Immunology Frontier Research Center

Ōsaka, Japan

Immunology Frontier Research Center

Ōsaka, Japan
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News Article | April 19, 2017
Site: www.eurekalert.org

Members at IFReC, Osaka University provide new insights on why the tumor suppression gene Foxo1 can actually be the cause of some cancers Germinal centers are transient structures in the lymph nodes where antibody-producing B cells proliferate and differentiate at extraordinary rates. Germinal centers can be visually divided into a dark zone and light zone. For the proliferation and differentiation to occur, B cells must cycle between the two zones. Investigators at the Immunology Frontier Research Center (IFReC), Osaka University have discovered how specific genes regulate this cycling. The findings, which can be read in the Journal of Experimental Medicine, provide new insights on how certain types of lymphomas form. To understand how B cells cycle in the germinal center, Prof. Tomohiro Kurosaki, who led the project, set his eyes on Foxo1. "Foxo1 is a tumor suppressor gene, but it promotes B cell proliferation in the germinal center," he said. Normally, the suppression of Foxo1 expression enables cells to proliferate. Even B cells outside the germinal center will proliferate when Foxo1 is suppressed. However, some lymphomas are associated with activated Foxo1, and Kurosaki and his team observed that inside germinal centers, B cells with Foxo1 suppressed will actually lower in numbers. Transferring the mutant B cells into mice, the researchers further showed that Foxo1 has a vital role in the cycling of B cells between light and dark zones. "We found B cells remained in the light zone," said Kurosaki of the Foxo1-deficient B cells. The dark zone is where B cells undergo proliferation. When in the light zone, B cells are selected by follicular helper T (T ) cells for migration to the dark zone. Kurosaki found that without Foxo1, B cells are not selected at all. "Knocking out Foxo1 reduced the expression of BCR," he said. BCR, or B cell receptors, describe the unit on the B cell that binds to the invasion and from which B cells are selected to proceed with the cycling. Moreover, even if the Foxo1-deficient B cells could be manipulated to be selected by the T cells, they still did not proliferate, suggesting another factor besides Foxo1 is also imperative to cycling. Kurosaki's team noticed that the knockout of Foxo1 also led to a reduction in BATF expression in B cells. Reviving the BATF levels recovered the proliferation of Foxo1-deficient B cells in the germinal center. Thus, the proliferation deficiency could be the result of poor crosstalk between the two genes. The findings provide important new knowledge on antibody production by the body and also the development of certain cancers. "Even though Foxo1 is a tumor suppressor gene, paradoxically its activity is associated with lymphomas," said Kurosaki. This study provides new candidate molecular targets for the treatment of such lymphomas.


News Article | June 29, 2017
Site: www.eurekalert.org

Pain neuron exaggerates inflammation of contact dermatitis and psoriasis. Despite its importance in allergic and autoimmune inflammation, it is not known so far whether pain neuron modulates pathogen-induced inflammation. Scientist at Immunology Frontier Research Center (IFReC) discovered that Nav1.8 ion channel expressing pain neuron inhibits fungal inflammation and bone destruction. "We generated the Nav1.8 ion channel expressing neuron null mice. After C. albicans or C. albicans derived β-glucan injection into the hind paw, these mice showed significantly increased footpad swelling and bone destruction" said Kenta Maruyama, M.D., Ph.D. (Assistant Professor, IFReC). Intriguingly, Nav1.8 ion channel positive neuron expresses Dectin-1, a β-glucan receptor, and Dectin-1 mediated inflammation is potently suppressed by pain neurons, rather than bacterial component-induced inflammation. Detailed experiments of pain neurons revealed that Dectin-1-stumulated pain neuron produces robust amount of CGRP, a neuropeptide that inhibits osteoclast and cytokine production via TRPV1 and TPRA1 ion channel activation. "To our surprise, TRPV1/TRPA1 double deficient mice exhibited exaggerated inflammation and bone destruction in response to β-glucan due to impaired CGRP production, and myeloid cell transcription factor Jdp2 is necessary for the immunosuppression triggered by this neuropeptide" said Kenta. A significant discovery in this study is that transcription factor Jdp2 is induced by CGRP and directly inhibits β-glucan-indeuced NF-κB activation in macrophages. Such findings are consistent with the results showing that Jdp2 deficiency hyper inflammatory phenotype induced by β-glucan was only observed in vivo. Additional study revealed that β-glucan-induced CGRP production from pain neuron is more potent than that induced by LPS, a gram negative bacterial component. "Previous reports suggested that pain neurons are deleterious for inflammation, but our findings suggest that pain neurons may function primarily in suppressing fungal inflammation, rather than bacterial inflammation" said Kenta. "Congenital insensitivity to pain with anhidrosis is an extremely rare hereditary disease characterized by impairment of nociceptor development. Manifestations of this disease are recurrent episodes of skin injury, osteomyelitis, bony fractures, and oral osteolysis. Our discovery may improve the therapeutic strategies of this disease and precise microbiological observation of this patient may clarify the bona-fide role of human pain neurons in fungal infection."


News Article | June 3, 2017
Site: www.sciencedaily.com

Malaria caused by Plasmodium parasites is a life-threatening infectious disease that kills at least half a million people annually while causing over 200 million new infections. In some cases, complications can quickly develop such as cerebral malaria, respiratory distress and severe anemia, often leading to death. The majority of patients recover from disease, however, there is increasing evidence to suggest that survivors experience long-term 'hidden' pathologies due to infection that are as yet poorly defined. Now, the Laboratory of Malaria Immunology Team at the Immunology Frontier Research Center (IFReC), Osaka University, headed by Professor Cevayir COBAN, have used mouse malaria models to show that robust immune activation and invasion of parasite by-products into the bone marrow during and after malaria infection leads to an adverse balance in bone homeostasis -a process usually tightly controlled- by bone forming osteoblasts and bone resorbing osteoclasts. "Even after a one time malaria infection (it does not matter if the disease is completely cured or chronic low level infection continues), substantial chronic bone loss occurs," Dr. Coban, corresponding author of the study, says. Michelle Lee, a PhD candidate and the first author of the study explains, "We found that Plasmodium products continuously accumulate in the bone marrow niche which turns the bone noticeably black in color, and results in it being "eaten-up" by bone resorbing cells known as osteoclasts, eventually disrupting bone homeostasis." These products, including the major malarial by-product hemozoin, malarial proteins and as yet undefined virulence factors, induce MyD88-dependent inflammatory responses in osteoclast and osteoblast precursors, leading to increased RANKL expression (a key molecule inducing osteoclast differentiation), and over-stimulation of osteoclastogenesis favoring bone resorption." The Coban Team infected mice with a mutant Plasmodium parasite producing less by-products such as hemozoin, and discovered in this case bone loss did not occur, thereby confirming their findings. Dr. Coban explains, "Although chronic inflammatory conditions are known to facilitate bone disorders, our study -for the first time- shows that malaria can do the same thing, with hallmark "signatures" left in the bone tissue, a very unique feature of malaria infection. One may think that the infection has been completely cured by anti-malarial treatment, and be feeling fully recovered, however, sustained long-term accumulation of parasite by-products leave the bone in a state of chronic inflammation, leading to long term bone loss. This is particularly worrisome in the young of age, where it may cause growth problems and osteoporotic, fragile bones." Importantly, the study shows that there is a simple way to reverse the side effects of malaria infection on bone. Oral supplementation with alfacalcidol, a vitamin D3 analog, could completely prevent bone loss. Therefore, anti-malarials coupled with bone therapy may be beneficial in improving bone health in malaria-infected individuals.


News Article | June 2, 2017
Site: www.eurekalert.org

Osaka - Malaria caused by Plasmodium parasites is a life-threatening infectious disease that kills at least half a million people annually while causing over 200 million new infections. In some cases, complications can quickly develop such as cerebral malaria, respiratory distress and severe anemia, often leading to death. The majority of patients recover from disease, however, there is increasing evidence to suggest that survivors experience long-term 'hidden' pathologies due to infection that are as yet poorly defined. Now, the Laboratory of Malaria Immunology Team at the Immunology Frontier Research Center (IFReC), Osaka University, headed by Professor Cevayir COBAN, have used mouse malaria models to show that robust immune activation and invasion of parasite by-products into the bone marrow during and after malaria infection leads to an adverse balance in bone homeostasis -a process usually tightly controlled- by bone forming osteoblasts and bone resorbing osteoclasts. "Even after a one time malaria infection (it does not matter if the disease is completely cured or chronic low level infection continues), substantial chronic bone loss occurs", Dr. Coban, corresponding author of the study, says. Michelle Lee, a PhD candidate and the first author of the study explains, "We found that Plasmodium products continuously accumulate in the bone marrow niche which turns the bone noticeably black in color, and results in it being "eaten-up" by bone resorbing cells known as osteoclasts, eventually disrupting bone homeostasis". These products, including the major malarial by-product hemozoin, malarial proteins and as yet undefined virulence factors, induce MyD88-dependent inflammatory responses in osteoclast and osteoblast precursors, leading to increased RANKL expression (a key molecule inducing osteoclast differentiation), and over-stimulation of osteoclastogenesis favoring bone resorption (Figure 1)". The Coban Team infected mice with a mutant Plasmodium parasite producing less by-products such as hemozoin, and discovered in this case bone loss did not occur, thereby confirming their findings. Dr. Coban explains, "Although chronic inflammatory conditions are known to facilitate bone disorders, our study -for the first time- shows that malaria can do the same thing, with hallmark "signatures" left in the bone tissue, a very unique feature of malaria infection. One may think that the infection has been completely cured by anti-malarial treatment, and be feeling fully recovered, however, sustained long-term accumulation of parasite by-products leave the bone in a state of chronic inflammation, leading to long term bone loss. This is particularly worrisome in the young of age, where it may cause growth problems and osteoporotic, fragile bones." Importantly, the study shows that there is a simple way to reverse the side effects of malaria infection on bone. Oral supplementation with alfacalcidol, a vitamin D3 analog, could completely prevent bone loss. Therefore, anti-malarials coupled with bone therapy may be beneficial in improving bone health in malaria-infected individuals.


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.


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 | 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 | 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 | 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.

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