodies should be considered as well. Recent evidence has shown that autoantibodies
are generated at a high frequency as part of a response to foreign antigens. These antibodies are produced by B cells arising
from the process of somatic mutation. Thus anti-cytokine autoantibodies may be the result of a “leaky” B cell response triggered
by immunoinflammatory processes.
High-titered autoantibodies induced by cytokine therapy are of clinical concern since their occurrence is often associated
with the loss of response to treatment. Moreover, they may also neutralize endogenously produced cytokines with possible pathological
consequences.
In this paper we have reviewed the available information on the biological and clinical significance of both naturally occurring
and therapeutically induced anti-cytokine autoantibodies in animals and man with the emphasis on antibodies directed to interferons. 相似文献
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ROCK and PRK-2 mediate the inhibitory effect of Y-27632 on polyglutamine aggregation 总被引:2,自引:0,他引:2
Polyglutamine expansion in huntingtin (Htt) and the androgen receptor (AR) causes untreatable neurodegenerative diseases. Y-27632, a therapeutic lead, reduces Htt and AR aggregation in cultured cells, and Htt-induced neurodegeneration in Drosophila. Y-27632 inhibits both Rho-associated kinases ROCK and PRK-2, making its precise intracellular target uncertain. Over-expression of either kinase increases Htt and AR aggregation. Three ROCK inhibitors (Y-27632, HA-1077, and H-1152P), and a specific ROCK inhibitory peptide reduce polyglutamine protein aggregation, as does knockdown of ROCK or PRK-2 by RNAi. RNAi also indicates that each kinase is required for the inhibitory effects of Y-27632 to manifest fully. These two actin regulatory kinases are thus involved in polyglutamine aggregation, and their simultaneous inhibition may be an important therapeutic goal. 相似文献
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Hirotaka Kanoh Hiroyuki Kato Yamato Suda Aki Hori Shoichiro Kurata Takayuki Kuraishi 《Biochemical and biophysical research communications》2019,508(1):332-337
The Drosophila Toll pathway is involved in embryonic development, innate immunity, and cell-cell interactions. However, compared to the mammalian Toll-like receptor innate immune pathway, its intracellular signaling mechanisms are not fully understood. We have previously performed a series of ex vivo genome-wide RNAi screenings to identify genes required for the activation of the Toll pathway. In this study, we have conducted an additional genome-wide RNAi screening using the overexpression of Tube, an adapter molecule in the Toll pathway, and have performed a co-immunoprecipitation assay to identify components present in the dMyd88-Tube complex. Based on the results of these assays, we have performed a bioinformatic analysis, and describe candidate molecules and post-translational modifications that could be involved in Drosophila Toll signaling. 相似文献
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RNA interference in protozoan parasites 总被引:10,自引:1,他引:9
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Jin Hagiwara Leon Nozawa Itsuki Ohtsu Tadashi Shinohara Hiroki Gotoh 《Entomological Science》2023,26(2):e12548
Holometabolous insects dramatically change their morphology via molt, both from larva to pupa and from pupa to adult. In nonmodel insects, RNA interference (RNAi) is a strong tool for analyzing gene function during postembryonic development. In many cases, larval RNAi is effective for analyzing genes involved in morphogenesis via metamorphosis. However, RNAi of genes involved in development sometimes results in lethality before animals metamorphose to pupae and/or adults, making it impossible to analyze their function during the pupal period. In this study, we establish a pupal RNAi system in the stag beetle Dorcus rectus. We selected the genes white and scarlet for RNAi knockdown to investigate appropriate injection timing and position. Both genes are known to be involved in eye pigmentation. By using these candidate genes, we demonstrate the potential of pupal RNAi in this experimental system. This method will be useful for analyzing pupal-specific morphogenesis including fine-shaping of the enlarged male mandible in this species. 相似文献
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《Autophagy》2013,9(12):1865-1867
Staphylococcus aureus is an intracellular bacterium responsible for serious infectious processes. This pathogen escapes from the phagolysosomal pathway into the cytoplasm, a strategy that allows intracellular bacterial replication and survival with the consequent killing of the eukaryotic host cell and spreading of the infection. S. aureus is able to secrete several virulence factors such as enzymes and toxins. Our recent findings indicate that the main virulence factor of S. aureus, the pore-forming toxin α-hemolysin (Hla), is the secreted factor responsible for the activation of an alternative autophagic pathway. We have demonstrated that this noncanonical autophagic response is inhibited by artificially elevating the intracellular levels of cAMP. This effect is mediated by RAPGEF3/EPAC (Rap guanine nucleotide exchange factor (GEF)3/exchange protein activated by cAMP), a cAMP downstream effector that functions as a GEF for the small GTPase Rap. We have presented evidence that RAPGEF3 and RAP2B, through calpain activation, are the proteins involved in the regulation of Hla and S. aureus-induced autophagy. In addition, we have found that both, RAPGEF3 and RAP2B, are recruited to the S. aureus–containing phagosome. Of note, adding purified α-toxin or infecting the cells with S. aureus leads to a decrease in intracellular cAMP levels, which promotes autophagy induction, a response that favors pathogen intracellular survival, as previously demonstrated. We have identified some key signaling molecules involved in the autophagic response upon infection with a bacterial pathogen, which have important implications in understanding innate immune defense mechanisms. 相似文献
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Antinuclear autoantibodies (ANAs) derived from patients with systemic autoimmune diseases have proven to be powerful tools in cell and molecular biology. The availability of these autoantibodies has been instrumental in the identification and characterization of a wide range of intracellular proteins involved in essential cellular activities. Recently, these autoantibodies have been used in molecular studies of apoptosis, particularly in the identification of substrates cleaved by proteases of the ICE/CED-3 family during this cell death pathway. The identification of these substrates may help to understand the role of proteolysis in apoptosis. Examples of nuclear autoantigens whose cleavage during apoptosis have been defined using ANAs include the 70 kD protein of the U1 small nuclear ribonucleoprotein particle (U1-70 kD), the nuclear mitotic apparatus protein (NuMA), DNA topoisomerase I, the RNA polymerase I upstream binding factor (UBF), and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). The use of ANAs as probes for defining proteolytic events associated with apoptosis promises to yield important insights into the mechanisms driving this cell death pathway.Abbreviations ANAs
Antinuclear autoantibodies
- DNA-PKcs
DNA-dependent protein kinase
- ICE
interleukin-1 (IL-1)-converting enzyme
- MARs or SARs
matrix or scaffold attachment regions
- NuMA
nuclear mitotic apparatus protein
- PARP
poly (ADP) ribose polymerase
- snRNPs
small nuclear ribonucleoproteins
- SLE
systemic lupus erythematosus
- UBF
upstream binding factor 相似文献
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The Wnt and Src pathways are widely used signal transduction pathways in development. β-catenin is utilized in both pathways, as a signal transducer and a component of the cadherin cell adhesion complex, respectively. A C. elegans β-catenin HMP-2 is involved in cell adhesion, but its signaling role has been unknown. Here, we report that in early embryogenesis HMP-2 acts as a signaling molecule in the Src signal. During early embryogenesis in C. elegans, the Wnt and Src pathways are redundantly involved in endoderm induction at the four-cell stage and spindle orientation in an ABar blastomere. RNAi experiments demonstrated that HMP-2 functions in the Src pathway, but in parallel with the Wnt pathway in these processes. HMP-2 localized at the cell boundaries and nuclei, and its localization at cell boundaries was negatively regulated by SRC-1. In addition, HMP-2 was Tyr-phosphorylated in a SRC-1-dependent manner in vivo. Taken together, we propose that HMP-2 functions downstream of the Src signaling pathway and contribute to endoderm induction and ABar spindle orientation, in parallel with the Wnt signaling pathway. 相似文献
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Cláudia Rosa‐Ferreira David E Gordon Xavier Franch‐Marro Andrew A Peden Jean‐Paul Vincent Sean Munro 《The EMBO journal》2010,29(2):304-314
Genetic screens in the yeast Saccharomyces cerevisiae have identified many proteins involved in the secretory pathway, most of which have orthologues in higher eukaryotes. To investigate whether there are additional proteins that are required for secretion in metazoans but are absent from yeast, we used genome‐wide RNA interference (RNAi) to look for genes required for secretion of recombinant luciferase from Drosophila S2 cells. This identified two novel components of the secretory pathway that are conserved from humans to plants. Gryzun is distantly related to, but distinct from, the Trs130 subunit of the TRAPP complex but is absent from S. cerevisiae. RNAi of human Gryzun (C4orf41) blocks Golgi exit. Kish is a small membrane protein with a previously uncharacterised orthologue in yeast. The screen also identified Drosophila orthologues of almost 60% of the yeast genes essential for secretion. Given this coverage, the small number of novel components suggests that contrary to previous indications the number of essential core components of the secretory pathway is not much greater in metazoans than in yeasts. 相似文献
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O A Vartanian 《Molekuliarnaia biologiia》1991,25(4):1033-1039
Sera of patients bearing autoimmune diseases (rheumatoid arthritis and systemic lupus erythematosus) and sera of clinically healthy donors were examined by ELISA for the presence of autoantibodies against tryptophanyl-, tyrosyl- and phenylalanyl-tRNA synthetases. Pure bovine synthetases served as antigens. It was shown that in patients with both autoimmune diseases all three enzyme autoantibodies were revealed at serum dilution 1/1600-1/3200. Moreover, by means of monoclonal antibodies against the same enzymes used for immunoaffinity sorption, antiidiotypic antibodies of IgG type against autoantibodies were detected. A conclusion has been made that autoimmune diseases are characterized by autoimmune response for many aminoacyl-tRNA synthetases irrespectively of their quaternary structure, intracellular location etc both at the level of primary and secondary antibodies. 相似文献
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Legionella pneumophila requires the Dot/Icm translocation system to replicate in a vacuolar compartment within host cells. Strains lacking the translocated substrate SdhA form a permeable vacuole during residence in the host cell, exposing bacteria to the host cytoplasm. In primary macrophages, mutants are defective for intracellular growth, with a pyroptotic cell death response mounted due to bacterial exposure to the cytosol. To understand how SdhA maintains vacuole integrity during intracellular growth, we performed high‐throughput RNAi screens against host membrane trafficking genes to identify factors that antagonise vacuole integrity in the absence of SdhA. Depletion of host proteins involved in endocytic uptake and recycling resulted in enhanced intracellular growth and lower levels of permeable vacuoles surrounding the ΔsdhA mutant. Of interest were three different Rab GTPases involved in these processes: Rab11b, Rab8b and Rab5 isoforms, that when depleted resulted in enhanced vacuole integrity surrounding the sdhA mutant. Proteins regulated by these Rabs are responsible for interfering with proper vacuole membrane maintenance, as depletion of the downstream effectors EEA1, Rab11FIP1, or VAMP3 rescued vacuole integrity and intracellular growth of the sdhA mutant. To test the model that specific vesicular components associated with these effectors could act to destabilise the replication vacuole, EEA1 and Rab11FIP1 showed increased density about the sdhA mutant vacuole compared with the wild type (WT) vacuole. Depletion of Rab5 isoforms or Rab11b reduced this aberrant redistribution. These findings are consistent with SdhA interfering with both endocytic and recycling membrane trafficking events that act to destabilise vacuole integrity during infection. 相似文献
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