Response to Comment on “Flagellin as an Adjuvant: Cellular Mechanisms and Potential”
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We sincerely appreciate Dr. Pandey’s interest in our review on flagellin and its adjuvant property. With regard to his comments, it is important to note that we were referring to clinical trials that assess the adjuvant property of flagellin and not necessarily its immunogenic potential. We agreeKeywords:
Flagellin
Flagellin
TLR5
Salmonella enteritidis
Salmonella enterica
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Seperti pada dewasa, teknik regional anestesi pada pediatrik kini makin popular digunakan oleh ahli anestesikarena keuntungannya. Namun demikian selalu ada risiko dan kemungkinan timbulnya komplikasi dari setiap tindakan yang dilakukan, termasuk tindakan anestesi regional pada pediatrik. Insidensi komplikasi anestesi regional pada pediatrik tidak banyak, dan kalaupun terjadi komplikasi adalah minor. Komplikasi bisa diakibatkan dari identifikasi ruang saraf, alat, obat, teknis tindakan anestesi regionalnya dan komplikasi lainnya.Walaupun tidak banyak kejadian komplikasi regional anestesi yang dilaporkan pada pediatrik, dan bukanlah komplikasi yang fatal, teknik regional anestesi pada pediatrik harus dilakukan dengan lebih hatihati, pertimbangan risiko dan keuntungannya untuk menghindari terjadinya komplikasi, terlebih karena kebanyakan komplikasi dapat dihindari dengan mempelajari teknik yang benar, menggunakan peralatan yang sesuai, dan sangat menerapkan prinsip keamanan pada pasien dengan baik.
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Abstract Flagellin is amongst the most abundant proteins in flagellated bacterial species and constitutes the major building block of the flagellar filament. The proteins FliW and FliS serve in the post-transcriptional control of flagellin and guide the protein to the flagellar type III secretion system (fT3SS), respectively. Here, we present the high-resolution structure of FliS/flagellin heterodimer and show that FliS and FliW bind to opposing interfaces located at the N- and C-termini of flagellin. The FliS/flagellin/FliW heterotrimer is able to interact with FlhA-C suggesting that FliW and FliS are released during flagellin export. After release, FliW and FliS are recycled to execute a new round of post-transcriptional regulation and targeting. Taken together, our study provides a mechanism explaining how FliW and FliS synchronize the production of flagellin with the capacity of the fT3SS to secrete flagellin.
Flagellin
Homeostasis
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Bacterial flagellin, as a pathogen-associated molecular pattern (PAMP), can activate both innate and adaptive immunity. Its unique structural characteristics endow an effective and flexible adjuvant activity, which allow the design of different types of vaccine strategies to prevent various diseases. This review will discuss recent progress in the mechanism of action of flagellin and its prospects for use as a vaccine adjuvant.Herein we summarize various types of information related to flagellin adjuvants from PubMed, including structures, signaling pathways, natural immunity, and extensive applications in vaccines, and it discusses the immunogenicity, safety, and efficacy of flagellin-adjuvanted vaccines in clinical trials.It is widely accepted that as an adjuvant, flagellin can induce an enhanced antigen-specific immune response. Flagellin adjuvants will allow more effective flagellin-based vaccines to enter clinical trials. Furthermore, vaccine formulations containing PAMPs are crucial to exert the maximum potential of vaccine antigens. Therefore, combinations of flagellin-adjuvanted vaccines with other adjuvants that act in a synergistic manner, particularly TLR ligands, represent a promising method for tailoring targeted vaccines to meet specific requirements.
Flagellin
TLR5
Vaccine adjuvant
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Genentech is partnering with the German cancer company Affimed to develop immunotherapies for multiple kinds of solid and blood cancers. Affimed is developing therapies that engage natural killer cells of the innate immune system to help direct them to attack cancer cells. Genentech will pay Affimed $96 million up front and up to $5 billion more in potential payments.
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We sincerely appreciate Dr. Pandey’s interest in our review on flagellin and its adjuvant property. With regard to his comments, it is important to note that we were referring to clinical trials that assess the adjuvant property of flagellin and not necessarily its immunogenic potential. We agree
Flagellin
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Many flagellated bacteria possess multiple flagellins, but the roles and the compositions of each flagellin are diverse and poorly understood. In Ligilactobacillus agilis BKN88, there are two active flagellin gene paralogues but their function and composition in its flagellar filaments have not been described. The aim of this study is to find the function and composition of the flagellins by employing mutant strains each of which expresses a single flagellin or a modified flagellin. Two single flagellin-expressing strains were both flagellated while the number of flagella per cell in the single flagellin-expressing derivatives was lower than that in the wild type. Nonetheless, these derivative strains were apparently equally motile as the wild type. This indicates that either flagellin is sufficient for cell motility. The immunological activity via Toll-like receptor 5 of the single flagellin-expressing strains or purified single flagellins was readily detectable but mostly variably weaker than that of the wild type. The flagellar filaments of wild type L. agilis BKN88 were more acid-/thermo-stable than those of single flagellin-expressing derivatives. Using a combination of immunoprecipitation and flagellin-specific staining, wild type BKN88 appeared to possess heteropolymeric flagellar filaments consisting of both flagellins and each flagellin appeared to be equally distributed throughout the filaments. The results of this study suggest that the two flagellins together form a more robust filament than either alone and are thus functionally complementary.
Flagellin
Wild type
Immunoprecipitation
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Flagellin 是涉及天生、适应的免疫的大量房间类型的有势力使活跃之物。因此，它是疫苗的一个好辅助候选人，并且它可能在癌症放射疗法和放射紧急情况的一个缓和者期间对主要尖锐放射症候群作为生物杀虫撒布剂工作。然而，积累证据含有在一些煽动性的疾病的出现的 flagellin 例如尖锐的肺发炎，心血管的倒塌和煽动性的肠疾病。这研究的目的是阐明 flagellin-TLR5 发信号激活是否仅仅或是否在肝的 pathophysiology 起一个作用某另外的 flagellin 活动也经由细菌的感染或在临床的应用期间贡献肝损害。Recombinant flagellin 蛋白质与或没有刺激 TLR5 活动被用来评估 flagellin-TLR5 在肝损害发信号在的角色野类型并且 TLR5 击倒老鼠。粗野损害和 hepatocellular 坏死的大区域在 100 或 200 µ 的 intraperitoneal 管理以后在肝织物 12 h 被观察；在一个剂量依赖者的 g flagellin (警察) 和在野类型的老鼠，然而并非在 TLR5 击倒老鼠的时间依赖者举止。flagellin 的 N 终端或 TLR5 绑定域的删除禁止了导致 flagellin 的煽动性的回答和随后的尖锐的肝函数反常和损坏。这些数据证实 flagellin 是肝损害的一个必要决定因素并且证明由高剂量的 flagellin 发信号的 TLR5 的在激活上在肝引起了尖锐煽动性的回答，嗜中性的累积和氧化应力，它贡献导致 flagellin 的肝损害的前进和严厉。
Flagellin
TLR5
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Summary Antibody production in the rat in response to the injection of Salmonella adelaide flagellin was considerably enhanced if the antigen were Injected In emulsion with Freund's complete adjuvant. Peak titres of antibody Were 1000‐fold higher than those obtained following the injection of antigen alone. However the minimal dose of flagellin. which would stimulate antibody production was found to be of the order of 10 ng. (10 −8 g.) regardless of whether it were injected in adjuvant or in aqueous solution. Simultaneous injection of flagellin and adjuvant into opposite sides of the body resulted in only a very moderate enhancement of the antibody response. Rats which had been given a ten‐week course of bi‐weekly injections of flagellin starting in the neonatal period, and which were virtually unresponsive to subsequent challenge with flagellin, broke tolerance and produced high titres of antibody when challenged with the same dose of flagellin in adjuvant. These results have been interpreted in terms of the ability of antigen injected in Freund's complete adjuvant to be retained in the body for a considerable period of time where it remains available to stimulate both cells which “escape” the state of immune unresponsiveness and newly recruited antigen‐ sensitive cells whose proliferation is accelerated by the presence of the adjuvant.
Flagellin
Antibody response
Freund's adjuvant
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