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Moyamoya disease (MMD) shows progressive cerebral angiopathy characterized by bilateral internal carotid artery stenosis and abnormal collateral vessels. Although ∼15% of MMD cases are familial, the MMD gene(s) remain unknown. A genome-wide association study of 785 720 single-nucleotide polymorphisms (SNPs) was performed, comparing 72 Japanese MMD patients with 45 Japanese controls and resulting in a strong association of chromosome 17q25-ter with MMD risk. This result was further confirmed by a locus-specific association study using 335 SNPs in the 17q25-ter region. A single haplotype consisting of seven SNPs at the RNF213 locus was tightly associated with MMD ( P =5.3 × 10 −10 ). RNF213 encodes a really interesting new gene finger protein with an AAA ATPase domain and is abundantly expressed in spleen and leukocytes. An RNA in situ hybridization analysis of mouse tissues indicated that mature lymphocytes express higher levels of Rnf213 mRNA than their immature counterparts. Mutational analysis of RNF213 revealed a founder mutation, p.R4859K, in 95% of MMD families, 73% of non-familial MMD cases and 1.4% of controls; this mutation greatly increases the risk of MMD ( P =1.2 × 10 −43 , odds ratio=190.8, 95% confidence interval=71.7–507.9). Three additional missense mutations were identified in the p.R4859K-negative patients. These results indicate that RNF213 is the first identified susceptibility gene for MMD.

CD4 + T lymphocytes consist of naïve, antigen-specific memory, and memory-phenotype (MP) cell compartments at homeostasis. We recently showed that MP cells exert innate-like effector function during host defense, but whether MP CD4 + T cells are functionally heterogeneous and, if so, what signals specify the differentiation of MP cell subpopulations under homeostatic conditions is still unclear. Here we characterize MP lymphocytes as consisting of T-bet high , T-bet low , and T-bet − subsets, with innate, Th1-like effector activity exclusively associated with T-bet high cells. We further show that the latter population depends on IL-12 produced by CD8α + type 1 dendritic cells (DC1) for its differentiation. Finally, our data demonstrate that this tonic IL-12 production requires TLR-MyD88 signaling independent of foreign agonists, and is further enhanced by CD40-CD40L interactions between DC1 and CD4 + T lymphocytes. We propose that optimal differentiation of T-bet high MP lymphocytes at homeostasis is driven by self-recognition signals at both the DC and Tcell levels. CD4 + T cells contain a T-bet high memory-phenotype (MP) population with innate-like functions. Here the authors characterize the requirements for their differentiation at homeostasis and identify a function for IL-12 that is tonically produced by type 1 dendritic cells in an MyD88- and CD40-dependent, but foreign PAMP-independent manner.

Bacterial ATP helps T H 17 cells The intestinal lamina propria, a layer of cells forming part of the mucous membrane, boasts a complicated mix of cell populations, including the selective presence of T H 17 or T helper 17 cells, the subset of T helpers that produces interleukin 17. A study in mice now shows that commensal bacteria activate a unique subset of intestinal dendritic cells to induce interleukin-6 production and TGF- beta activation, thereby promoting the local differentiation of T H 17 cells. It is the ATP that the bacteria produce that promotes this effect. This finding highlights the importance of commensal bacteria and ATP in immuno-logical diseases, and may help in determining the mechanisms by which aberrant T H 17 cell responses result in immune disorders including inflammatory bowel diseases. Interleukin (IL)-17-producing CD4 + T lymphocytes (T H 17 cells) constitute a subset of T-helper cells involved in host defence and several immune disorders 1 , 2 . An intriguing feature of T H 17 cells is their selective and constitutive presence in the intestinal lamina propria 3 . Here we show that adenosine 5′-triphosphate (ATP) that can be derived from commensal bacteria activates a unique subset of lamina propria cells, CD70 high CD11c low cells, leading to the differentiation of T H 17 cells. Germ-free mice exhibit much lower concentrations of luminal ATP, accompanied by fewer lamina propria T H 17 cells, compared to specific-pathogen-free mice. Systemic or rectal administration of ATP into these germ-free mice results in a marked increase in the number of lamina propria T H 17 cells. A CD70 high CD11c low subset of the lamina propria cells expresses T H 17-prone molecules, such as IL-6, IL-23p19 and transforming-growth-factor-β-activating integrin-αV and -β8, in response to ATP stimulation, and preferentially induces T H 17 differentiation of co-cultured naive CD4 + T cells. The critical role of ATP is further underscored by the observation that administration of ATP exacerbates a T-cell-mediated colitis model with enhanced T H 17 differentiation. These observations highlight the importance of commensal bacteria and ATP for T H 17 differentiation in health and disease, and offer an explanation of why T H 17 cells specifically present in the intestinal lamina propria.

There is growing evidence that tumor necrosis factor (TNF) receptor-associated factors (TRAFs) bind to unconventional membrane-bound receptors in many cell types and control their key signaling activity, in both positive and negative ways. TRAFs function in a variety of biological processes in health and disease, and dysregulation of TRAF expression or activity often leads to a patho-physiological outcome. We have identified a novel attribute of TRAF2 and TRAF5 in interleukin-6 (IL-6) receptor signaling in CD4 T cells. TRAF2 and TRAF5 are highly expressed by naïve CD4 T cells and constitutively bind to the signal-transducing receptor common chain gp130 via the C-terminal TRAF domain. The binding between TRAF and gp130 limits the early signaling activity of the IL-6 receptor complex by preventing proximal interaction of Janus kinases (JAKs) associated with gp130. In this reason, TRAF2 and TRAF5 in naïve CD4 T cells negatively regulate IL-6-mediated activation of signal transducer and activator of transcription 3 (STAT3) that is required for the development of IL-17-secreting CD4 T 17 cells. Indeed, -knockdown in differentiating CD4 T cells strongly promotes T 17 development. donor CD4 T cells exacerbate the development of neuroinflammation in experimental autoimmune encephalomyelitis (EAE) in wild-type recipient mice. In this review, we summarize the current understanding of the role for TRAF2 and TRAF5 in the regulation of IL-6-driven differentiation of pro-inflammatory CD4 T cells, especially focusing on the molecular mechanism by which TRAF2 and TRAF5 inhibit the JAK-STAT pathway that is initiated in the IL-6 receptor signaling complex.

The Great East Japan Earthquake (GEJE) and resulting tsunami of March 11, 2011 gave rise to devastating damage on the Pacific coast of the Tohoku region. The Tohoku Medical Megabank Project (TMM), which is being conducted by Tohoku University Tohoku Medical Megabank Organization (ToMMo) and Iwate Medical University Iwate Tohoku Medical Megabank Organization (IMM), has been launched to realize creative reconstruction and to solve medical problems in the aftermath of this disaster. We started two prospective cohort studies in Miyagi and Iwate Prefectures: a population-based adult cohort study, the TMM Community-Based Cohort Study (TMM CommCohort Study), which will recruit 80 000 participants, and a birth and three-generation cohort study, the TMM Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study), which will recruit 70 000 participants, including fetuses and their parents, siblings, grandparents, and extended family members. The TMM CommCohort Study will recruit participants from 2013 to 2016 and follow them for at least 5 years. The TMM BirThree Cohort Study will recruit participants from 2013 to 2017 and follow them for at least 4 years. For children, the ToMMo Child Health Study, which adopted a cross-sectional design, was also started in November 2012 in Miyagi Prefecture. An integrated biobank will be constructed based on the two prospective cohort studies, and ToMMo and IMM will investigate the chronic medical impacts of the GEJE. The integrated biobank of TMM consists of health and clinical information, biospecimens, and genome and omics data. The biobank aims to establish a firm basis for personalized healthcare and medicine, mainly for diseases aggravated by the GEJE in the two prefectures. Biospecimens and related information in the biobank will be distributed to the research community. TMM itself will also undertake genomic and omics research. The aims of the genomic studies are: 1) to construct an integrated biobank; 2) to return genomic research results to the participants of the cohort studies, which will lead to the implementation of personalized healthcare and medicine in the affected areas in the near future; and 3) to contribute the development of personalized healthcare and medicine worldwide. Through the activities of TMM, we will clarify how to approach prolonged healthcare problems in areas damaged by large-scale disasters and how useful genomic information is for disease prevention.

Natural killer (NK) cells contribute to not only innate but also to adaptive immunity by interacting with dendritic cells (DCs) and T cells. All activated human NK cells express HLA-DR and can initiate MHCII-dependent CD4+ T-cell proliferation; however, the expression of MHCII by mouse NK cells and its functional significance are controversial. In this study, we show that NK–DC interactions result in the emergence of MHCII-positive NK cells. Upon in vitro or in vivo activation, mouse conventional NK cells did not induce MHCII transcripts, but rapidly acquired MHCII protein from DCs. MHCII H2-Ab1–deficient NK cells turned I-Ab-positive when adoptively transferred into wild-type mice or when cultured with WT splenic DCs. NK acquisition of MHCII was mediated by intercellular membrane transfer called \"trogocytosis,\" but not upon DAP10/12- and MHCI-binding NK cell receptor signaling. MHCII-dressed NK cells concurrently acquired costimulatory molecules such as CD80 and CD86 from DCs; however, their expression did not reach functional levels. Therefore, MHCII-dressed NK cells inhibited DC-induced CD4+ T-cell responses rather than activated CD4+ T cells by competitive antigen presentation. In a mouse model for delayed-type hypersensitivity, adoptive transfer of MHCII-dressed NK cells attenuated footpad swelling. These results suggest that MHCII-dressed NK cells generated through NK–DC interactions regulate T cell-mediated immune responses.

Tissue-resident immune cells play a key role in local and systemic immune responses. The liver, in particular, hosts a large number of invariant natural killer T (iNKT) cells, which are involved in diverse immune responses. However, the mechanisms that regulate survival and homeostasis of liver iNKT cells are poorly defined. Here we have found that liver iNKT cells constitutively express the costimulatory TNF superfamily receptor OX40 and that OX40 stimulation results in massive pyroptotic death of iNKT cells, characterized by the release of potent proinflammatory cytokines that induce liver injury. This OX40/NKT pyroptosis pathway also plays a key role in concanavalin A-induced murine hepatitis. Mechanistically, we demonstrated that liver iNKT cells express high levels of caspase 1 and that OX40 stimulation activates caspase 1 via TNF receptor-associated factor 6-mediated recruitment of the paracaspase MALT1. We also found that activation of caspase 1 in iNKT cells results in processing of pro-IL-1β to mature IL-1β as well as cleavage of the pyroptotic protein gasdermin D, which generates a membrane pore-forming fragment to produce pyroptotic cell death. Thus, our study has identified OX40 as a death receptor for iNKT cells and uncovered a molecular mechanism of pyroptotic cell death. These findings may have important clinical implications in the development of OX40-directed therapies.

Background Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular injury and inflammation, followed by excessive fibrosis of the skin and other internal organs, including the lungs. CX3CL1 (fractalkine), a chemokine expressed on endothelial cells, supports the migration of macrophages and T cells that express its specific receptor CX3CR1 into targeted tissues. We previously reported that anti-CX3CL1 monoclonal antibody (mAb) treatment significantly inhibited transforming growth factor (TGF)-β1-induced expression of type I collagen and fibronectin 1 in human dermal fibroblasts. Additionally, anti-mouse CX3CL1 mAb efficiently suppressed skin inflammation and fibrosis in bleomycin- and growth factor-induced SSc mouse models. However, further studies using different mouse models of the complex immunopathology of SSc are required before the initiation of a clinical trial of CX3CL1 inhibitors for human SSc. Methods To assess the preclinical utility and functional mechanism of anti-CX3CL1 mAb therapy in skin and lung fibrosis, a sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) mouse model was analyzed with immunohistochemical staining for characteristic infiltrating cells and RNA sequencing assays. Results On day 42 after bone marrow transplantation, Scl-cGVHD mice showed increased serum CX3CL1 level. Intraperitoneal administration of anti-CX3CL1 mAb inhibited the development of fibrosis in the skin and lungs of Scl-cGVHD model, and did not result in any apparent adverse events. The therapeutic effects were correlated with the number of tissue-infiltrating inflammatory cells and α-smooth muscle actin (α-SMA)-positive myofibroblasts. RNA sequencing analysis of the fibrotic skin demonstrated that cGVHD-dependent induction of gene sets associated with macrophage-related inflammation and fibrosis was significantly downregulated by mAb treatment. In the process of fibrosis, mAb treatment reduced cGVHD-induced infiltration of macrophages and T cells in the skin and lungs, especially those expressing CX3CR1. Conclusions Together with our previous findings in other SSc mouse models, the current results indicated that anti-CX3CL1 mAb therapy could be a rational therapeutic approach for fibrotic disorders, such as human SSc and Scl-cGVHD.

Dietary obesity is regarded as a problem worldwide, and it has been revealed the strong linkage between obesity and allergic inflammation. Fatty acid-binding protein 5 (FABP5) is expressed in lung cells, such as alveolar epithelial cells (ECs) and alveolar macrophages, and plays an important role in infectious lung inflammation. However, we do not know precise mechanisms on how lipid metabolic change in the lung affects allergic lung inflammation. In this study, we showed that Fabp5 −/− mice exhibited a severe symptom of allergic lung inflammation. We sought to examine the role of FABP5 in the allergic lung inflammation and demonstrated that the expression of FABP5 acts as a novel positive regulator of ST2 expression in alveolar ECs to generate retinoic acid (RA) and supports the synthesis of RA from type II alveolar ECs to suppress excessive activation of innate lymphoid cell (ILC) 2 during allergic lung inflammation. Furthermore, high-fat diet (HFD)-fed mice exhibit the downregulation of FABP5 and ST2 expression in the lung tissue compared with normal diet (ND)-fed mice. These phenomena might be the reason why obese people are more susceptible to allergic lung inflammation. Thus, FABP5 is potentially a therapeutic target for treating ILC2-mediated allergic lung inflammation.

Accumulating evidence suggests that cancer stem cells (CSC) play an important role in tumorigenicity. Epithelial cell adhesion molecule (EpCAM) is one of the markers that identifies tumor cells with high tumorigenicity. The expression of EpCAM in liver progenitor cells prompted us to investigate whether CSC could be identified in hepatocellular carcinoma (HCC) cell lines. The sorted EpCAM+ subpopulation from HCC cell lines showed a greater colony formation rate than the sorted EpCAM− subpopulation from the same cell lines, although cell proliferation was comparable between the two subpopulations. The in vivo evaluation of tumorigenicity, using supra‐immunodeficient NOD/scid/γcnull (NOG) mice, revealed that a smaller number of EpCAM+ cells (minimum 100) than EpCAM− cells was necessary for tumor formation. The bifurcated differentiation of EpCAM+ cell clones into both EpCAM+ and EpCAM− cells was obvious both in vitro and in vivo, but EpCAM− clones sustained their phenotype. These clonal analyses suggested that EpCAM+ cells may contain a multipotent cell population. Interestingly, the introduction of exogenous EpCAM into EpCAM+ clones, but not into EpCAM− clones, markedly enhanced their tumor‐forming ability, even though both transfectants expressed a similar level of EpCAM. Therefore, the difference in the tumor‐forming ability between EpCAM+ and EpCAM− cells is probably due to the intrinsic biological differences between them. Collectively, our results suggest that the EpCAM+ population is biologically quite different from the EpCAM− population in HCC cell lines, and preferentially contains a highly tumorigenic cell population with the characteristics of CSC. (Cancer Sci 2010)