Norisuke Kano, Takeo Miki, Yurina Uehara, Daisuke Ori, Taro Kawai
Interleukin-6 (IL-6) plays a crucial role in various cellular functions, including the innate and adaptive immune responses. Dysregulated expression of IL-6 is associated with hyperinflammation and chronic inflammatory diseases. In this study, we aimed to identify the enhancer regions responsible for robust Il6 mRNA expression in murine macrophages. Through comprehensive genome-wide ChIP-seq and ATAC-seq analyses, we identified two distinct clusters, termed E1 and E2 regions, located at -144 kb to -163 kb relative to the Il6 transcription start site in lipopolysaccharide (LPS)-activated murine macrophages...
April 22, 2024: International Immunology
Jalal Alshaweesh, Rashmi Dash, Michelle S J Lee, Pinar Kahyaoglu, Ece Erci, Mengling Xu, Julia Matsuo-Dapaah, Camila Del Rosario Zorrilla, Kubra Aykac, Suheyla Ekemen, Kouji Kobiyama, Ken J Ishii, Cevayir Coban
Chronic bone loss is an under-recognized complication of malaria, the underlying mechanism of which remains incompletely understood. We have previously shown that persistent accumulation of Plasmodium products in the bone marrow leads to chronic inflammation in osteoblast (OB) and osteoclast (OC) precursors causing bone loss through MyD88, an adaptor molecule for diverse inflammatory signals. However, the specific contribution of MyD88 signaling in OB or OC precursors in malaria-induced bone loss remains elusive...
April 20, 2024: International Immunology
Hodaka Hayabuchi, Yukiko Tokifuji, Hayato Takahashi, Masayuki Amagai, Akihiko Yoshimura, Shunsuke Chikuma
Autoimmune diseases often arise from conditions where the immune system is compromised. While lymphopenia-induced proliferation (LIP) is crucial for immune system development and maturation, it is also caused by environmental insult, such as infection and becomes a risk factor for autoimmunity in adults. We used Dsg3H1 TCR Transgenic mice, whose T cells are designed to recognize desmogrein-3, a skin antigen, to explore the impact of lymphopenia on post-thymic tolerance. Dsg3H1 mice are known to delete the most highly autoreactive T cells in thymus, and develop only subtle immune-mediated pathology in a steady state...
April 5, 2024: International Immunology
Taiichiro Shirai, Akiko Nakai, Kazuhiro Suzuki
Efficient induction of humoral immune responses depends on orchestrated migration of B cells within lymphoid organs, which is governed by G protein-coupled receptors (GPCRs) responding to chemoattractants, represented by chemokines. After ligand binding, GPCRs are phosphorylated by different GPCR kinases (GRKs) at distinct sites on the receptor C termini, which dictates functional outcomes of β-arrestin-mediated signaling, ranging from receptor inactivation to effector molecule activation. However, the molecular mechanisms by which individual GRKs are selectively targeted to GPCRs have been poorly understood...
April 4, 2024: International Immunology
Tanveer Ali, Huong Minh Nguyen, Naeem Abbas, Osamu Takeuchi, Shizuo Akira, Toshihiko Suzuki, Goro Matsuzaki, Giichi Takaesu
Transforming growth factor-β-activated kinase 1 (TAK1) plays a pivotal role in innate and adaptive immunity. TAK1 is essential for the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB pathways downstream of diverse immune receptors, including Toll-like receptors (TLRs). Upon stimulation with TLR ligands, TAK1 is activated via recruitment to lysine 63-linked polyubiquitin chain through TAK1-binding proteins (TAB) 2 and TAB3. However, the physiological importance of TAB2 and TAB3 in macrophages is still controversial...
April 3, 2024: International Immunology
Saeko Yanaka, Atsuji Kodama, Shigetaka Nishiguchi, Rina Hiramine, Jiana Shen, Pornthip Boonsri, Duckyong Sung, Yukiko Isono, Hirokazu Yagi, Yohei Miyanoiri, Takayuki Uchihashi, Koichi Kato
IgG molecules that bind antigen on the membrane of target cells spontaneously form hexameric rings, thus recruiting C1 to initiate the complement pathway. However, our previous report indicated that a mouse IgG mutant lacking the Cγ1 domain activates the pathway independently of antigen presence through its monomeric interaction with C1q via the CL domain, as well as Fc. In this study, we investigated the potential interaction between C1q and human CL isoforms. Quantitative single molecule observations using high-speed atomic force microscopy revealed that human Cκ exhibited comparable C1q binding capabilities with its mouse counterpart, surpassing the Cλ types, which have a higher isoelectric point than the Cκ domains...
April 2, 2024: International Immunology
Kazuya Iwabuchi, Masashi Satoh, Kazuhisa Yoshino, Naoki Ishimori
Invariant natural killer T (iNKT) cells, which bear αβ-type T cell antigen-receptors, recognize glycolipid antigens in a cluster of differentiation 1d (CD1d)-restricted manner. Regarding these cells, the unique modes of thymic selection and maturation elucidate innateness, irrespective of them also being members of the adaptive immune system as a T cell. iNKT cells develop and differentiate into NKT1 [interferon γ (IFN-γγ-producing], NKT2 [interleukin 4 (IL-4)/IL-13-producing], or NKT17 (IL-17-producing) subsets in the thymus...
April 1, 2024: International Immunology
Tugce Canavar Yildirim, Yasemin Ozsurekci, Muzaffer Yildirim, Irem Evcili, Volkan Yazar, Kubra Aykac, Ulku Guler, Bekir Salih, Mayda Gursel, Ihsan Gursel
Invasive meningococcal disease (IMD) is caused by Neisseria meningitidis, with the main serogroups responsible for the disease being A, B, C, W, X, and Y. To date, several vaccines targeting N.meningitidis have been developed albeit with a short-lived protection. Given that MenW and MenB are the most common causes of IMD in Europe, Turkey, and Middle East, we aimed to develop an outer membrane vesicle (OMV) based bivalent vaccine as the heterologous antigen source. Herein, we compared the immunogenicity, and breadth of serum bactericidal assays (SBA) based protective coverage of OMV vaccine to X serotype with existing commercial meningococcal conjugate and polysaccharide (PS) vaccines in a murine model...
March 27, 2024: International Immunology
Hitomi Kasuya, Haosong Zhang, Yusuke Ito, Toshiaki Yoshikawa, Takahiro Nakashima, Yang Li, Tetsuya Matsukawa, Satoshi Inoue, Yuki Kagoya
Efficient generation of chimeric antigen receptor (CAR) T cells is highly influenced by the quality of apheresed T cells. Healthy donor-derived T cells usually proliferate better than patients-derived T cells and are precious resources to generate off-the-shelf CAR-T cells. However, relatively little is known about the determinants that affect the efficient generation of CAR-T cells from healthy donor-derived peripheral blood mononuclear cells (PBMC) compared with those from the patients' own PBMC. We here examined the efficiency of CAR-T cell generation from multiple healthy donor samples and analyzed its association with the phenotypic features of the starting peripheral blood T cells...
March 22, 2024: International Immunology
Wenjie Li, Wei Wang
BACKGROUND: previous observational and experimental studies have suggested a relationship between statin treatments and the augmentation of immunotherapy effects; however, the causal role of statin usage in promoting antitumor immunity remains largely unexplored. METHODS: utilizing large-scale genome-wide association studies, we conducted a Mendelian Randomization (MR) analysis to examine the association between genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a specific target of statins, and 524 immunotherapy-related profiles, encompassing immune cells, inflammatory cytokines, immune checkpoints, and gut microbiota...
March 7, 2024: International Immunology
Yu-Hsien Lin, Satoko Tahara-Hanaoka, Nozomu Obana, Shinji Fukuda, Akira Shibuya
The intestinal barrier consists of mucosal, epithelial, and immunological barriers and serves as a dynamic interface between the host and its environment. Disruption of the intestinal barrier integrity is a leading cause of various gastrointestinal diseases, such as inflammatory bowel disease. The homeostasis of the intestinal barrier is tightly regulated by crosstalk between gut microbes and the immune system; however, the implication of the immune system on the imbalance of gut microbes that disrupts barrier integrity remains to be fully elucidated...
March 5, 2024: International Immunology
Satoshi Nakamizo, Kenji Kabashima
This review article delves into the complexities of granuloma formation, focusing on the metabolic reprogramming within these immune structures, especially in tuberculosis and sarcoidosis. It underscores the role of the monocyte-macrophage lineage in granuloma formation and maintenance, emphasizing the adaptability of these cells to environmental cues and inflammatory stimuli. Key to the discussion is the macrophage polarization influenced by various cytokines, with a detailed exploration of the metabolic shifts towards glycolysis under hypoxic conditions and the utilization of the pentose phosphate pathway (PPP) for crucial biosynthetic processes...
March 5, 2024: International Immunology
Michelle Sue Jann Lee, Julia Matsuo Dapaah, Camila Del Rosario Zorrilla, Yoshiki Omatsu, Takashi Nagasawa, Shun Uemura, Atsushi Iwama, Ken J Ishii, Cevayir Coban
Bone marrow is a dynamic organ composed of stem cells that constantly receive signals from stromal cells and other hematopoietic cells in the niches of the bone marrow to maintain hematopoiesis and generate immune cells. Perturbation of the bone marrow microenvironment by infection and inflammation affects hematopoiesis and may affect immune cell development. Little is known about the effect of malaria on the bone marrow stromal cells that govern the hematopoietic stem cell (HSC) niche. In this study, we demonstrate that the mesenchymal stromal CXCL12-abundant reticular (CAR) cell population is reduced during acute malaria infection...
March 2, 2024: International Immunology
Qianqian Liu, Wei Xiong, Sachiyo Obara, Hirohito Abo, Hiroko Nakatsukasa, Hiroto Kawashima
Lymphocyte homing to peripheral lymph nodes (PLN) is critical for immune surveillance. However, autoimmune diseases such as multiple sclerosis (MS) can occur due to excessive immune responses in the PLN. Here we show that 6-sulfo sialyl Lewis X (6-sulfo sLex) glycans on high endothelial venules that function as ligands for L-selectin on lymphocytes play a critical role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In N-acetylglucosamine-6-O-sulfotransferase (GlcNAc6ST)-1 and GlcNAc6ST-2 double knockout mice lacking the expression of 6-sulfo sLeX glycans, the EAE symptoms and the numbers of effector Th1 and Th17 cells in the draining lymph nodes (dLN) and spinal cords (SC) were significantly reduced...
February 22, 2024: International Immunology
Shotaro Mori, Masamichi Nagae, Sho Yamasaki
C-type lectin receptors (CLRs) are a family of pattern recognition receptors, which detect a broad spectrum of ligands via small carbohydrate recognition domains (CRDs). CLEC12A is an inhibitory CLR that recognizes crystalline structures such as monosodium urate crystals. CLEC12A also recognizes mycolic acid, a major component of mycobacterial cell walls, and suppresses host immune responses. Although CLEC12A could be a therapeutic target for mycobacterial infection, structural information on CLEC12A was not available...
February 22, 2024: International Immunology
Meghan Kates, Samuel D Saibil
Adoptive cell therapy (ACT) is an immunotherapeutic approach that involves isolating T cells from a patient, culturing them ex vivo, then re-infusing the cells back into the patient. Although this strategy has shown remarkable efficacy in hematological malignancies, the solid-tumour microenvironment (TME) has presented serious challenges for therapy efficacy. Particularly, the TME has immunosuppressive signaling and presents a metabolically challenging environment that leads to T cell suppression. T cell metabolism is an expanding field of research with a focus on understanding its inherent link to T cell function...
February 14, 2024: International Immunology
Saeko Tahara, Genki Okumura, Tomohei Matsuo, Akira Shibuya, Kazuko Shibuya
CD155 is highly expressed on tumor cells and augments or inhibits the cytotoxic activities of natural killer (NK) cells and T cells through its receptor ligands DNAM-1 and T cell immunoglobulin immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), respectively. Although CD155 is heavily glycosylated, the role of glycosylation of CD155 in the cytotoxic activity of effector lymphocytes remains unknown. Here, we show that the N-linked glycosylation at residue 105 (N105 glycosylation) in the first immunoglobulin-like domain of CD155 is involved in the binding of CD155 to both DNAM-1 and TIGIT...
January 30, 2024: International Immunology
Hiroaki Shiratori, Kisara M Hattori, Kazuaki Nakata, Takuma Okawa, Seiga Komiyama, Yusuke Kinashi, Yuma Kabumoto, Yuria Kaneko, Motoyoshi Nagai, Tomoko Shindo, Nobuko Moritoki, Yuki I Kawamura, Taeko Dohi, Daisuke Takahashi, Shunsuke Kimura, Koji Hase
The gut microbiota plays a crucial role in maintaining epithelial barrier function. Although multiple studies have demonstrated the significance of dietary factors on gut microbiota and mucosal barrier function, the impact of a purified diet, which has long been used in various animal experiments, on intestinal homeostasis remains to be elucidated. Here, we compared the impact of two different types of diets, a crude diet and an AIN-93G-formula purified diet, on epithelial integrity and the gut microbiota. Purified diet-fed mice exhibited shorter villi and crypt lengths and slower epithelial turnover, particularly in the ileum...
January 23, 2024: International Immunology
Yagiz Pat, Duygu Yazici, Paolo D'Avino, Manru Li, Sena Ardicli, Ozge Ardicli, Yasutaka Mitamura, Mübeccel Akdis, Raja Dhir, Kari Nadeau, Ioana Agache, Ismail Ogulur, Cezmi A Akdis
The epithelial barrier theory links the recent rise in chronic non-communicable diseases, notably autoimmune and allergic disorders, to environmental agents disrupting the epithelial barrier. Global pollution and environmental toxic agent exposure have worsened over six decades because of uncontrolled growth, modernisation, and industrialisation, affecting human health. Introducing new chemicals without any reasonable control of their health effects through these years has led to documented adverse effects, especially on the skin and mucosal epithelial barriers...
January 16, 2024: International Immunology
Hiroshi Kawamoto, Kyoko Masuda
In currently ongoing adoptive T cell therapies, T cells collected from patients are given back to them after ex-vivo activation and expansion. In some cases, T cells are transduced with chimeric antigen receptor (CAR) or T cell receptor (TCR) genes during the ex-vivo culture period in order to endow T cells with the desired antigen specificity. Although such strategies have been shown to be effective in some types of cancer, there remain issues to be solved: (i) the limited number of cells, (ii) it is time-consuming, (iii) it is costly, and (iv) the quality can be unstable...
January 8, 2024: International Immunology
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