scholarly journals P0022INNATE IMMUNE RESPONSES ELICITED BY TOLL-LIKE RECEPTORS ARE POSSIBLY INVOLVED IN THE PATHOGENESIS OF NEPHROTIC SYNDROME

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Eriko Tanaka ◽  
Ichiro Hada ◽  
Naoaki Mikami ◽  
Kunimasa Yan
Keyword(s):  
Innate Immunity ◽  
Nephrotic Syndrome ◽  
Immune System ◽  
Innate Immune System ◽  
Expression Profiles ◽  
Kidney Tissue ◽  
Innate Immune ◽  
Rna Expression ◽  
Toll Like Receptors ◽  
Tissue Samples

Abstract Background and Aims Pathogenesis of idiopathic nephrotic syndrome (INS) is yet to be fully elucidated. Immunological disorders are reported to be involved in the etiology of INS. Due to the efficacy of immunosuppressant agents such as calcineurin inhibitor and rituximab in treating nephrotic syndrome, aberrant activation of the acquired immune system through T and B cells are considered to be the underlying pathogenic mechanisms of INS. Nevertheless, there is a possibility that the innate immune system plays a key role in INS pathogenesis. This study aims to investigate the involvement of innate immunity in INS pathogenesis by examining the expressions of toll-like receptors (TLRs). Method Kidney tissue samples from two INS patients were collected at two points of time: the first biopsy was performed during nephrosis and the second during remission. Total RNA was extracted from the kidney tissue samples, and RNA-sequencing was performed to investigate RNA expression profiles. The differences between RNA expression profiles of TLRs and molecules related to TLR pathways in the tissue samples collected during nephrosis and remission were analyzed. Results There was a significant decrease in RNA expression of TLR9 and TLR10 during remission compared to nephrosis: fold change in each patient was -2.12 and -2.12 for TLR9, and -2.51 and -2.09 for TLR10. RNA expression of TLR8 also decreased: fold change in each patient was -1.19 and -1.75. There were no significant changes in the RNA expression profiles of TLR1, 2, 3, 4, 5, 6, and 7. In addition, there were no differences in the RNA expression profiles of MYD88, IRAK family, and TRAF family molecules that are associated with TLR pathways. However, RNA expressions of IL6, IL1B, IL12B, and TNF, as well as the cytokines controlled by TLR8 and TLR9 pathways, which were activated during nephrosis, disappeared or decreased during remission. Conclusion The involvement of the innate immune system in the pathogenesis of nephrotic syndrome has been suggested in some reports. Based on the fact that the onset or recurrence of nephrosis is triggered by non-specific viral infection, it is highly possible that innate immunity is involved in the pathogenesis of nephrotic syndrome. TLRs play a key role in innate immunity as they elicit the innate immune system after detecting pathogens, induce inflammatory cytokine production, and trigger signaling pathways that activate lymphocytes via maturation of dendritic cells. Specifically, TLR8, 9, and 10 mediate pathways of the first immune response to viral infections. Our study reveals that TLRs play a pivotal role in innate immunity associated with renal tissue during the onset of nephrosis.

scholarly journals Innate immunity and the pneumococcus

Microbiology ◽  
2006 ◽  
Vol 152 (2) ◽  
pp. 285-293 ◽  
Author(s):  
Gavin K. Paterson ◽  
Tim J. Mitchell
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Streptococcus Pneumoniae ◽  
Immune Responses ◽  
Innate Immune System ◽  
Innate Immune ◽  
First Line ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Made In

The innate immune system provides a non-specific first line of defence against microbes and is crucial both in the development and effector stages of subsequent adaptive immune responses. Consistent with its importance, study of the innate immune system is a broad and fast-moving field. Here we provide an overview of the recent key advances made in this area with relation to the important pathogen Streptococcus pneumoniae (the pneumococcus).

scholarly journals Still Enigmatic: Innate Immunity in the Ctenophore Mnemiopsis leidyi

2019 ◽  
Vol 59 (4) ◽  
pp. 811-818 ◽  
Author(s):  
Nikki Traylor-Knowles ◽  
Lauren E Vandepas ◽  
William E Browne
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Innate Immune System ◽  
Defense Mechanism ◽  
Innate Immune ◽  
Phylogenetic Position ◽  
Mnemiopsis Leidyi ◽  
Immunity Genes ◽  
Review Current

Abstract Innate immunity is an ancient physiological response critical for protecting metazoans from invading pathogens. It is the primary pathogen defense mechanism among invertebrates. While innate immunity has been studied extensively in diverse invertebrate taxa, including mollusks, crustaceans, and cnidarians, this system has not been well characterized in ctenophores. The ctenophores comprise an exclusively marine, non-bilaterian lineage that diverged early during metazoan diversification. The phylogenetic position of ctenophore lineage suggests that characterization of the ctenophore innate immune system will reveal important features associated with the early evolution of the metazoan innate immune system. Here, we review current understanding of the ctenophore immune repertoire and identify innate immunity genes recovered from three ctenophore species. We also isolate and characterize Mnemiopsis leidyi cells that display macrophage-like behavior when challenged with bacteria. Our results indicate that ctenophores possess cells capable of phagocytosing microbes and that two distantly related ctenophores, M. leidyi and Hormiphora californiensis, possess many candidate innate immunity proteins.

scholarly journals The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors

2000 ◽  
Vol 97 (25) ◽  
pp. 13766-13771 ◽  
Author(s):  
A. Ozinsky ◽  
D. M. Underhill ◽  
J. D. Fontenot ◽  
A. M. Hajjar ◽  
K. D. Smith ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Immune System ◽  
Innate Immune System ◽  
Innate Immune ◽  
Toll Like Receptors

A Critical Role for Innate Immunity In Allogeneic Hematopoietic Cell Rejection Via the TLR4/TRIF Pathway

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 77-77
Author(s):  
Hong Xu ◽  
Jun Yan ◽  
Ziqiang Zhu ◽  
Yiming Huang ◽  
Yujie Wen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Innate Immunity ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Innate Immune System ◽  
Critical Role ◽  
Innate Immune ◽  
Wild Type

Abstract Abstract 77 Adaptive immunity, especially T cells, has long been believed to be the dominant immune barrier in allogeneic transplantation. Targeting host T cells significantly reduces conditioning for bone marrow cell (BMC) engraftment. Innate immunity has been recently shown to pose a significant barrier in solid organ transplantation, but has not been addressed in bone marrow transplantation (BMT). Using T cell deficient (TCR-β/δ−/−) or T and B cell deficient (Rag−/−) mice, we found that allogeneic BMC rejection occurred early before the time required for T cell activation and was T- and B-cell independent, suggesting an effector role for innate immune cells in BMC rejection. Therefore, we hypothesized that by controlling both innate and adaptive immunity, the donor BMC would have a window of advantage to engraft. Survival of BMC in vivo was significantly improved by depleting recipient macrophages and/or NK cells, but not neutrophils. Moreover, depletion of macrophages and NK cells in combination with co-stimulatory blockade with anti-CD154 and rapamycin as a novel form of conditioning resulted in 100% allogeneic engraftment without any irradiation and T cell depletion. Donor chimerism remained stable and durable up to 6 months. Moreover, specific Vβ5½ and Vβ11 clonal deletion was detected in host CD4+ T cells in chimeras, indicating central tolerance to donor alloantigens. Whether and how the innate immune system recognizes or responds to allogeneic BMCs remains unknown. Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. The signaling function of TLR depends on intracellular adaptors. The adaptor MyD88 transmits signals emanating from all TLR, except TLR3 while TRIF specifically mediates TLR3 and TLR4 signaling via type 1 IFN. To further determine the innate signaling pathways in allogeneic BMC rejection, B6 background (H2b) MyD88−/− and TRIF−/− mice were conditioned with anti-CD154/rapamycin plus 100 cGy total body irradiation and transplanted with 15 × 106 BALB/c (H2d) BMC. Only 33.3% of MyD88−/− recipients engrafted at 1 month, resembling outcomes for wild-type B6 mice. In contrast, 100% of TRIF−/− mice engrafted. The level of donor chimerism in TRIF−/− mice was 5.1 ± 0.6% at one month, significantly higher than in MyD88−/− and wild-type B6 controls (P < 0.005). To determine the mechanism of innate signaling in BMC rejection, we examined whether TRIF linked TLR3 or TLR4 is the key pattern recognition receptor involved in BMC recognition. To this end, TLR3−/− and TLR4−/− mice were transplanted with BALB/c BMC with same conditioning. None of the TLR3−/− mice engrafted. In contrast, engraftment was achieved in 100% of TLR4−/− mice up to 6 months follow up. Taken together, these results suggest that rejection of allogeneic BMC is uniquely dependent on the TLR4/TRIF signaling pathway. Thus, our results clearly demonstrate a previously unappreciated role for innate immunity in allogeneic BMC rejection. Our current findings are distinct from prior reports demonstrating a critical role of MyD88 in rejection of allogeneic skin grafts and lung, and may reflect unique features related to BMC. The findings of the role of innate immunity in BMC rejection would lead to revolutionary changes in our understanding and management of BMT. This would be informative in design of more specific innate immune targeted conditioning proposals in BMT to avoid the toxicity. Disclosures: Bozulic: Regenerex LLC: Employment. Ildstad:Regenerex LLC: Equity Ownership.

scholarly journals Interaction of Antibiotics with Innate Host Defense Factors against Salmonella enterica Serotype Newport

mSphere ◽  
2017 ◽  
Vol 2 (6) ◽  
Author(s):  
George Sakoulas ◽  
Monika Kumaraswamy ◽  
Armin Kousha ◽  
Victor Nizet
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Innate Immune System ◽  
Salmonella Enterica ◽  
Clinical Performance ◽  
Innate Immune ◽  
Content Type ◽  
Antimicrobial Assay

ABSTRACT It is becoming increasingly understood that the current paradigms of in vitro antimicrobial susceptibility testing may have significant shortcomings in predicting activity in vivo. This study evaluated the activity of several antibiotics alone and in combination against clinical isolates of Salmonella enterica serotype Newport (meningitis case) utilizing both conventional and physiological media. In addition, the interactions of these antibiotics with components of the innate immune system were evaluated. Azithromycin, which has performed quite well clinically despite high MICs in conventional media, was shown to be more active in physiological media and to enhance innate immune system killing. Alternatively, chloramphenicol did not show enhanced immune system killing, paralleling its inferior clinical performance to other antibiotics that have been used to treat Salmonella meningitis. These findings are important additions to the building understanding of current in vitro antimicrobial assay limitations that hopefully will amount to future improvements in these assays to better predict clinical efficacy and activity in vivo. This study examines the pharmacodynamics of antimicrobials that are used to treat Salmonella with each other and with key components of the innate immune system. Antimicrobial synergy was assessed using time-kill and checkerboard assays. Antimicrobial interactions with innate immunity were studied by employing cathelicidin LL-37, whole-blood, and neutrophil killing assays. Ceftriaxone and ciprofloxacin were found to be synergistic in vitro against Salmonella enterica serotype Newport. Ceftriaxone, ciprofloxacin, and azithromycin each demonstrated synergy with the human cathelicidin defense peptide LL-37 in killing Salmonella. Exposure of Salmonella to sub-MICs of ceftriaxone resulted in enhanced susceptibility to LL-37, whole blood, and neutrophil killing. The activity of antibiotics in vivo against Salmonella may be underestimated in bacteriologic media lacking components of innate immunity. The pharmacodynamic interactions of antibiotics used to treat Salmonella with each other and with components of innate immunity warrant further study in light of recent findings showing in vivo selection of antimicrobial resistance by single agents in this pathogen. IMPORTANCE It is becoming increasingly understood that the current paradigms of in vitro antimicrobial susceptibility testing may have significant shortcomings in predicting activity in vivo. This study evaluated the activity of several antibiotics alone and in combination against clinical isolates of Salmonella enterica serotype Newport (meningitis case) utilizing both conventional and physiological media. In addition, the interactions of these antibiotics with components of the innate immune system were evaluated. Azithromycin, which has performed quite well clinically despite high MICs in conventional media, was shown to be more active in physiological media and to enhance innate immune system killing. Alternatively, chloramphenicol did not show enhanced immune system killing, paralleling its inferior clinical performance to other antibiotics that have been used to treat Salmonella meningitis. These findings are important additions to the building understanding of current in vitro antimicrobial assay limitations that hopefully will amount to future improvements in these assays to better predict clinical efficacy and activity in vivo.

Role of Toll-like receptors in liver health and disease

2011 ◽  
Vol 121 (10) ◽  
pp. 415-426 ◽  
Author(s):  
Ruth Broering ◽  
Mengji Lu ◽  
Joerg F. Schlaak
Keyword(s):  
Immune System ◽  
Liver Disease ◽  
Innate Immune System ◽  
Innate Immune ◽  
Toll Like Receptors ◽  
Evolutionarily Conserved ◽  
Liver Health ◽  
Health And Disease ◽  
Molecular Patterns

TLRs (Toll-like receptors), as evolutionarily conserved germline-encoded pattern recognition receptors, have a crucial role in early host defence by recognizing so-called PAMPs (pathogen-associated molecular patterns) and may serve as an important link between innate and adaptive immunity. In the liver, TLRs play an important role in the wound healing and regeneration processes, but they are also involved in the pathogenesis and progression of various inflammatory liver diseases, including autoimmune liver disease, alcoholic liver disease, non-alcoholic steatohepatitis, fibrogenesis, and chronic HBV (hepatitis B virus) and HCV (hepatitis C virus) infection. Hepatitis viruses have developed different evading strategies to subvert the innate immune system. Thus recent studies have suggested that TLR-based therapies may represent a promising approach in the treatment in viral hepatitis. The present review focuses on the role of the local innate immune system, and TLRs in particular, in the liver.

scholarly journals Toll-like Receptors on Hematopoietic Progenitor Cells Stimulate Innate Immune System Replenishment

Immunity ◽  
2006 ◽  
Vol 24 (6) ◽  
pp. 801-812 ◽  
Author(s):  
Yoshinori Nagai ◽  
Karla P. Garrett ◽  
Shoichiro Ohta ◽  
Uleng Bahrun ◽  
Taku Kouro ◽  
...  
Keyword(s):  
Immune System ◽  
Progenitor Cells ◽  
Innate Immune System ◽  
Innate Immune ◽  
Hematopoietic Progenitor Cells ◽  
Toll Like Receptors ◽  
Hematopoietic Progenitor

scholarly journals Toward a structural understanding of nucleic acid-sensing Toll-like receptors in the innate immune system

FEBS Letters ◽  
2017 ◽  
Vol 591 (20) ◽  
pp. 3167-3181 ◽  
Author(s):  
Zhikuan Zhang ◽  
Umeharu Ohto ◽  
Toshiyuki Shimizu
Keyword(s):  
Immune System ◽  
Nucleic Acid ◽  
Innate Immune System ◽  
Innate Immune ◽  
Toll Like Receptors

scholarly journals Toll-like receptors and hypertension

2014 ◽  
Vol 307 (5) ◽  
pp. R501-R504 ◽  
Author(s):  
Madhu V. Singh ◽  
François M. Abboud
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Expression Patterns ◽  
Adaptor Proteins ◽  
Nuclear Factor Κb ◽  
Innate Immune ◽  
Toll Like Receptors ◽  
Cardiovascular Damage ◽  
Inflammatory Processes ◽  
Molecular Patterns

Hypertension and associated inflammatory processes that accelerate cardiovascular damage are regulated by the innate immune system. Toll-like receptors (TLR) are major components of the innate immune system that recognize endogenous damage-associated molecular patterns to activate prominent inflammatory signaling including activation of nuclear factor-κB (NF-κB). However, the role of TLR in the etiology of hypertension is not well understood. TLR signaling is dependent on adaptor proteins that, along with the TLR expression patterns, confer specificity of the inflammatory response and its pathological targets. Here we review the conceptual framework of how TLR and their adaptor proteins may differentially affect hypertension and cardiac hypertrophy by different stimuli.

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