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Kumagai Y.,Immunology Frontier Research Center | Akira S.,Immunology Frontier Research Center
Journal of Allergy and Clinical Immunology | Year: 2010

Since the identification of Toll-like receptors, our knowledge about pattern-recognition receptors (PRRs) has increased rapidly. Classes of PRRs that have been recently discovered include RIG-I-like receptors, Nod-like receptors, and C-type lectin receptors. Recent studies have started to clarify the molecular basis of PRR-ligand interactions, yet the numbers of PRRs and their ligands continue to increase. New technologies have elucidated the network regulation of immune responses at the cellular and in vivo levels. We review the most recent discoveries about PRRs and their ligands, their roles in intracellular and in vivo regulation of immune responses, and the systems biology of innate immunity. © 2010 American Academy of Allergy, Asthma & Immunology.


Kumar H.,Immunology Frontier Research Center | Kumar H.,Indian Institute of Science | Kawai T.,Immunology Frontier Research Center | Kawai T.,Osaka University | And 2 more authors.
International Reviews of Immunology | Year: 2011

Microbial infection initiates complex interactions between the pathogen and the host. Pathogens express several signature molecules, known as pathogen-associated molecular patterns (PAMPs), which are essential for survival and pathogenicity. PAMPs are sensed by evolutionarily conserved, germline-encoded host sensors known as pathogen recognition receptors (PRRs). Recognition of PAMPs by PRRs rapidly triggers an array of anti-microbial immune responses through the induction of various inflammatory cytokines, chemokines and type I interferons. These responses also initiate the development of pathogen-specific, long-lasting adaptive immunity through B and T lymphocytes. Several families of PRRs, including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), and DNA receptors (cytosolic sensors for DNA), are known to play a crucial role in host defense. In this review, we comprehensively review the recent progress in the field of PAMP recognition by PRRs and the signaling pathways activated by PRRs. © 2011 Informa Healthcare USA, Inc.


News Article | February 21, 2017
Site: www.eurekalert.org

Osaka University and Otsuka Pharmaceutical Co., Ltd. (Otsuka) signed a comprehensive collaboration agreement for advanced research in immunology between the Osaka University Immunology Frontier Research Center (IFReC) and Otsuka. This agreement allows researchers at IFReC to focus on original basic research areas and, with Otsuka, to develop innovative new treatments therefore contributing back to society with the results of their advanced immunology research. IFReC was selected for the World Premier International Research Center (WPI) Initiative Program initiated by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) in 2007 and launched at Osaka University in October of the same year as a research center in immunology. Led by Director Shizuo Akira, an eminent immunologist, IFReC brings together around 170 of the world's leading investigators in the fields of immunology, live imaging and bioinformatics from Japan and across the world to conduct innovative immunological research. The center provides an international environment coupled with excellent research facilities, making it possible to pursue leading-edge research. IFReC researchers publish in internationally renowned academic journals to high acclaim including the award of several prestigious international prizes. Guided by our corporate philosophy, Otsuka-people creating new products for better health worldwide, Otsuka is committed to improving the health and well-being of patients and consumers through "treating diseases" and "promoting daily health". As a total healthcare company, Otsuka continues to focus on creating creative and innovative products. In order to address unmet needs in medicine, we focus our research on central nervous system disorders and oncology, and also develop treatments in cardiovascular, infectious, ophthalmological, and dermatological disease fields. According to the agreement, Otsuka will have access to information regarding results of independent basic research projects at IFReC. Although Chugai Pharmaceutical Co., Ltd., which signed a prior agreement has the right of first refusal on joint research projects and intellectual property. Otsuka can discuss future joint research with IFReC, and receive disclosure about future patent rights in immunology from Osaka University. As part of this agreement, Otsuka will contribute to the research activity expenses of IFReC for a period of 10 years.


News Article | October 31, 2016
Site: www.eurekalert.org

Researchers in Japan have discovered that the adrenergic nervous system controls when white blood cells circulate through the body, boosting the immune response by retaining T and B cells in lymph nodes at the time of day when they are most likely to encounter foreign antigens. The study, "Adrenergic control of the adaptive immune response by diurnal lymphocyte recirculation through lymph nodes," will be published online October 31 ahead of issue in The Journal of Experimental Medicine. On their way around the body, T and B cells pass through lymph nodes, where specialized cells may present them with antigen molecules captured from bacteria or other pathogens. The T and B cells then reenter the bloodstream in search of these pathogens so that they can kill them and fight off infection. Previous studies have suggested that number of T and B cells present in the bloodstream varies over the course of the day. Kazuhiro Suzuki and colleagues from the WPI Immunology Frontier Research Center at Osaka University found that, in mice, the number of T and B cells in the blood peaked during the day and decreased during the night, when they accumulated in lymph nodes instead. This daily, or circadian, cycle of immune cell trafficking was regulated by the neurotransmitter noradrenaline, released from adrenergic nerves innervating the lymph nodes. The nerves secreted more noradrenaline at night, activating β2-adrenergic receptor molecules on the surface of T and B cells that impede the cells' exit from lymph nodes. Mice mounted a stronger immune response if they were injected with antigens at night, when more of their T and B cells were exposed to antigen-presenting cells in lymph nodes. This makes sense, Suzuki and colleagues note, because mice are nocturnal creatures and are therefore more likely to encounter pathogens when they are active during the night. Accordingly, the daily cycle may be flipped in humans, whose T and B cells appear to accumulate in lymph nodes during the day, when adrenergic nerves are thought to be more active. About The Journal of Experimental Medicine The Journal of Experimental Medicine (JEM) features peer-reviewed research on immunology, cancer biology, stem cell biology, microbial pathogenesis, vascular biology, and neurobiology. All editorial decisions are made by research-active scientists in conjunction with in-house scientific editors. JEM provides free online access to many article types from the date of publication and to all archival content. Established in 1896, JEM is published by The Rockefeller University Press. For more information, visit jem.org. Follow us on Twitter at @JExpMed and @RockUPress.


News Article | December 22, 2016
Site: www.eurekalert.org

Scientists at the Immunology Frontier Research Center (IFReC) at Osaka University, Japan have pinpointed a specific molecular events that could explain allergic reactions to air pollution. These findings provide a new therapeutic candidate to treat asthma and related respiratory diseases. Photos of cities darkened by pollution are becoming evermore common. These same cities are seeing a rise in cases of asthma and other respiratory ailments, marking a relationship between pollution and health costs. Nanoscopic particulates polluting the air enter the lungs to cause the allergic reactions. Which immune-related events in the lung lead to this response, however, are unclear. "We found that particulates kill macrophages, which then go on to release interleukin-1α (IL-1α)", explains Etsushi Kuroda, who first-authored a new study in Immunity that indicates IL-1α triggers a series of events that causes respiratory illnesses. The release of IL-1α in mice primed the lungs for inflammation when the mice were later exposed to an allergen. Kuroda added, "Particulates that did not kill macrophages did not cause an allergic reaction." However, the vulnerability of macrophages to particulates remains unclear, which is why understanding the events following IL-1α secretion may be key to prevention and treatment. "IL-1α secretion was followed by the formation of iBALTs. iBALTs are frequently found in infected or inflamed lungs and in patients with asthma," said Osaka University Professor Ken J. Ishii, who led the study. The increase in iBALTs led to an increase in IgE antibodies, which intensified the immune response. On the other hand, mutant mice that were insensitive to IL-1α did not produce iBALTs and reduced IgE responses. The presence of iBALTs would suggest that a human population could remain susceptible to high levels of asthma attacks even on clear days, as the iBALTs could form on days of high pollution, but the patient could then be exposed to the allergen much later. This finding suggested that iBALTs could prime the lungs to an allergic reaction, which is why Ishii believes that iBALTs could make a promising therapeutic target to combat the rise of respiratory illnesses associated with air pollution. But first, he said, "we must identify the molecular signals and key chemicals that form these iBALTs."


News Article | December 23, 2016
Site: www.biosciencetechnology.com

Scientists at the Immunology Frontier Research Center (IFReC) at Osaka University, Japan, report a new group of monocytes they call SatM. Studies in mice show that SatM may be responsible for causing fibrosis and creates a new drug target for an ailment that has little effective therapies. Fibrosis is a form of scarring that could if uncontrolled cause deleterious thickening of tissues. Although it is known that fibrosis is caused by an activated immune system, which specific cells are responsible continuous to elude researchers. Scientists at IFReC may have found this subgroup, as they report in Nature a class of monocyte cells with strange morphology. "The cells had a bi-lobed segmented nuclear shape and many cytoplasmic granules. We therefore called them 'Segregated nucleus atypical monocytes (SatM)'", said IFReC Professor Shizuo Akira. To identify this subgroup, the researchers looked at immune cell subpopulations that predominantly appeared in fibrosis. "These cells were regulated by C/EBPβ," observed Akira. Detailed examination of immune cells showed that the C/EBPβ mutant mice, unlike normal mice, produced no SatM, whereas no other observed immune cell population was changed. The mice were also significantly more resistant to fibrosis. On the other hand, when the mutant mice were exposed to SatM, their susceptibility to fibrosis rose. Although Dr. Akira, Dr. Satoh and his colleagues describe SatM as a subset of monocytes, SatM showed characteristics that suggested they were hybrids of different immune cells. According to Akira, gene analysis found SatM "showed granulocyte markers, but SatM are definitely not granulocytes. These cell type is one of monocyte." Additional study found the progenitor cells responsible for producing SatM. Adoptive transfer of these progenitors into mutant mice unable to produce SatM resulted in a SatM population, and C/EBPβ was found to be essential for maintaining the progenitors. The ability to isolate cells specifically related to fibrosis gives hope for new therapies. "Decades of research have shown that immune cells are extremely diverse," said Akira. "Clear definitions of the subpopulations are essential for properly diagnosing and treating diseases. Our discovery of SatM should improve therapeutic strategies against fibrosis."


News Article | December 27, 2016
Site: www.eurekalert.org

Scientists at the Immunology Frontier Research Center (IFReC), Osaka University, Japan, report a new molecular mechanism that could explain the cause of some autoimmune diseases. While the immune system is crucial for protecting the body from infection and disease, prolonged activation can damage healthy tissue. After its activation, the immune system is shut off by specialized immune cells known as regulatory T cells (Treg cells). Understanding the development of Treg cells is thought to be critical for combating autoimmune diseases. "The development of Treg cells in the thymus depends on super-enhancer establishment," explains IFReC Professor Shimon Sakaguchi. This super-enhancer establishment permits the expression of genes specific for Treg cell development. "Super-enhancers appeared to be a pre-requisite for Treg cell development, so we sought molecules controlling super-enhancers," he added. In the most recent publication by the Sakaguchi lab, which can be seen in Nature Immunology, Sakaguchi and his team report that Satb1 regulates the super enhancers essential for Treg cell development. Looking at the Treg cell development pathway, the scientists found that the level of Satb1 was highest before Treg cells develop, and dropped after Treg cell development. Further study showed that Satb1 bound to the super enhancers responsible for Treg cell development, but again, only in progenitors that differentiated into Treg cells and not Treg cells themselves. Therefore, Satb1 may regulate the epigenetic changes that precede the creation of Treg cells. "Satb1 appears to be necessary for the differentiation of Treg cells, but not for the maintenance of Treg cells," said Dr. Yohko Kitagawa, who first-authored the study. Indeed, in mice lacking Satb1, the development of Treg cells was impaired and the mice showed symptoms of autoimmune disease. Furthermore, the progenitors cells of these mice showed inferior super enhancer activity, which resulted in less expression of the genes necessary for Treg cell development. Based on these findings, Sakaguchi theorizes that defective Satb1-dependent super-enhancer establishment could be a cause of autoimmune diseases and allergy. "Autoimmune diseases are due to hyperactive immune systems. One cause is not having enough Treg cells. Understanding how this occurs is an important step towards treating autoimmune diseases," he said.


News Article | October 31, 2016
Site: www.sciencedaily.com

Researchers in Japan have discovered that the adrenergic nervous system controls when white blood cells circulate through the body, boosting the immune response by retaining T and B cells in lymph nodes at the time of day when they are most likely to encounter foreign antigens. The study, "Adrenergic control of the adaptive immune response by diurnal lymphocyte recirculation through lymph nodes," will be published online October 31 ahead of issue in The Journal of Experimental Medicine. On their way around the body, T and B cells pass through lymph nodes, where specialized cells may present them with antigen molecules captured from bacteria or other pathogens. The T and B cells then reenter the bloodstream in search of these pathogens so that they can kill them and fight off infection. Previous studies have suggested that number of T and B cells present in the bloodstream varies over the course of the day. Kazuhiro Suzuki and colleagues from the WPI Immunology Frontier Research Center at Osaka University found that, in mice, the number of T and B cells in the blood peaked during the day and decreased during the night, when they accumulated in lymph nodes instead. This daily, or circadian, cycle of immune cell trafficking was regulated by the neurotransmitter noradrenaline, released from adrenergic nerves innervating the lymph nodes. The nerves secreted more noradrenaline at night, activating β2-adrenergic receptor molecules on the surface of T and B cells that impede the cells' exit from lymph nodes. Mice mounted a stronger immune response if they were injected with antigens at night, when more of their T and B cells were exposed to antigen-presenting cells in lymph nodes. This makes sense, Suzuki and colleagues note, because mice are nocturnal creatures and are therefore more likely to encounter pathogens when they are active during the night. Accordingly, the daily cycle may be flipped in humans, whose T and B cells appear to accumulate in lymph nodes during the day, when adrenergic nerves are thought to be more active.


News Article | December 22, 2016
Site: www.eurekalert.org

Scientists at the Immunology Frontier Research Center (IFReC) at Osaka University, Japan, report a new group of monocytes they call SatM. Studies in mice show that SatM may be responsible for causing fibrosis and creates a new drug target for an ailment that has little effective therapies. Fibrosis is a form of scarring that could if uncontrolled cause deleterious thickening of tissues. Although it is known that fibrosis is caused by an activated immune system, which specific cells are responsible continuous to elude researchers. Scientists at IFReC may have found this subgroup, as they report in Nature a class of monocyte cells with strange morphology. "The cells had a bi-lobed segmented nuclear shape and many cytoplasmic granules. We therefore called them 'Segregated nucleus atypical monocytes (SatM)'", said IFReC Professor Shizuo Akira. To identify this subgroup, the researchers looked at immune cell subpopulations that predominantly appeared in fibrosis. "These cells were regulated by C/EBPβ," observed Akira. Detailed examination of immune cells showed that the C/EBPβ mutant mice, unlike normal mice, produced no SatM, whereas no other observed immune cell population was changed. The mice were also significantly more resistant to fibrosis. On the other hand, when the mutant mice were exposed to SatM, their susceptibility to fibrosis rose. Although Dr. Akira, Dr. Satoh and his colleagues describe SatM as a subset of monocytes, SatM showed characteristics that suggested they were hybrids of different immune cells. According to Akira, gene analysis found SatM "showed granulocyte markers, but SatM are definitely not granulocytes. These cell type is one of monocyte." Additional study found the progenitor cells responsible for producing SatM. Adoptive transfer of these progenitors into mutant mice unable to produce SatM resulted in a SatM population, and C/EBPβ was found to be essential for maintaining the progenitors. The ability to isolate cells specifically related to fibrosis gives hope for new therapies. "Decades of research have shown that immune cells are extremely diverse," said Akira. "Clear definitions of the subpopulations are essential for properly diagnosing and treating diseases. Our discovery of SatM should improve therapeutic strategies against fibrosis."


News Article | December 26, 2016
Site: www.techtimes.com

Researchers in Japan have pinned down a set of molecular level events that could easily relate allergic reactions and respiratory problems to the presence of air pollution. As the pollution level in the air rises, the cases of asthma and other respiratory troubles also seem to be increasing. Nano-scopic particle matter pollutes the air and gets into the lungs. Macrophages, or the white blood cells responsible for consuming the foreign pollutants, fail to protect the immune system, causing the allergic reactions. A research conducted on mice, by scientists at the Immunology Frontier Research Center (IFReC) at Osaka University, Japan, revealed that certain molecular level happenings can help explain allergic reactions in human due to air pollution. Etsushi Kuroda, researcher at Osaka University, performed and penned the study in Immunity, showing that release of IL-1α, group of cytokines responsible for regulating immunity and inflammatory responses to infections, initiates a series of events that result in respiratory diseases. "We found that particulates kill macrophages, which then go on to release interleukin-1α (IL-1α)," stated Kuroda, in a press release. The release of IL-1α in mice primed the lungs for inflammation when the mice were later exposed to an allergen. "Particulates that did not kill macrophages did not cause an allergic reaction," Kuroda added. The immune-related events occurring in the lungs leading to allergic reactions are still not known. The scientists feel that uncovering these events can be a breakthrough that is required in the treatment and prevention of respiratory ailments. Osaka University Professor Ken J. Ishii, who was leading the study, explained that emission of IL-1α was followed by development iBALTs (Inducible Bronchus-Associated Lymphoid Tissue). iBALTs are type of tissues that are usually found in lungs of patients with asthma or lungs with inflammation or infection. Formation of iBALTs in humans indicates that people could remain vulnerable to high levels of asthma attacks, even on clear and pollution-free days. Given that iBALTs could develop in people's lungs on high pollution days, the victims could be exposed to allergen much later. The experiment conducted on mutant mice revealed that they were not sensitive to IL-1α and hence did not produce iBALTs. Scientists believe that targeting the reason behind formation of iBALTs in infected lungs can help in the treatment and prevention of all kinds of respiratory ailments arising due to air pollution. Discovering the molecular signals and chief chemicals responsible for development of iBALTs in lungs can be the next step in the raging battle against asthma and other respiratory diseases. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.

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