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  • Outstanding Merit Award 2020
    Int. Immunol. (IF 3.519) Pub Date : 2020-09-24
    Ishii K, Kurosaki T.

    The development of sophisticated, modern vaccinology from the ancient practice of variolation has paralleled our ever-increasing knowledge about the immune system and the infectious agents that have always faced each other. The challenge of smallpox eventually led to one, ultimately effective, strategy to eradicate this disease and the success of vaccination inspired further research into our immune

  • ATG16L1 negatively regulates RICK/RIP2-mediated innate immune responses.
    Int. Immunol. (IF 3.519) Pub Date : 2020-09-10
    Hajime Honjo,Tomohiro Watanabe,Yasuyuki Arai,Ken Kamata,Kosuke Minaga,Yoriaki Komeda,Kouhei Yamashita,Masatoshi Kudo

    Polymorphisms in the autophagy-related protein 16 like 1 (ATG16L1) and nucleotide-binding oligomerization domain 2 (NOD2) genes are associated with Crohn’s disease (CD). Impaired interaction between ATG16L1 and NOD2 underlies CD immunopathogenesis. Although activation of the receptor-interacting serine/threonine kinase (RICK, also known as RIP2), a downstream signaling molecule for NOD2 and multiple

  • AMBRA1 controls antigen-driven activation and proliferation of naïve T cells.
    Int. Immunol. (IF 3.519) Pub Date : 2020-09-10
    Kaori Masuhara,Hisako Akatsuka,Mizuki Tokusanai,Chenyang Li,Yumi Iida,Yoshinori Okada,Takahiro Suzuki,Masato Ohtsuka,Ituro Inoue,Minoru Kimura,Hiroyuki Hosokawa,Katsuto Hozumi,Takehito Sato

    AMBRA1 is a member of the BECN1 (BECLIN1) complex protein, and it plays a role in autophagy, cell death, tumorigenesis, and proliferation. We recently reported that on TCR stimulation, AMBRA1 controlled both autophagy and the cell cycle with metabolic regulation. Accumulating evidence has shown that autophagy and metabolic control are pivotal for T cell activation, clonal expansion, and effector/memory

  • Introduction: Memory and Vaccination Special Issue
    Int. Immunol. (IF 3.519) Pub Date : 2020-08-22
    Ken J Ishii; Tomohiro Kurosaki

    The development of sophisticated, modern vaccinology from the ancient practice of variolation has paralleled our ever-increasing knowledge about the immune system and the infectious agents that have always faced each other. The challenge of smallpox eventually led to one, ultimately effective, strategy to eradicate this disease and the success of vaccination inspired further research into our immune

  • Multiple developmental pathways lead to the generation of CD4 T-cell memory.
    Int. Immunol. (IF 3.519) Pub Date : 2020-08-07
    Shintaro Hojyo,Damon Tumes,Akihiko Murata,Koji Tokoyoda

    Long-term immunological memory mediated by CD4 T cells provides a rapid protection against previously encountered pathogens or antigens. However, it is still controversial how memory CD4 T cells are generated and maintained. Unclear definitions of T-cell memory may be partially responsible for this controversy. It is becoming clear that diverse pathways are responsible for the differentiation and long-term

  • The relationship between CD4+ follicular helper T cells and CD8+ resident memory T cells: sisters or distant cousins?
    Int. Immunol. (IF 3.519) Pub Date : 2020-07-03
    Changwei Peng,Stephen C Jameson

    Independent studies over the last decade have characterized the properties of non-circulating CD8+ ‘resident’ memory T cells (TRM), which offer barrier protective immunity in non-lymphoid tissues and CD4+ follicular helper T cells (TFH), which mediate B-cell help in lymphoid sites. Despite their very different biological roles in the immune system, intriguing parallels have been noted between the trafficking

  • Bim establishes the B cell repertoire from early to late in the immune response.
    Int. Immunol. (IF 3.519) Pub Date : 2020-09-05
    Akiko Sugimoto-Ishige,Michishige Harada,Miho Tanaka,Tommy Terooatea,Yu Adachi,Yoshimasa Takahashi,Takashi Tanaka,Peter D Burrows,Masaki Hikida,Toshitada Takemori

    In T cell-dependent antibody responses, some of the activated B cells differentiate along extrafollicular pathways into low-affinity memory and plasma cells, whereas others are involved in subsequent GC formation in follicular pathways, in which somatic hypermutation and affinity maturation occur. The present study demonstrated that Bim, a proapoptotic BH3-only member of the Bcl-2 family, contributes

  • Increased levels of plasma nucleotides in patients with rheumatoid arthritis.
    Int. Immunol. (IF 3.519) Pub Date : 2020-08-31
    Toshihiro Kishikawa,Yuichi Maeda,Takuro Nii,Noriko Arase,Jun Hirata,Ken Suzuki,Kenichi Yamamoto,Tatsuo Masuda,Kotaro Ogawa,Shigeyoshi Tsuji,Masato Matsushita,Hidetoshi Matsuoka,Maiko Yoshimura,Shinichiro Tsunoda,Shiro Ohshima,Masashi Narazaki,Atsushi Ogata,Yukihiko Saeki,Hidenori Inohara,Atsushi Kumanogoh,Kiyoshi Takeda,Yukinori Okada

    Novel biomarkers of rheumatoid arthritis (RA), in addition to antibodies against cyclic citrullinated peptides, are required. Metabolome analysis is a promising approach to identify metabolite biomarkers for clinical diagnosis. We adopted a comprehensive nontargeted metabolomics approach combining capillary electrophoresis time-of-flight mass-spectrometry (TOFMS) and liquid chromatography TOFMS. We

  • The impact of cell maturation and tissue microenvironments on the expression of endosomal Toll-like receptors in monocytes and macrophages.
    Int. Immunol. (IF 3.519) Pub Date : 2020-08-25
    Ryota Sato,Tatjana Reuter,Ryosuke Hiranuma,Takuma Shibata,Ryutaro Fukui,Yuji Motoi,Yusuke Murakami,Hiroki Tsukamoto,Satoshi Yamazaki,Kaiwen Liu,Shin-Ichiroh Saitoh,Eicke Latz,Kensuke Miyake

    Toll-like receptors (TLRs) impact myeloid cell responsiveness to environmental cues such as pathogen components and metabolites. Although TLR protein expression in monocytes and tissue macrophages is thought to be optimized for microenvironments in each tissue, a comprehensive study has not been reported. We here examined protein expression of endogenous TLRs in tissue resident myeloid cells. Neutrophils

  • Type I interferons induce peripheral T regulatory cell differentiation under tolerogenic conditions.
    Int. Immunol. (IF 3.519) Pub Date : 2020-08-25
    Sara Vitale,Valentina Russo,Beatrice Dettori,Cecilia Palombi,Denis Baev,Enrico Proietti,Agnes Le Bon,Filippo Belardelli,Luigia Pace

    The type I interferons (type I IFNs) are central to a vast array of immunological functions. The production of these immune-modulatory molecules is initiated at the early stages of the innate immune responses and, therefore, plays a dominant role in shaping downstream events in both innate and adaptive immunity. Indeed, the major role of IFNα/β is the induction of priming states, relevant for the functional

  • Organized immune cell interactions within tumors sustain a productive T cell response.
    Int. Immunol. (IF 3.519) Pub Date : 2020-08-22
    Maria A Cardenas,Nataliya Prokhnevska,Haydn T Kissick

    Tumor-infiltrating CD8 T cells are associated with improved patient survival and response to immunotherapy in various cancers. Persistent antigen leads to CD8 T cell exhaustion, where proliferation/self-renewal and killing are divided within distinct subsets of CD8 T cells in the tumor. CD8 T cell responses in chronic antigen settings must be maintained for long periods of time, suggesting that mechanisms

  • Immunodietica: interrogating the role of diet in autoimmune disease.
    Int. Immunol. (IF 3.519) Pub Date : 2020-08-18
    Iosif M Gershteyn,Andrey A Burov,Brenda Y Miao,Vasco H Morais,Leonardo M R Ferreira

    Diet is an environmental factor in autoimmune disorders, where the immune system erroneously destroys one’s own tissues. Yet, interactions between diet and autoimmunity remain largely unexplored, particularly the impact of immunogenetics, one’s human leukocyte antigen (HLA) allele make-up, in this interplay. Here, we interrogated animals and plants for the presence of epitopes implicated in human autoimmune

  • Fc receptor-like 4 and 5 define human atypical memory B cells.
    Int. Immunol. (IF 3.519) Pub Date : 2020-08-17
    Huifang Li,Jessica Dement-Brown,Pei-Jyun Liao,Ilya Mazo,Frederick Mills,Zachary Kraus,Sean Fitzsimmons,Mate Tolnay

    Atypical memory B cells accumulate in chronic infections and autoimmune conditions, and commonly express FCRL4 and FCRL5, respective IgA and IgG receptors. We characterized memory cells from tonsils based on both FCRL4 and FCRL5 expression, defining three subsets with distinct surface proteins and gene expression. Atypical FCRL4+FCRL5+ memory cells had the most discrete surface protein expression and

  • Overcoming immune dysfunction in the elderly: trained immunity as a novel approach.
    Int. Immunol. (IF 3.519) Pub Date : 2020-08-07
    Ozlem Bulut,Gizem Kilic,Jorge Domínguez-Andrés,Mihai G Netea

    People with advanced age have a higher susceptibility to infections and exhibit increased mortality and morbidity as the ability of the immune system to combat infections decreases with age. While innate immune cells display functional defects such as decreased phagocytosis, chemotaxis and cytokine production, adaptive immune cells exhibit reduced receptor diversity, defective antibody production and

  • Newly emerged immunogenic neoantigens in established tumors enable hosts to regain immunosurveillance in a T cell-dependent manner.
    Int. Immunol. (IF 3.519) Pub Date : 2020-07-30
    Tomoaki Muramatsu,Takuro Noguchi,Daisuke Sugiyama,Yoshie Kanada,Kaori Fujimaki,Sachiko Ito,Momokazu Gotoh,Hiroyoshi Nishikawa

    Tumor neoantigens derived from genetic alterations are potential T cell targets for antitumor immunity. However, tumors develop immune escape mechanisms including loss of preexisting neoantigens and/or impairment of T cell responses during tumor development and progression. Here, we addressed whether newly emerged immunogenic neoantigens in established tumors enabled hosts to inhibit tumor growth via

  • Crystal structure of the ternary complex of TCR, MHC class I, and lipopeptides.
    Int. Immunol. (IF 3.519) Pub Date : 2020-07-28
    Daisuke Morita,Chieri Iwashita,Tatsuaki Mizutani,Naoki Mori,Bunzo Mikami,Masahiko Sugita

    The covalent conjugation of a 14-carbon fatty acid (myristic acid) to the N-terminal Gly residue, termed N-myristoylation, occurs in some viral proteins to dictate their pathological function. This protein lipidation reaction, however, is monitored by host cytotoxic T-lymphocytes that are capable of recognizing N-terminal lipopeptide fragments in the context of MHC class I molecules. In a rhesus model

  • In This Issue
    Int. Immunol. (IF 3.519) Pub Date : 2020-07-28

    The active form of vitamin D3 is delivered and can also be generated in, e.g., keratinocytes and binds the nuclear receptor, vitamin D3 receptor (VDR), leading to the expression of various target genes to modulate a wide range of immune responses. Oxarol ointment provides supraphysiological concentrations of active vitamin D3 and is an effective and safe anti-inflammatory treatment for psoriasis. In

  • Immune-enhancing effects of glucocorticoids in response to day-night cycles and stress.
    Int. Immunol. (IF 3.519) Pub Date : 2020-07-25
    Akihiro Shimba,Koichi Ikuta

    Environmental cues such as the day–night cycle or stressors trigger the production of glucocorticoids (GCs) by the adrenal cortex. GCs are well known for their anti-inflammatory effects that suppress the production of inflammatory cytokines and induce the apoptosis of lymphocytes. Recent studies in mice, however, have revealed pro-inflammatory effects. The diurnal oscillation of GCs induces the expression

  • Assessment of Th1/Th2 cytokines among patients with Middle East respiratory syndrome coronavirus infection.
    Int. Immunol. (IF 3.519) Pub Date : 2020-07-10
    Abdulkarim Alhetheel,Ahmed Albarrag,Zahid Shakoor,Ali Somily,Mazin Barry,Hifa Altalhi,Muhammed Bakhrebah,Majed Nassar,Mohamed B Alfageeh,Ayed Assiri,Sarah H Alfaraj,Ziad A Memish

    Middle East respiratory syndrome coronavirus (MERS-CoV) is a member of the beta-coronavirus genus of zoonotic origin that emerged in the Arabian Peninsula and is associated with significant morbidity and mortality. This study was conducted to assess the plasma levels of cytokines to evaluate the Th1/Th2 status among 46 MERS-CoV infected patients (19 asymptomatic and 27 symptomatic) and 52 normal healthy

  • Immune metabolism in PD-1 blockade-based cancer immunotherapy.
    Int. Immunol. (IF 3.519) Pub Date : 2020-07-05
    Alok Kumar,Kenji Chamoto

    Energy metabolism plays an important role in proliferating cells. Recent reports indicate that metabolic regulation or metabolic products can control immune cell differentiation, fate and reactions. Cancer immunotherapy based on blockade of programmed cell death protein 1 (PD-1) has been used worldwide, but a significant fraction of patients remain unresponsive. Therefore, clarifying the mechanisms

  • Autosomal recessive complete STAT1 deficiency caused by compound heterozygous intronic mutations.
    Int. Immunol. (IF 3.519) Pub Date : 2020-06-30
    Sonoko Sakata,Miyuki Tsumura,Tadashi Matsubayashi,Shuhei Karakawa,Shunsuke Kimura,Moe Tamaura,Tsubasa Okano,Takuya Naruto,Yoko Mizoguchi,Reiko Kagawa,Shiho Nishimura,Kohsuke Imai,Tom Le Voyer,Jean-Laurent Casanova,Jacinta Bustamante,Tomohiro Morio,Osamu Ohara,Masao Kobayashi,Satoshi Okada

    Autosomal recessive (AR) complete signal transducer and activator of transcription 1 (STAT1) deficiency is an extremely rare primary immunodeficiency that causes life-threatening mycobacterial and viral infections. Only seven patients from five unrelated families with this disorder have been so far reported. All causal STAT1 mutations reported are exonic and homozygous. We studied a patient with susceptibility

  • Introduction: Special Issue—Immunometabolism
    Int. Immunol. (IF 3.519) Pub Date : 2020-06-22
    Heiichiro Udono; Atsushi Kumanogoh

    Cell metabolism can be defined as the anabolic and catabolic biochemical pathways that generate energy, supply building blocks for synthesis and enable the breakdown of complex molecules. Vast efforts have succeeded in delineating these processes in a huge number of cell types across the entire range of species. Many basic pathways are in fact shared across this range and by all cells within individuals

  • Role of dendritic cell metabolic reprogramming in tumor immune evasion.
    Int. Immunol. (IF 3.519) Pub Date : 2020-05-25
    Michael P Plebanek,Michael Sturdivant,Nicholas C DeVito,Brent A Hanks

    The dendritic cell (DC) is recognized as a vital mediator of anti-tumor immunity. More recent studies have also demonstrated the important role of DCs in the generation of effective responses to checkpoint inhibitor immunotherapy. Metabolic programming of DCs dictates their functionality and can determine which DCs become immunostimulatory versus those that develop a tolerized phenotype capable of

  • Danger-associated metabolic modifications during bacterial infection of macrophages.
    Int. Immunol. (IF 3.519) Pub Date : 2020-05-22
    Mariatou Dramé,Carmen Buchrieser,Pedro Escoll

    In this review, we propose that certain modifications in cellular metabolism might function as danger signals triggering inflammasome-mediated immune responses. We propose to call them danger-associated metabolic modifications (DAMMs). As intracellular bacteria can actively modulate macrophage metabolism for their benefit, infected host cells might sense bacteria-induced metabolic alterations and activate

  • Amino acids: key sources for immunometabolites and immunotransmitters.
    Int. Immunol. (IF 3.519) Pub Date : 2020-05-08
    Michio Miyajima

    Immune-cell activation and functional plasticity are closely linked to metabolic reprogramming that is required to supply the energy and substrates for such dynamic transformations. During such processes, immune cells metabolize many kinds of molecules including nucleic acids, sugars and lipids, which is called immunometabolism. This review will mainly focus on amino acids and their derivatives among

  • Tet DNA demethylase is required for plasma cell differentiation by controlling expression levels of IRF4.
    Int. Immunol. (IF 3.519) Pub Date : 2020-06-25
    Kentaro Fujii,Shinya Tanaka,Takanori Hasegawa,Masashi Narazaki,Atsushi Kumanogoh,Haruhiko Koseki,Tomohiro Kurosaki,Wataru Ise

    Antibodies produced by plasma cells are critical for protection from infection. It has been demonstrated that global epigenetic modification, such as changes in DNA methylation, occurs during differentiation of plasma cells from B cells. However, the precise mechanisms by which DNA methylation controls plasma cell differentiation are not fully understood. We examined the effect of deficiency of DNA

  • The impact of metabolites derived from the gut microbiota on immune regulation and diseases.
    Int. Immunol. (IF 3.519) Pub Date : 2020-06-20
    Hiroshi Ohno

    Gut microbiota strongly impacts the physiology and pathology in the host. To understand the complex interactions between host and gut microbiota, an “integrated omics” approach has been employed, where exhaustive analyses for the different layers of cellular functions, such as epigenomics, transcriptomics and metabolomics, in addition to metagenomics, are combined. With this approach, the mechanisms

  • Impact of multiple hits with cognate antigen on memory CD8+ T-cell fate.
    Int. Immunol. (IF 3.519) Pub Date : 2020-06-07
    Shiki Takamura

    Antigen-driven activation of CD8+ T cells results in the development of a robust anti-pathogen response and ultimately leads to the establishment of long-lived memory T cells. During the primary response, CD8+ T cells interact multiple times with cognate antigen on distinct types of antigen-presenting cells. The timing, location and context of these antigen encounters significantly impact the differentiation

  • Stereotyped B-cell response that counteracts antigenic variation of influenza viruses.
    Int. Immunol. (IF 3.519) Pub Date : 2020-06-06
    Keisuke Tonouchi,Yu Adachi,Saya Moriyama,Kaori Sano,Koshiro Tabata,Keigo Ide,Haruko Takeyama,Tadaki Suzuki,Yoshimasa Takahashi

    Influenza A subtypes are categorized into group 1 and group 2 based on the hemagglutinin (HA) sequence. Owing to the phylogenetic distance of HAs in different groups, antibodies that bind multiple HA subtypes across different groups are extremely rare. In this study, we demonstrated that an immunization with acid-treated HA antigen elicits germinal center (GC) B cells that bind multiple HA subtypes

  • Near-infrared photoimmunotherapy of cancer: a new approach that kills cancer cells and enhances anti-cancer host immunity.
    Int. Immunol. (IF 3.519) Pub Date : 2020-06-04
    Hisataka Kobayashi,Aki Furusawa,Adrian Rosenberg,Peter L Choyke

    Near-infrared photoimmunotherapy (NIR-PIT) is a recently developed hybrid cancer therapy that directly kills cancer cells as well as producing a therapeutic host immune response. Conventional immunotherapies, such as immune-activating cytokine therapy, checkpoint inhibition, engineered T-cells and suppressor cell depletion, do not directly destroy cancer cells, but rely exclusively on activating the

  • Lung fibroblasts produce interleukin-33 in response to stimulation by retinoblastoma-binding protein 9 via production of prostaglandin E2.
    Int. Immunol. (IF 3.519) Pub Date : 2020-06-03
    Takumi Adachi,Koubun Yasuda,Taichiro Muto,Satoshi Serada,Tomohiro Yoshimoto,Ken J Ishii,Etsushi Kuroda,Kimi Araki,Masaki Ohmuraya,Tetsuji Naka,Kenji Nakanishi

    Intestinal nematode infection induces pulmonary eosinophilia via interleukin (IL)-33, although the mechanism of pulmonary IL-33 induction remains unclear. Because nematode migration damages lungs, we speculated that lung-derived damage-associated molecular patterns (DAMPs) possess an IL-33-inducing activity (IL33ia). Indeed, intranasal administration of a lung extract induced IL-33 production in lungs

  • In This Issue
    Int. Immunol. (IF 3.519) Pub Date : 2020-05-30

    Keratinocytes produce cytokines and participate in immune responses and skin healing. Poly(I:C) is a ligand for TLR3 that induces the production of IL-8 in skin and promotes wound repair. Bee venom (BV) has many effects on skin, and Nakashima et al. show that BV synergizes with various TLR ligands to enhance the IL-8 production in HaCaT cells (a human keratinocyte cell line). This is especially marked

  • Pivotal role of carbohydrate recognition domain in self-interaction of CLEC4A to elicit the ITIM-mediated inhibitory function in murine conventional dendritic cells in vitro.
    Int. Immunol. (IF 3.519) Pub Date : 2020-05-16
    Junta Nasu,Tomofumi Uto,Tomohiro Fukaya,Hideaki Takagi,Takehito Fukui,Noriaki Miyanaga,Yotaro Nishikawa,Sho Yamasaki,Yoshihiro Yamashita,Katsuaki Sato

    C-type lectin receptors (CLRs), pattern recognition receptors (PRRs) characteristic with a carbohydrate recognition domain (CRD) in the extracellular portion, mediate crucial cellular functions upon recognition of glycosylated pathogens and self-glycoproteins. CLEC4A is the only classical CLR that possesses an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM), which possibly transduces

  • Increased urinary exosomal SYT17 levels in chronic active antibody-mediated rejection after kidney transplantation via the IL-6 amplifier.
    Int. Immunol. (IF 3.519) Pub Date : 2020-05-05
    Yusuke Takada,Daisuke Kamimura,Jing-Jing Jiang,Haruka Higuchi,Daiki Iwami,Kiyohiko Hotta,Yuki Tanaka,Mitsutoshi Ota,Madoka Higuchi,Saori Nishio,Tatsuya Atsumi,Nobuo Shinohara,Yoshihiro Matsuno,Takahiro Tsuji,Tatsu Tanabe,Hajime Sasaki,Naoya Iwahara,Masaaki Murakami

    Chronic active antibody-mediated rejection (CAAMR) is a particular problem in kidney transplantation, and about 25% of grafts are lost by CAAMR. Further, the pathogenesis remains unclear, and there is no effective cure or marker. We previously found that a hyper NFκB-activating mechanism in non-immune cells, called the IL-6 amplifier, is induced by the co-activation of NFκB and STAT3, and that this

  • Impaired mucociliary motility enhances antigen-specific nasal IgA immune responses to a cholera toxin-based nasal vaccine.
    Int. Immunol. (IF 3.519) Pub Date : 2020-04-29
    Huangwenxian Lan,Hidehiko Suzuki,Takahiro Nagatake,Koji Hosomi,Koji Ikegami,Mitsutoshi Setou,Jun Kunisawa

    Nasal mucosal tissues are equipped with physical barriers, mucus and cilia, on their surface. The mucus layer captures inhaled materials, and the cilia remove the inhaled materials from the epithelial layer by asymmetrical beating. The effect of nasal physical barriers on the vaccine efficacy remains to be investigated. Tubulin tyrosine ligase-like family, member 1 (Ttll1) is an essential enzyme for

  • The origin, fate and function of macrophages in the peripheral nervous system - an update.
    Int. Immunol. (IF 3.519) Pub Date : 2020-04-23
    Lukas Amann,Marco Prinz

    The field of macrophage biology has made enormous progress over recent years. This was triggered by the advent of several new techniques such as the establishment of Cre/loxP-based transgenic mouse models that allowed for the first time to delineate the ontogeny and function of specific macrophage populations across many tissues. In addition, the introduction of new high-throughput technologies like

  • Hide and seek: interplay between influenza viruses and B cells.
    Int. Immunol. (IF 3.519) Pub Date : 2020-04-18
    Masayuki Kuraoka,Yu Adachi,Yoshimasa Takahashi

    Influenza virus constantly acquires genetic mutations/reassortment in the major surface protein, hemagglutinin (HA), resulting in the generation of strains with antigenic variations. There are, however, HA epitopes that are conserved across influenza viruses and are targeted by broadly protective antibodies. A goal for the next-generation influenza vaccines is to stimulate B-cell responses against

  • Lipid mediators and sterile inflammation in ischemic stroke.
    Int. Immunol. (IF 3.519) Pub Date : 2020-04-17
    Akari Nakamura,Kento Otani,Takashi Shichita

    Stroke is one of the major causes of lethality and disability, yet few effective therapies have been established for ischemic stroke. Inflammation in the ischemic brain is induced by the infiltration and subsequent activation of immune cells. Loss of cerebral blood flow and ischemic brain-cell death trigger the activation of infiltrating immune cells and drastic changes in the lipid content of the

  • Immune-checkpoint profiles for T cells in bronchoalveolar lavage fluid of patients with immune-checkpoint inhibitor-related interstitial lung disease.
    Int. Immunol. (IF 3.519) Pub Date : 2020-04-07
    Kunihiro Suzuki,Toyoshi Yanagihara,Koichiro Matsumoto,Hitoshi Kusaba,Takuji Yamauchi,Yuki Ikematsu,Kentaro Tanaka,Kohei Otsubo,Hiroyuki Inoue,Yasuto Yoneshima,Eiji Iwama,Masako Arimura-Omori,Eiji Harada,Naoki Hamada,Isamu Okamoto,Yoichi Nakanishi

    Immune-checkpoint inhibitors (ICIs) have improved clinical outcomes and are becoming a standard treatment for many cancer types. However, these drugs also induce immune-related adverse events, among which interstitial lung disease (ILD) is potentially fatal. The underlying mechanism of ILD induction by ICIs is largely unknown. With the use of flow cytometry, we determined the expression levels of the

  • Citrullinated fibrinogen is a target of auto-antibodies in interstitial lung disease in mice with collagen-induced arthritis.
    Int. Immunol. (IF 3.519) Pub Date : 2020-04-02
    Tomomi Sato,Hiroki Satooka,Satoko Ichioka,Yoshihiro Maruo,Takako Hirata

    Interstitial lung disease (ILD) is a very common and lethal complication of rheumatoid arthritis (RA), yet its pathogenesis is not well understood, in part due to the lack of adequate animal models. Although collagen-induced arthritis (CIA) is the most widely used animal model for RA, the lung involvement occurring in this model has scarcely been studied. To evaluate the suitability of CIA as a model

  • PD-L1 is induced on the hepatocyte surface via CKLF-like MARVEL transmembrane domain-containing protein 6 up-regulation by the anti-HBV drug Entecavir.
    Int. Immunol. (IF 3.519) Pub Date : 2020-04-01
    Yuichiro Yamamoto,Masatoshi Kakizaki,Takayuki Shimizu,Joaquim Carreras,Tetsuhiro Chiba,Kenji Chamoto,Tatehiro Kagawa,Taku Aoki,Naoya Nakamura,Kiyoshi Ando,Ai Kotani

    Chronic hepatitis B is now controllable when treated with nucleoside reverse transcriptase inhibitors (NRTIs), which inhibit hepatitis B virus (HBV) replication. However, once the NRTIs are discontinued, most patients relapse, necessitating lifelong NRTIs treatment. HBV infection relapse is assumed to be caused by the persistent existence of covalently closed circular DNA (cccDNA) in the nuclei of

  • Diversity of energy metabolism in immune responses regulated by micro-organisms and dietary nutrition.
    Int. Immunol. (IF 3.519) Pub Date : 2020-03-27
    Koji Hosomi,Jun Kunisawa

    Immune metabolism has been recognized as a new paradigm in the regulation of host immunity. In the environment, there are many micro-organisms including pathogenic and non-pathogenic and/or beneficial ones. Immune cells exhibit various responses against different types of microbes, which seem to be associated with changes in energy metabolism. In addition, dietary nutrition influences host metabolism

  • Corrigendum: Orosomucoid 1 is involved in the development of chronic allograft rejection after kidney transplantation.
    Int. Immunol. (IF 3.519) Pub Date : 2020-03-27
    Haruka Higuchi,Daisuke Kamimura,Jing-Jing Jiang,Toru Atsumi,Daiki Iwami,Kiyohiko Hotta,Hiroshi Harada,Yusuke Takada,Hiromi Kanno-Okada,Kanako C Hatanaka,Yuki Tanaka,Nobuo Shinohara,Masaaki Murakami

    International Immunology, Volume 32, Issue 5, 1 May 2020, Pages 335–346, https://doi.org/10.1093/intimm/dxaa003

  • The spectrum of macrophage activation by immunometabolism.
    Int. Immunol. (IF 3.519) Pub Date : 2020-03-16
    Sujin Kang,Atsushi Kumanogoh

    Macrophages are heterogeneous and plastic, and play several diverse functions in immune responses. Emerging data provide evidence of multiple roles for metabolic pathways in the control of macrophage effector functions. The diverse functions of macrophages are categorized into two main subsets: classical activated macrophages (M1) and alternative activated macrophages (M2). M1 macrophages secrete pro-inflammatory

  • Sestrin3 enhances macrophage-mediated generation of T helper 1 and T helper 17 cells in a mouse colitis model.
    Int. Immunol. (IF 3.519) Pub Date : 2020-03-10
    Liuqing Ge,Min Xu,Steven R Brant,Shaoping Liu,Chengliang Zhu,Jian Shang,Qiu Zhao,Feng Zhou

    Intestinal macrophages participate in the pathogenesis of inflammatory bowel diseases (IBDs) through secreting pro-inflammatory and tissue-damaging factors as well as inducing the differentiation of T helper 1 (Th1) and T helper 17 (Th17) cells. Elucidating the regulatory mechanisms of intestinal macrophage activity in IBDs is important for developing new therapeutic approaches. In the current study

  • Effects of BMP7 produced by group 2 innate lymphoid cells on adipogenesis.
    Int. Immunol. (IF 3.519) Pub Date : 2020-03-09
    Yurina Miyajima,Kafi N Ealey,Yasutaka Motomura,Miho Mochizuki,Natsuki Takeno,Motoko Yanagita,Aris N Economides,Manabu Nakayama,Haruhiko Koseki,Kazuyo Moro

    Group 2 innate lymphoid cells (ILC2s) are type 2 cytokine-producing cells that have important roles in helminth infection and allergic inflammation. ILC2s are tissue-resident cells, and their phenotypes and roles are regulated by tissue-specific environmental factors. While the role of ILC2s in the lung, intestine and bone marrow has been elucidated in many studies, their role in adipose tissues is

  • Metabolic and immunologic control of intestinal cell function by mTOR.
    Int. Immunol. (IF 3.519) Pub Date : 2020-03-06
    Stephanie D Fritsch,Thomas Weichhart

    The intestinal epithelium is one of the most quickly dividing tissues in our body, combining the absorptive advantages of a single layer with the protection of a constantly renewing barrier. It is continuously exposed to nutrients and commensal bacteria as well as microbial and host-derived metabolites, but also to hazards such as pathogenic bacteria and toxins. These environmental cues are sensed

  • Tolerogenic properties of CD206+ macrophages appeared in the sublingual mucosa after repeated antigen-painting.
    Int. Immunol. (IF 3.519) Pub Date : 2020-03-04
    Yue Yang,Shigenori Nagai,Siwen Kang,Yulong Xia,Yohei Kawano,Kensuke Miyake,Hajime Karasuyama,Miyuki Azuma

    The sublingual mucosa (SLM) in the oral cavity is utilized as the site for sublingual immunotherapy to induce tolerance against allergens. We previously reported that CD206+ round-type macrophage-like cells were induced in the SLM after repeated antigen (e.g. cedar pollen or fluorescein isothiocyanate (FITC))-painting. In this study, we examined the phenotypic and functional properties of CD206+ cells

  • Repurposing the psoriasis drug Oxarol to an ointment adjuvant for the influenza vaccine.
    Int. Immunol. (IF 3.519) Pub Date : 2020-02-15
    Ryota Sato,Chieko Makino-Okamura,Quingshun Lin,Muying Wang,Jason E Shoemaker,Tomohiro Kurosaki,Hidehiro Fukuyama

    Aluminum precipitates have long been used as adjuvants for human vaccines, but there is a clear need for safer and more effective adjuvants. Here we report in a mouse model that the psoriasis drug Oxarol ointment is a highly effective vaccine adjuvant. By applying Oxarol ointment onto skin, humoral responses and germinal center (GC) reactions were augmented, and the treated mice were protected from

  • PD-1+ Tim3+ tumor-infiltrating CD8 T cells sustain the potential for IFN-γ production, but lose cytotoxic activity in ovarian cancer.
    Int. Immunol. (IF 3.519) Pub Date : 2020-02-03
    Masaaki Sawada,Kumiko Goto,Akiko Morimoto-Okazawa,Miya Haruna,Kei Yamamoto,Yoko Yamamoto,Satoshi Nakagawa,Kosuke Hiramatsu,Shinya Matsuzaki,Eiji Kobayashi,Atsunari Kawashima,Michinari Hirata,Kota Iwahori,Toshihiro Kimura,Yutaka Ueda,Tadashi Kimura,Hisashi Wada

    Persistent exposure to tumor antigens results in exhausted tumor-infiltrating T cells (TILs) that express the immune checkpoint molecules, PD-1 and Tim3, and lack anti-tumor immunity. To examine the exhausted status of TILs in ovarian cancer, the potential for cytokine production, proliferation and cytotoxicity by purified PD-1+ Tim3+ CD8 TILs was assessed. The production of IFN-γ and TNF-α by PD-1+

  • Ubiquitination of IgG1 cytoplasmic tail modulates B-cell signalling and activation.
    Int. Immunol. (IF 3.519) Pub Date : 2020-02-01
    Tadahiro Kodama,Mika Hasegawa,Yui Sakamoto,Kei Haniuda,Daisuke Kitamura

    Upon antigen stimulation, IgG+ B cells rapidly proliferate and differentiate into plasma cells, which has been attributed to the characteristics of membrane-bound IgG (mIgG), but the underlying molecular mechanisms remain elusive. We have found that a part of mouse mIgG1 is ubiquitinated through the two responsible lysine residues (K378 and K386) in its cytoplasmic tail and this ubiquitination is augmented

  • Mechanisms of new blood-vessel formation and proliferative heterogeneity of endothelial cells.
    Int. Immunol. (IF 3.519) Pub Date : 2020-05-08
    Hisamichi Naito,Tomohiro Iba,Nobuyuki Takakura

    The vast blood-vessel network of the circulatory system is crucial for maintaining bodily homeostasis, delivering essential molecules and blood cells, and removing waste products. Blood-vessel dysfunction and dysregulation of new blood-vessel formation are related to the onset and progression of many diseases including cancer, ischemic disease, inflammation and immune disorders. Endothelial cells (ECs)

  • Physiology and pathology of T-cell aging.
    Int. Immunol. (IF 3.519) Pub Date : 2020-04-12
    Nagahiro Minato,Masakazu Hattori,Yoko Hamazaki

    Acquired immune function shows recognizable changes over time with organismal aging. These changes include T-cell dysfunction, which may underlie diminished resistance to infection and possibly various chronic age-associated diseases in the elderly. T-cell dysfunction may occur at distinct stages, from naive cells to the end stages of differentiation during immune responses. The thymus, which generates

  • Phospholipase A2 from bee venom increases poly(I:C)-induced activation in human keratinocytes.
    Int. Immunol. (IF 3.519) Pub Date : 2020-01-20
    Akina Nakashima,Susumu Tomono,Tatsuya Yamazaki,Masanori Inui,Naoko Morita,Isao Ichimonji,Hidekazu Takagi,Fumiaki Nagaoka,Misako Matsumoto,Yasuhiko Ito,Takeshi Yanagishita,Kensuke Miyake,Daisuke Watanabe,Sachiko Akashi-Takamura

    Bee venom (BV) induces skin inflammation, characterized by erythema, blisters, edemas, pain and itching. Although BV has been found to have an inhibitory effect on toll-like receptors (TLRs), we here show that BV enhances keratinocyte responses to polyinosinic-polycytidylic acid [poly(I:C)], a ligand for TLR3. Our results revealed that the enhanced TLR activity was primarily induced by secretory phospholipase

  • Clinical importance of the expression of CD4+CD8+ T cells in renal cell carcinoma.
    Int. Immunol. (IF 3.519) Pub Date : 2020-05-08
    Kentaro Nishida,Atsunari Kawashima,Takayuki Kanazawa,Yujiro Kidani,Tetsuya Yoshida,Michinari Hirata,Kei Yamamoto,Yoko Yamamoto,Masaaki Sawada,Ryo Kato,Taigo Kato,Koji Hatano,Takeshi Ujike,Kazutoshi Fujita,Motohide Uemura,Akiko Morimoto-Okazawa,Kota Iwahori,Makoto Yamasaki,Naganari Ohkura,Shimon Sakaguchi,Norio Nonomura,Yuichiro Doki,Hisashi Wada

    OBJECTIVE CD4+CD8+ T cells are expressed in some cancer patients including those with renal cell carcinoma (RCC). However, no reports have mentioned the clinical importance of this expression. We evaluated the expression of CD4+CD8+ T cells in patients with various cancer types to clarify clinical characteristics and prognostic importance significantly correlating with these T cells. METHODS Expression

  • Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by stabilizing the β-catenin destruction complex.
    Int. Immunol. (IF 3.519) Pub Date : 2020-05-08
    Jianhua Rao,Chao Yang,Shikun Yang,Hao Lu,Yuanchang Hu,Ling Lu,Feng Cheng,Xuehao Wang

    Intrahepatic cholestasis induced by drug toxicity may cause cholestatic hepatic injury (CHI) leading to liver fibrosis and cirrhosis. The G protein-coupled bile acid receptor 1 (TGR5) is a membrane receptor with well-known roles in the regulation of glucose metabolism and energy homeostasis. However, the role and mechanism of TGR5 in the context of inflammation during CHI remains unclear. Wild-type

  • Orosomucoid 1 is involved in the development of chronic allograft rejection after kidney transplantation.
    Int. Immunol. (IF 3.519) Pub Date : 2020-05-08
    Haruka Higuchi,Daisuke Kamimura,Jing-Jing Jiang,Toru Atsumi,Daiki Iwami,Kiyohiko Hotta,Hiroshi Harada,Yusuke Takada,Hiromi Kanno-Okada,Kanako C Hatanaka,Yuki Tanaka,Nobuo Shinohara,Masaaki Murakami

    Chronic allograft rejection is the most common cause of long-term allograft failure. One reason is that current diagnostics and therapeutics for chronic allograft rejection are very limited. We here show that enhanced NFκB signaling in kidney grafts contributes to chronic active antibody-mediated rejection (CAAMR), which is a major pathology of chronic kidney allograft rejections. Moreover, we found

  • Development of prime-boost-type next-generation mucosal vaccines.
    Int. Immunol. (IF 3.519) Pub Date : 2019-12-28
    Kosuke Fujimoto,Satoshi Uematsu

    Our bodies are constantly exposed to a wide variety of pathogenic micro-organisms through mucosal sites. Therefore, effective vaccines that can protect at the mucosa are vital; however, only a few clinically established mucosal vaccines are available. Although conventional injectable vaccines can induce antigen-specific serum immunoglobulin G (IgG) and prevent severe infection, it is difficult to efficiently

  • Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome.
    Int. Immunol. (IF 3.519) Pub Date : 2020-04-12
    Sou Niitsuma,Hiroki Kudo,Atsuo Kikuchi,Takaya Hayashi,Satoshi Kumakura,Shuhei Kobayashi,Yuko Okuyama,Naonori Kumagai,Tetsuya Niihori,Yoko Aoki,Takanori So,Ryo Funayama,Keiko Nakayama,Matsuyuki Shirota,Shuji Kondo,Shoji Kagami,Hiroyasu Tsukaguchi,Kazumoto Iijima,Shigeo Kure,Naoto Ishii

    Nephrotic syndrome (NS) is a renal disease characterized by severe proteinuria and hypoproteinemia. Although several single-gene mutations have been associated with steroid-resistant NS, causative genes for steroid-sensitive NS (SSNS) have not been clarified. While seeking to identify causative genes associated with SSNS by whole-exome sequencing, we found compound heterozygous variants/mutations (c

  • Selective suppression of oral allergen-induced anaphylaxis by Allergin-1 on basophils in mice.
    Int. Immunol. (IF 3.519) Pub Date : 2020-03-07
    Yu-Hsien Lin,Satoko Tahara-Hanaoka,Kei Nagai,Soichiro Yoshikawa,Masato Kubo,Shiro Shibayama,Hajime Karasuyama,Akira Shibuya

    Mast cells (MCs) play a critical role in oral allergen-induced anaphylaxis. However, the contribution of basophils to the anaphylaxis remains unclear. The inhibitory immunoreceptor Allergin-1 is highly expressed on MCs and basophils and inhibits FcεRI-mediated signaling in MCs. Here, we show that Allergin-1-deficient (Milr1-/-) mice developed more severe hypothermia, a higher mortality rate and a greater

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