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International Immunology

Yi Li Wong, Mei-Tzu Su, Akiko Sugahara-Tobinai, So Itoi, Dai Kezuka, Shota Endo, Masanori Inui, Toshiyuki Takai
Immune homeostasis is critically regulated by the balance between activating and inhibitory receptors expressed on various immune cells such as T and B lymphocytes, and myeloid cells. The inhibitory receptors play a fundamental role in the immune-checkpoint pathway, thus maintaining peripheral tolerance. We recently found that expression of leukocyte immunoglobulin-like receptor (LILR)B4, an inhibitory member of the human LILR family, is augmented in autoantibody-producing plasmablasts/plasma cells of systemic lupus erythematosus (SLE) patients...
February 15, 2019: International Immunology
Hisako Kayama, Haruka Tani, Shoko Kitada, Anunya Opasawatchai, Ryu Okumura, Daisuke Motooka, Shota Nakamura, Kiyoshi Takeda
Inappropriate activation of the interleukin (IL)-23 signaling pathway causes chronic inflammation through the induction of immunopathological Th17 cells in several tissues including the intestine, whereas adequate Th17 responses are essential for host defense against harmful organisms. In the intestinal lamina propria, IL-23 is primarily produced by innate myeloid cells including dendritic cells (DCs) and macrophages (Ms). However, the molecular mechanisms underlying the regulation of IL-23 production by these cells remains poorly understood...
February 12, 2019: International Immunology
Kelly G Paulson, Miranda Lahman, Aude G Chapuis, Isaac Brownell
Among all tumor types, skin cancers are profoundly sensitive to immunotherapy. Indeed, the recently reported response rates for anti-PD-1 (anti-programmed-death 1) therapy for cutaneous malignant melanomas (MM), Merkel cell carcinomas, basal cell carcinomas, cutaneous squamous cell carcinomas and Kaposi sarcomas are all above 40%. This unique immunogenicity renders skin cancers as a paradigm for tumor-immune interactions and is driven by high mutational burdens, overexpressed tumor antigens and/or viral antigens...
February 8, 2019: International Immunology
Takayoshi Morita, Yoshihito Shima, Kosuke Fujimoto, Hideki Tsuboi, Yukihiko Saeki, Masashi Narazaki, Atsushi Ogata, Atsushi Kumanogoh
The receptor activator of nuclear factor kappa-B ligand (RANKL) is an important factor for osteoclastogenesis and contributes to the pathology of rheumatoid arthritis (RA); thus, the anti-RANKL antibody (Ab) has been expected to protect joint destruction in RA patients. Interleukin (IL)-8 also has osteoclastogenic activity; however, the role of IL-8 in the bone pathology of RA as well as the relation between IL-8 and RANKL remain unclear. In the present study, clinical observation revealed serum IL-8 levels of 611 pg/ml in RA patients with anti-RANKL Ab and 266 pg/ml in the same patients without anti-RANKL Ab...
February 8, 2019: International Immunology
Shin-Ichiroh Saitoh, Yoshiko Mori Saitoh, Kenji Kontani, Katsuaki Sato, Kensuke Miyake
Toll-like receptor (TLR) 7 and type I interferon (IFN-1) are essential for the development of systemic lupus erythematosus (SLE) models such as BXSB.Yaa and 2,6,10,14-tetramethyl-pentadecane (TMPD)-induced experimental lupus. However, the mechanism underlying the development of SLE remains undefined. We report a requirement for ADP-ribosylation factor-like 8b (Arl8b) for TLR7-dependent IFN-1 production in plasmacytoid dendritic cells (pDCs). We analyzed whether Arl8b plays a role in two SLE models by comparing wild-type and Arl8b-deficient Arl8b GeneTrap (Arl8bGt/Gt) mice...
February 7, 2019: International Immunology
Jun-Ichi Kashiwakura, Shinsuke Yamashita, Mari Yoshihara, Kyosuke Inui, Kodai Saitoh, Yuichi Sekine, Ryuta Muromoto, Yuichi Kitai, Kenji Oritani, Tadashi Matsuda
Basophils are an important cell type in the regulation of Th2 immune responses. Recently, we revealed that STAP-2 negatively regulates mast cell activation via FcRI. However, the role of STAP-2 in basophil maturation and activation remained unclear. In this study, we demonstrated the normal development of basophils in STAP-2 deficient (STAP-2-/-) mice. We also demonstrated in vitro normal basophil differentiation and FcRI expression in STAP-2-/- mice, suggesting that STAP-2 is dispensable for basophil maturation...
February 6, 2019: International Immunology
Hiroko Nakatsukasa, Mayumi Oda, Jinghua Yin, Shunsuke Chikuma, Minako Ito, Mana Koga-Iizuka, Kazue Someya, Yohko Kitagawa, Naganari Ohkura, Shimon Sakaguchi, Ikuko Koya, Tsukasa Sanosaka, Jun Kohyama, Yu-Ichi Tsukada, Soichiro Yamanaka, Takeji Takamura-Enya, Qianjin Lu, Akihiko Yoshimura
Ten-eleven translocation (TET) proteins regulate DNA methylation and gene expression by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Although Tet2/Tet3 deficiency has been reported to lead to myeloid cell, B cell, and invariant natural killer T (iNKT) cell malignancy, the effect of TET on regulatory T cells (Tregs) has not been elucidated. We found that Tet2/Tet3 deficiency in Tregs led to lethal hyperproliferation of CD4+Foxp3+ T cells in the spleen and mesenteric lymph nodes after 5 months of age...
February 6, 2019: International Immunology
Nagatake Takahiro, Kunisawa Jun
The gastrointestinal tract is continuously exposed to the external environment, which contains numerous non-self antigens, including food materials and commensal micro-organisms. For the maintenance of mucosal homeostasis, the intestinal epithelial layer and mucosal immune system simultaneously provide the first line of defense against pathogens and are tightly regulated to prevent their induction of inflammatory responses to non-pathogenic antigens. Defects in mucosal homeostasis lead to the development of inflammatory and associated intestinal diseases, such as Crohn's disease, ulcerative colitis, food allergy and colorectal cancer...
February 5, 2019: International Immunology
Yuta Shimizu, Masako Kohyama, Hideki Yorifuji, Hui Jin, Noriko Arase, Tadahiro Suenaga, Hisashi Arase
Natural killer (NK) cells are a major FcγRIIIA-expressing lymphocyte population that mediate antibody-dependent cellular cytotoxicity. Although NK cells are critical for immunity against viruses and tumors, they are also activated in the joints of patients with rheumatoid arthritis (RA) and may be involved in disease progression. We previously found that HLA class II molecules transport misfolded cellular proteins, such as immunoglobulin G heavy chain (IgGH), to the cell surface via association with their peptide-binding grooves...
February 5, 2019: International Immunology
Bukhari Shoiab, Mertz Aaron F, Naik Shruti
The skin epithelium covers our body and serves as a vital interface with the external environment. Here, we review the context-specific interactions between immune cells and the epithelium that underlie barrier fitness and function. We highlight the mechanisms by which these two systems engage each other and how immune-epithelial interactions are tuned by microbial and inflammatory stimuli. Epithelial homeostasis relies on a delicate balance of immune surveillance and tolerance, breakdown of which results in disease...
February 5, 2019: International Immunology
Honda Tetsuya, Kabashima Kenji
Lipid mediators, such as prostanoids and leukotrienes (LTs), exert a range of actions through their own receptors on cell surfaces in various pathophysiological conditions. It has been reported that the production of prostanoids and LTs is significantly elevated in the skin lesions of some chronic inflammatory skin diseases, such as atopic dermatitis (AD) and psoriasis, showing the possible involvement of these lipid mediators in the development of those diseases. Although the actual significance of these lipid mediators in humans is still unclear, the findings from studies in mice suggest diverse roles of the lipid mediators in the progression or regulation of these diseases...
February 3, 2019: International Immunology
Takashi Orimo, Izumi Sasaki, Hiroaki Hemmi, Toshiya Ozasa, Yuri Fukuda-Ohta, Tomokazu Ohta, Mio Morinaka, Mariko Kitauchi, Takako Yamaguchi, Yayoi Sato, Takashi Tanaka, Katsuaki Hoshino, Kei-Ichi Katayama, Shinji Fukuda, Kensuke Miyake, Masahiro Yamamoto, Takashi Satoh, Koichi Furukawa, Etsushi Kuroda, Ken J Ishii, Kiyoshi Takeda, Tsuneyasu Kaisho
Cholera toxin B (CTB) is a subunit of cholera toxin, a bacterial enterotoxin secreted by Vibrio cholerae and also functions as an immune adjuvant. However, it remains unclear how CTB activates immune cells. We here evaluated whether or how CTB induces production of a proinflammatory cytokine, interleukine-1β (IL-1β). CTB induced IL-1β production not only from bone marrow-derived macrophages (BMMs) but also from resident peritoneal macrophages in synergy with O111:B4-derived lipopolysaccharide (LPS O111:B4) that can bind to CTB...
January 25, 2019: International Immunology
Tetsuya Honda, Gyohei Egawa, Kenji Kabashima
For the induction of adequate cutaneous immune responses, the antigen presentation and recognition that occur in both the skin and skin-draining lymph nodes are essential. In each process of cutaneous immune responses, several distinct subsets of immune cells, including dendritic cells and T cells, are involved, and they elicit their respective functions in a harmonious manner. For example, in the elicitation phase of cutaneous acquired immunity, immune cells form a specific lymphoid structure named inducible skin-associated lymphoid tissue (iSALT) to facilitate efficient antigen presentation in situ...
January 22, 2019: International Immunology
Yoshikazu Kuboi, Miyuki Nishimura, Wataru Ikeda, Tomoya Nakatani, Yukie Seki, Yui Yamaura, Kana Ogawa, Akiko Hamaguchi, Kenzo Muramoto, Keiko Mizuno, Hideaki Ogasawara, Toshihiko Yamauchi, Nobuyuki Yasuda, Hiroshi Onodera, Toshio Imai
Chemokine systems modulate inflammatory and immune responses in inflammatory bowel disease (IBD). The colons of IBD patients show increased levels of fractalkine (FKN) and high number of fractalkine receptor-positive (CX3CR1+) cells; however, the FKN-CX3CR1 axis's role in intestinal inflammation, especially in intravascular leukocyte behaviors, still remains unclear. Here, we show that interruption of the FKN-CX3CR1 axis by anti-FKN monoclonal antibody (mAb) ameliorates murine colitis through regulation of intravascular monocyte behaviors in murine colitis models...
January 18, 2019: International Immunology
Masayoshi Onuki, Masaki Watanabe, Narumi Ishihara, Koichiro Suzuki, Kei Takizawa, Masato Hirota, Takahiro Yamada, Aiko Egawa, Osamu Shibahara, Midori Nishii, Michiko Fujihara, Makoto Makishima, Daisuke Takahashi, Yukihiro Furusawa, Hiroki Kakuta, Koji Hase
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is an intractable disease of the gastrointestinal tract. Multiple environmental factors, including food ingredients, have been implicated in the development of these diseases. For example, animal fat-rich diets are predisposing factors for UC, whereas n-3 unsaturated fatty acids such as docosahexaenoic acid (DHA) show protective effects in experimental colitis and are negatively correlated with the incidence of UC and CD...
December 26, 2018: International Immunology
Kaoru Toshima, Masakazu Nagafuku, Toshiro Okazaki, Toshihide Kobayashi, Jin-Ichi Inokuchi
Sphingomyelin (SM) in combination with cholesterol forms specialized membrane lipid microdomains in which specific receptors and signaling molecules are localized or recruited to mediate intracellular signaling. SM-microdomain levels in mouse thymus were low in early CD4 +CD8 + double positive (DP) stage prior to thymic selection, and increased >10-fold during late selection. TCR signal strength is a key factor determining whether DP thymocytes undergo positive or negative selection. We examined the role of SM-microdomains in thymocyte development and related TCR signaling, using SM synthase 1 (SMS1) deficient (SMS1-/-) mice which display low SM expression in all thymocyte populations...
December 16, 2018: International Immunology
Katsuhiro Furusho, Takuma Shibata, Ryota Sato, Ryutaro Fukui, Yuji Motoi, Yun Zhang, Shin-Ichiroh Saitoh, Takeshi Ichinohe, Masafumi Moriyama, Seiji Nakamura, Kensuke Miyake
Toll-like receptor 8 (TLR8), a sensor for pathogen-derived single-stranded RNA (ssRNA), binds to uridine (Uri) and ssRNA to induce defense responses. We here show that cytidine (Cyd) with ssRNA also activated TLR8 in peripheral blood leukocytes (PBLs) and a myeloid cell line U937, but not in an embryonic kidney cell line 293T. Cyd deaminase (CDA), an enzyme highly expressed in leukocytes, deaminates Cyd to Uri. CDA expression enabled TLR8 response to Cyd and ssRNA in 293T cells. CDA deficiency and a CDA inhibitor both reduced TLR8 responses to Cyd and ssRNA in U937...
December 10, 2018: International Immunology
Jianwei Wang, Miho Sekai, Takeshi Matsui, Yosuke Fujii, Mitsuru Matsumoto, Osamu Takeuchi, Nagahiro Minato, Yoko Hamazaki
Hassall's corpuscles (HCs) are composed of cornifying, terminally differentiated medullary thymic epithelial cells (mTECs) that are developed under the control of Aire. Here, we demonstrated that HC-mTECs show features of cellular senescence and produce inflammatory cytokines and chemokines including CXCL5, thereby recruiting and activating neutrophils to produce IL-23 in the thymic medulla. We further indicated that thymic plasmacytoid dendritic cells (pDCs) expressing IL-23 receptors constitutively produced Ifna, which plays a role in single positive (SP) cell maturation, in an Il23a-dependent manner...
December 10, 2018: International Immunology
Takuya Yamamoto, Yuji Masuta, Masatoshi Momota, Masaru Kanekiyo, Tomohiro Kanuma, Shoukichi Takahama, Eiko Moriishi, Yasuhiro Yasutomi, Takashi Saito, Barney S Graham, Yoshimasa Takahashi, Ken J Ishii
The development of a universal influenza vaccine that can provide a robust and long-lasting protection against a broader range of influenza virus strains is a global public health priority. One approach to improve vaccine efficacy is to use an adjuvant to boost immune responses to the target antigens; nevertheless, the role of adjuvants in the context of influenza vaccines is not fully understood. We have previously developed the K3-schizophyllan (SPG) adjuvant, which is composed of nanoparticulated oligodeoxynucleotides K3, a TLR9 agonist, with SPG, a non-agonistic β-glucan ligand of Dectin-1...
December 7, 2018: International Immunology
Takenori Uehara, Shingo Eikawa, Mikako Nishida, Yuki Kunisada, Aki Yoshida, Tomohiro Fujiwara, Toshiyuki Kunisada, Toshifumi Ozaki, Heiichiro Udono
CD11b+ myeloid subpopulations, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), play crucial roles in the suppression of T-cell-mediated antitumor immunity. Regulation of these cell types is a primary goal for achieving efficient cancer immunotherapy. We found that metformin (Met) induces CD11b+ cell-mediated growth inhibition of a K7M2neo osteosarcoma independent of T cells, as growth inhibition of K7M2neo was still observed in wild type (WT) mice depleted of T cells by antibodies and in SCID; this contrasted with the effect of Met on Meth-A fibrosarcoma, which was entirely T cell-dependent...
December 2, 2018: International Immunology
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