scholarly journals Synthetic Double-stranded RNA Poly(I:C) Aggravates IgA Nephropathy by Triggering IgA Class Switching Recombination Through TLR3-BAFF Axis

2015 ◽  
Vol 17 (2) ◽  
pp. S42
Author(s):  
H.L.Y. He ◽  
P.Y.M. Peng ◽  
L.F.Y. Liu ◽  
L.H. Liu
Keyword(s):  
Iga Nephropathy ◽  
Poly I:C ◽  
Class Switching ◽  
Double Stranded Rna ◽  
Class Switching Recombination

Synthetic Double-Stranded RNA Poly(I:C) Aggravates IgA Nephropathy by Triggering IgA Class Switching Recombination through the TLR3-BAFF Axis

2015 ◽  
Vol 42 (3) ◽  
pp. 185-197 ◽  
Author(s):  
Liyu He ◽  
Xiaofei Peng ◽  
Jiayi Wang ◽  
Chengyuan Tang ◽  
Xun Zhou ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Rat Model ◽  
Mononuclear Cells ◽  
Vital Role ◽  
Poly I:C ◽  
Double Stranded Rna ◽  
Class Switch ◽  
Polyriboinosinic:Polyribocytidylic Acid ◽  
Tissue Specimens

Background: Immunoglobulin class-switch recombination (CSR) is crucial for the expression of IgA, and it plays a vital role in the physiopathology of IgA nephropathy (IgAN). The aim of the study is to investigate the effect of polyriboinosinic:polyribocytidylic acid (poly(I:C)) in modulating toll-like receptor (TLR) 3-B-cell-activating factor belonging to the TNF family (BAFF) axis activation, which in turn promotes IgA CSR of IgAN patients and the IgAN rat model. Methods: Blood samples and tonsillar tissue specimens were obtained from 24 patients with IgAN and 26 patients with chronic tonsillitis as control. We also used the IgAN rat model to investigate the relationship between viral infection and IgA CSR. Results: Immunohistochemical and ELISA western blotting examination revealed that the TLR3/BAFF axis is activated in IgAN patients when compared to controls. Synthetic double-stranded RNA poly(I:C) stimulation upregulates the TACI/TLR3/TRIF/TRAF6 expression and promotes IgA CSR and BAFF productions in tonsil mononuclear cells. TLR3 or BAFF siRNA decreases IgA expression. In IgAN rat models, TLR3/BAFF signaling was highly activated. With 200 μg poly(I:C) sodium salt into the left naris for 8 weeks, IgA was highly deposited on glomeruli. It also revealed that poly(I:C) activated TLR3/BAFF axis and IgA CSR in vivo. Conclusion: These data points toward the role of TLR3/BAFF axis in IgA CSR of IgAN, and the data also support the notion that mucosal immunization with virus infection results in impaired mucosal and systemic IgA responses.

Triptolide Inhibits Tonsillar IgA Class Switching by Upregulating FDC-SP in IgA Nephropathy

2019 ◽  
Author(s):  
Huining Li ◽  
Dan Kong ◽  
Guodong Yao ◽  
Yang Xu ◽  
Yan Cao ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Class Switching

Immune responses of porcine airway epithelial cells to poly(I:C), a synthetic analogue of viral double-stranded RNA

2015 ◽  
Vol 95 (1) ◽  
pp. 13-20 ◽  
Author(s):  
Xiu-qin Yang ◽  
Liang Wang ◽  
Hai-tao Li ◽  
Di Liu
Keyword(s):  
Epithelial Cells ◽  
Immune Responses ◽  
Digital Gene Expression ◽  
Enrichment Analysis ◽  
Airway Epithelial Cells ◽  
Poly I:C ◽  
Synthetic Analogue ◽  
Airway Epithelial ◽  
Transcriptional Responses ◽  
Double Stranded Rna

Yang, X.-q., Wang, L., Li, H.-t. and Liu, D. 2015. Immune responses of porcine airway epithelial cells to poly(I:C), a synthetic analogue of viral double-stranded RNA. Can. J. Anim. Sci. 95: 13–20. Swine respiratory disease (SRD) is one of the most economically important diseases affecting the pig industry. The main infectious agents that cause SRD are viruses, but the molecular pathogenesis of viral SRD has not been extensively studied. Here, using digital gene expression tag profiling, the global transcriptional responses to poly(I:C), a synthetic analogue of viral double-stranded RNA, was analyzed in porcine airway epithelial cells (PAECs). The profiling analysis revealed numerous differentially expressed genes (DEGs), including unknown sequences in the porcine nucleotide databases. Gene ontology enrichment analysis showed that DEGs were mainly enriched in response to stress (GO: 0006950), of which, defense response is one sub-process. Poly(I:C) challenge induced a general inflammation response as indicated by marked upregulation of a variety of pathogen recognition receptors, interferon-stimulated genes, proinflammatory cytokines, and chemokines, together with the significant downregulation of anti-inflammatory molecules. Furthermore, the antiapoptotic pathway was triggered, as demonstrated by the significant suppression of molecules involved in the induction of apoptosis, together with the significant stimulation of putative inhibitor of apoptosis. The results indicate that PAECs initiated defense against poly(I:C) challenge through the inflammation responses, whereas poly(I:C) can utilize antiapoptotic pathway to evade host defense.

scholarly journals An Anti-Inflammatory Azaphenothiazine Inhibits Interferon β Expression and CXCL10 Production in KERTr Cells

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2443 ◽  
Author(s):  
Leon Strzadala ◽  
Anna Fiedorowicz ◽  
Edyta Wysokinska ◽  
Ewa Ziolo ◽  
Małgorzata Grudzień ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Mouse Models ◽  
Inhibitory Activity ◽  
Protein Level ◽  
The Other ◽  
Poly I:C ◽  
Interferon Β ◽  
Double Stranded Rna ◽  
Inducible Protein ◽  
Toxic Concentrations

An azaphenothiazine derivative, 6-chloroethylureidoethyldiquino[3,2-b;2′,3′-e][1,4]thiazine (DQT), has recently been shown to exhibit immunosuppressive activities in mouse models. It also inhibited the expression of CXCL10 at the protein level, at non-toxic concentrations, in the culture of KERTr cells treated with double-stranded RNA, poly(I:C). In this report, we demonstrated that DQT inhibits the transcription of the CXCL10 gene. Although CXCL10 is an IFNγ-inducible protein, we found that the CXCL10 protein was induced without the detectable release of IFNγ or IκB degradation. Hence, we concluded that IFNγ or NFκB was not involved in the regulation of the CXCL10 gene in KERTr cells transfected with poly(I:C), nor in the inhibitory activity of DQT. On the other hand, we found that IFNβ was induced under the same conditions and that its expression was inhibited by DQT. Kinetic analysis showed that an increase in IFNβ concentrations occurred 4–8 h after poly(I:C) treatment, while the concentration of CXCL10 was undetectable at that time and started to increase later, when IFNβ reached high levels. Therefore, DQT may be regarded as a new promising inhibitor of IFNβ expression and IFNβ-dependent downstream genes and proteins, e.g., CXCL10 chemokine, which is implicated in the pathogenesis of autoimmune diseases.

scholarly journals An Anti-Inflammatory Azaphenothiazine Inhibits Interferon β Expression and CXCL10 Production in KERTr Cells

2018 ◽  
Author(s):  
Leon Strzadala ◽  
Anna Fiedorowicz ◽  
Edyta Wysokinska ◽  
Ewa Ziolo ◽  
Małgorzata Grudzien ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Mouse Models ◽  
Inhibitory Activity ◽  
Protein Level ◽  
Interferon Beta ◽  
The Other ◽  
Poly I:C ◽  
Double Stranded Rna ◽  
Inducible Protein ◽  
Toxic Concentrations

An azaphenothiazine derivative, 6-chloroethylureidoethyldiquino[3,2-b;2’,3’-e][1,4]thiazine (DQT) has recently been shown to exhibit immunosuppressive activities in mouse models. It also inhibited the expression of CXCL10 at the protein level, at non-toxic concentrations, in the culture of KERTr cells treated with double-stranded RNA, poly(I:C). In this report, we demonstrated that DQT inhibits the transcription of the CXCL10 gene. Although CXCL10 is an IFNγ-inducible protein, we found that the CXCL10 protein was induced without the detectable release of IFNγ or IκB degradation. Hence, we concluded that IFNγ or NFκB were not involved in the regulation of the CXCL10 gene in KERTr cells transfected with poly(I:C) as well as in the inhibitory activity of DQT. On the other hand, we found that IFNβ was induced under the same conditions and its expression was inhibited by DQT. Kinetic analysis showed that an increase in IFNβ concentrations occurred 4-8 h after poly(I:C) treatment, while the concentration of CXCL10 was undetectable at that time and started to increase later, when IFNβ reached high levels. Therefore, DQT may be regarded as a new promising inhibitor of IFNβ expression and IFNβ-dependent downstream genes and proteins, e.g., CXCL10 chemokine, which is implicated in pathogenesis of autoimmune diseases.

scholarly journals Subsets of Human Dendritic Cell Precursors Express Different Toll-like Receptors and Respond to Different Microbial Antigens

2001 ◽  
Vol 194 (6) ◽  
pp. 863-870 ◽  
Author(s):  
Norimitsu Kadowaki ◽  
Stephen Ho ◽  
Svetlana Antonenko ◽  
Rene de Waal Malefyt ◽  
Robert A. Kastelein ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Expression Profiles ◽  
Lipoteichoic Acid ◽  
Poly I:C ◽  
Human Dendritic Cell ◽  
Toll Like Receptors ◽  
Double Stranded Rna ◽  
Tlr9 Ligand ◽  
Tnf Α ◽  
Necrosis Factor

Toll-like receptors (TLRs) are ancient microbial pattern recognition receptors highly conserved from Drosophila to humans. To investigate if subsets of human dendritic cell precursors (pre-DC), including monocytes (pre-DC1), plasmacytoid DC precursors (pre-DC2), and CD11c+ immature DCs (imDCs) are developed to recognize different microbes or microbial antigens, we studied their TLR expression and responses to microbial antigens. We demonstrate that whereas monocytes preferentially express TLR 1, 2, 4, 5, and 8, plasmacytoid pre-DC strongly express TLR 7 and 9. In accordance with these TLR expression profiles, monocytes respond to the known microbial ligands for TLR2 (peptidoglycan [PGN], lipoteichoic acid) and TLR4 (lipopolysaccharide), by producing tumor necrosis factor (TNF)-α and interleukin (IL)-6. In contrast, plasmacytoid pre-DCs only respond to the microbial TLR9-ligand, CpG-ODNs (oligodeoxynucleotides [ODNs] containing unmethylated CpG motifs), by producing IFN-α. CD11c+ imDCs preferentially express TLR 1, 2, and 3 and respond to TLR 2-ligand PGN by producing large amounts of TNF-α, and to viral double-stranded RNA-like molecule poly I:C, by producing IFN-α and IL-12. The expression of distinct sets of TLRs and the corresponding difference in reactivity to microbial molecules among subsets of pre-DCs and imDCs support the concept that they have developed through distinct evolutionary pathways to recognize different microbial antigens.

Lack of Alloantibody Response to Red Blood Cell Antigens in Juvenile Mice Following Transfusion: Non-Immunogenic or Tolerogenic Response?.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 955-955
Author(s):  
Jeanne E. Hendrickson ◽  
Cassandra D. Josephson ◽  
Traci E. Chadwick ◽  
James C. Zimring
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Poly I:C ◽  
Clinical Implications ◽  
Early Exposure ◽  
Juvenile Period ◽  
Double Stranded Rna ◽  
Adult Mice ◽  
Pediatric Populations ◽  
Membrane Bound

Abstract Introduction: Alloimmunization to red blood cell (RBC) antigens occurs in approximately 6% of chronically transfused adults, with some patient populations having significantly higher rates of alloimmunization. Despite these numbers, multiple studies have failed to detect alloantibodies to RBC antigens in neonates following transfusion, even after repeat exposures from the same donor. This is consistent with two possible scenarios: RBC antigens are non-immunogenic in neonates, or RBC antigens are tolerogenic. If early exposure to RBC antigens is a tolerogenic stimulus, then the potential clinical implications are considerable. To allow a controlled testing of these hypotheses, we have constructed a murine model of alloimmunization to RBC antigens in pediatric populations. Methods: Weight-adjusted volumes of leukoreduced blood from mHEL donors, expressing membrane bound hen-egg lysozyme as a unique RBC antigen, were transfused into B10.BR recipients at 3 weeks (juveniles) or 3 months (adults) of age. To assess the effects of inflammation, which we have recently reported augments RBC alloimmunization in adult mice, half of the recipients were treated with Poly (I:C), a double-stranded RNA that mimics viral inflammation. Two weeks post-transfusion, RBC alloimmunization was determined by measuring serum anti-HEL IgG levels by ELISA. Results: In 2 out of 2 experiments, as part of an ongoing study, whereas all 10 adult mice mounted a low level alloantibody response by ELISA, only one out of 10 juvenile mice made a detectable alloantibody response. The non-responsiveness of juvenile mice was not significantly altered by inflammation, as only 2 out of 10 juvenile mice treated with Poly (I:C) mounted an alloantibody response. Conclusion: Our data demonstrate that transfused RBCs are weakly immunogenic in adult mice, but only rarely result in alloimmunization in juvenile mice. This is consistent with the pattern of alloimmunization seen in adult versus neonatal humans. Since our model system detects alloantibodies by ELISA, which is 2000 fold more sensitive than agglutination assays using mHEL RBCs, these data support the notion that the majority of juvenile mice do not make alloantibodies to the mHEL RBC antigen. Additionally, inflammation enhances alloimmunization in juvenile mice to a significantly lesser extent than in adult mice. Ongoing studies will utilize the ability of this model to assess if juvenile transfusion recipients are tolerized, by challenging with an immunogenic stimulus (transfusion in the presence of inflammation or subcutaneous injection of HEL/CFA ). If these studies demonstrate that tolerance to RBC antigens occurs after exposure in the neonatal or juvenile period, then the potential clinical implications are significant.

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