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| Open AccessGenome-wide mapping of gene–microbiota interactions in susceptibility to autoimmune skin blistering
The pathogenesis of inflammatory disorders afflicting the skin is multifactorial. Srinivas et al. show that diversity of the skin microbiota is a critical factor determining the susceptibility to epidermolysis bullosa acquisita, a chronic mucocutaneous autoimmune skin blistering disease.
- Girish Srinivas
- , Steffen Möller
- & Saleh M. Ibrahim
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Inflammation-induced proteolytic processing of the SIRPα cytoplasmic ITIM in neutrophils propagates a proinflammatory state
SIRPα is an anti-inflammatory signalling receptor expressed on neutrophils. Here Zenet al.show that during inflammation, SIRPα signalling is inhibited by cleavage of its intracellular signalling motif.
- Ke Zen
- , Yalan Guo
- & Yuan Liu
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Article
| Open AccessQuantal and graded stimulation of B lymphocytes as alternative strategies for regulating adaptive immune responses
B lymphocytes respond to stimulation by proliferating and differentiating. Here the authors quantify and model the responses of B lymphocytes to TLR and CD40-dependent stimulation, and find that the latter induces a more complex response to signals of varying strength.
- E.D. Hawkins
- , M.L. Turner
- & P.D. Hodgkin
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| Open AccessIMGT/HighV QUEST paradigm for T cell receptor IMGT clonotype diversity and next generation repertoire immunoprofiling
Dynamic changes in T cell repertoire underlie immune responses during infection, allergy, autoimmunity and cancer. Here, Li et al. present a workflow for high throughput sequencing and analysis of T cell receptor sequences, and use it to monitor the T cell response to influenza vaccination in a human patient.
- Shuo Li
- , Marie-Paule Lefranc
- & Eric J. Gowans
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Article
| Open Accessp53 increases MHC class I expression by upregulating the endoplasmic reticulum aminopeptidase ERAP1
The protein p53 is an important tumour suppressor. Here Wanget al.show that p53 can induce expression of MHC class I on the cell surface by promoting expression of the aminopeptidase ERAP1, and that this mechanism operates in cancer cells as well as those infected with influenza virus.
- Bei Wang
- , Dandan Niu
- & Ee Chee Ren
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Article
| Open AccessLRRFIP2 negatively regulates NLRP3 inflammasome activation in macrophages by promoting Flightless-I-mediated caspase-1 inhibition
Inflammasomes promote the maturation of inflammatory cytokines in response to signals associated with damage and infection, but it remains unclear how these signals are attenuated. Here, the authors show that the NLRP3 inflammasome is inhibited by LRRFIP2 through recruitment of the protein Flightless I.
- Jing Jin
- , Qian Yu
- & Xuetao Cao
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NF-κB non-cell-autonomously regulates cancer stem cell populations in the basal-like breast cancer subtype
Aggressive types of breast cancer often exhibit constitutive activation of the pro-inflammatory transcription factor NF-κB. Here, Yamamoto et al. show that, in basal-like breast cancer, NF-κB upregulates the Notch receptor ligand JAG1 in non-cancer stem cells and thereby induces proliferation of breast cancer stem cells.
- Mizuki Yamamoto
- , Yuu Taguchi
- & Jun-ichiro Inoue
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Highly self-reactive naive CD4 T cells are prone to differentiate into regulatory T cells
The differentiation of naive CD4 T cells into T-helper-cell subsets is thought to be influenced by factors in the T-cell environment. Martin et al.reveal that cell intrinsic differences also determine lineage commitment and show that cells with the highest avidity for self are most likely to become induced regulatory T cells.
- Bruno Martin
- , Cédric Auffray
- & Bruno Lucas
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The RAG2 C-terminus and ATM protect genome integrity by controlling antigen receptor gene cleavage
Mice lacking the C-terminal non-core domain of RAG2 and ATM mutant mice develop thymic lymphomas harbouring recurrentTcra/d–Ightranslocations. Here the authors show that ATM and the non-core domain of RAG2 prevent bi-locus recombination by modulating higher-order chromatin structure.
- Julie Chaumeil
- , Mariann Micsinai
- & Jane A. Skok
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Recognition of vitamin B metabolites by mucosal-associated invariant T cells
T-cell receptors expressed on mucosal-associated invariant T cells function in a similar manner to innate immune receptors by recognizing small molecules such as microbial metabolites. Here, the authors report structures of this receptor in complex with vitamin B metabolites presented by the MHC-like protein MR1.
- Onisha Patel
- , Lars Kjer-Nielsen
- & Jamie Rossjohn
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The ARNT–STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+ cells
Intraepithelial lymphocytes (IELs) defend against pathogens in the gut, and their differentiation depends on both diet and microbiota-derived factors. Nakajima et al. show that signalling through the aryl hydrocarbon receptor nuclear translocator and STAT3 is required for the development of a subset of IELs.
- Kohei Nakajima
- , Yoichi Maekawa
- & Koji Yasutomo
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Article
| Open AccessBacterial colonization dampens influenza-mediated acute lung injury via induction of M2 alveolar macrophages
Bacterial infections can influence disease outcome in influenza infection; however, the mechanisms mediating these complex interactions remain unclear. Wang et al. reveal how infection with a component of the airway microbiota enhances survival during influenza infection via induction of anti-inflammatory macrophages.
- Jian Wang
- , Fengqi Li
- & Zhigang Tian
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Thymosin β4-sulfoxide attenuates inflammatory cell infiltration and promotes cardiac wound healing
Hydrogen peroxide attracts immune cells and induces wound inflammation. Evans et al. show that hydrogen peroxide also leads to the production of thymosin β4–sulfoxide in zebrafish wounds and in mouse hearts after myocardial infarction, where it acts as an anti-inflammatory factor that promotes wound healing.
- Mark A. Evans
- , Nicola Smart
- & Paul R. Riley
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Article
| Open AccessExploring the MHC-peptide matrix of central tolerance in the human thymus
T cells learn to tolerate self-antigens in the thymus, where self-peptides are presented by thymic antigen-presenting cells. Here, the authors present an ex vivomass spectrometric analysis of the self-peptide repertoire associated with MHC I and II in human thymic tissue.
- Eleni Adamopoulou
- , Stefan Tenzer
- & Christina Stoeckle
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B7-H5 costimulates human T cells via CD28H
The end-result of stimulation of T-cell receptors by antigen is in part determined by co-signalling pathways such as the B7/CD28 axis. Zhu et al.identify a novel costimulatory CD28-like receptor and ligand pathway in human T cells.
- Yuwen Zhu
- , Sheng Yao
- & Lieping Chen
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An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing
Toll-like receptor 9 detects microbial DNA, and is activated by cleavage in the endolysosome. Onji et al. discover that following cleavage, the two parts of the protein remain associated, and this interaction is required for DNA sensing.
- Masahiro Onji
- , Atsuo Kanno
- & Kensuke Miyake
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Persistent infection with Crohn’s disease-associated adherent-invasive Escherichia coli leads to chronic inflammation and intestinal fibrosis
Intestinal infection with adherent-invasive Escherichia coliis associated with Crohn’s disease in humans; however, its functional role remains unclear, in part due to a lack of animal models, which sustain chronic disease. Here the authors establish such a model in mice and show that it shares features with human Crohn’s disease.
- Cherrie-Lee N. Small
- , Sarah A. Reid-Yu
- & Brian K. Coombes
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HSV-1 exploits the innate immune scavenger receptor MARCO to enhance epithelial adsorption and infection
Herpes simplex virus type 1 infects human skin and mucous membranes. MacLeod and colleagues identify MARCO as a novel cell-surface receptor bound by herpes simplex virus type 1, and show that this interaction enhances infection of keratinocytes and promotes the development of skin lesions in mice.
- Daniel T. MacLeod
- , Teruaki Nakatsuji
- & Richard L. Gallo
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The basis for limited specificity and MHC restriction in a T cell receptor interface
Although structural insights into antigen recognition by T cell receptors are increasingly available, the thermodynamic underpinnings are less well understood. Here the authors deconstruct the energetics of a representative interface and discover that peptide specificity, cross-reactivity and MHC restriction can be inextricably linked.
- Kurt H. Piepenbrink
- , Sydney J. Blevins
- & Brian M. Baker
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Sam68 modulates the promoter specificity of NF-κB and mediates expression of CD25 in activated T cells
The NF-κB complex is a core regulator of inflammatory gene expression and activates transcription of many different target genes. Fu et al. show that NF-κB promoter specificity can be tuned by Sam68, which is required for targeting NF-κB to the CD25 promoter during T cell activation.
- Kai Fu
- , Xin Sun
- & Fengyi Wan
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Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation
Monocytes are recruited to sites of damage or infection where they differentiate into inflammatory macrophages. Here the authors demonstrate that, contrary to the prevailing model, these differentiated cells are able to proliferate at sites of inflammation.
- Luke C. Davies
- , Marcela Rosas
- & Philip R. Taylor
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Crystal structures of interleukin 17A and its complex with IL-17 receptor A
Interleukin-17A homodimers preferentially interact with heterodimeric IL-17 receptors. By solving the crystal structure of an IL-17A homodimer in complex with a single IL-17RA receptor subunit, the authors reveal conformational changes in IL-17A that lead to exclusion of a second IL-17RA subunit.
- Shenping Liu
- , Xi Song
- & Matthew C. Griffor
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High doses of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9–TRIF pathway
CpG oligodeoxynucleotides stimulate innate immune signalling and are of significant interest as therapeutics. Here the authors show that at high doses, these molecules induce an opposite, tolerogenic effect, acting through a previously uncharacterized Toll-like receptor-dependent pathway.
- Claudia Volpi
- , Francesca Fallarino
- & Paolo Puccetti
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Toll-like receptor 3 recognizes incomplete stem structures in single-stranded viral RNA
Toll-like receptor 3 is a sensor of viral infection and sterile tissue necrosis, and is known to be activated by double-stranded RNA. Tatematsu et al. demonstrate that TLR3 also recognizes incomplete stem structures that form in single-stranded poliovirus RNA.
- Megumi Tatematsu
- , Fumiko Nishikawa
- & Misako Matsumoto
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Article
| Open AccessPrimary tumours modulate innate immune signalling to create pre-metastatic vascular hyperpermeability foci
Tumours are thought to pave the way for metastases to distant organs by secreting factors create regions of increased vascular permeability. Hiratsuka et al.identify innate immune pathways that underlie this process in the pre-metastatic lungs of tumour-bearing mice and patients.
- Sachie Hiratsuka
- , Sachie Ishibashi
- & Yoshiro Maru
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Article
| Open AccessGANP regulates recruitment of AID to immunoglobulin variable regions by modulating transcription and nucleosome occupancy
The affinity of antibodies for their targets is enhanced by somatic hypermutation, in which the cytidine deaminase AID is recruited to immunoglobulin variable region genes in B cells. Here the authors show that the nuclear protein GANP has an important role in this process by modifying chromatin structure and enhancing AID recruitment.
- Shailendra Kumar Singh
- , Kazuhiko Maeda
- & Nobuo Sakaguchi
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Regulation of asymmetric cell division and polarity by Scribble is not required for humoral immunity
B cells are thought to divide asymmetrically to generate distinct lineages required for adaptive immunity. Hawkins et al. find that surprisingly, mice lacking components of a complex required for asymmetric cell division display normal responses to vaccination and viral infection.
- Edwin D. Hawkins
- , Jane Oliaro
- & Sarah M. Russell
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Article
| Open AccessBasophils are required for the induction of Th2 immunity to haptens and peptide antigens
Both dendritic cells and basophils have been shown to influence T helper 2 cell induction, however the relative importance of their roles remains unclear. Otsuka et al. find that basophils present hapten and peptide antigens to T cells, but are unable to present protein antigens in the absence of dendritic cells.
- Atsushi Otsuka
- , Saeko Nakajima
- & Kenji Kabashima
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Article
| Open AccessMicrobe-dependent CD11b+ IgA+ plasma cells mediate robust early-phase intestinal IgA responses in mice
Intestinal plasma cells contribute to the delicate balance between immunity against pathogens and tolerance of intestinal microflora. Kunisawa et al. identify a subpopulation of plasma cells whose proliferation depends on stimulation by microbes and IL-10, and which mediate early-phase responses to oral antigens.
- Jun Kunisawa
- , Masashi Gohda
- & Hiroshi Kiyono
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Article
| Open AccessMutually exclusive regulation of T cell survival by IL-7R and antigen receptor-induced signals
Before antigen exposure, T cell survival is dependent on signalling stimulated by IL-7. Koenen et al. show that upon encountering specific antigen, T cell receptor signalling initiates a different set of survival pathways, which actively suppress those that sustain naive T cells.
- Paul Koenen
- , Susanne Heinzel
- & Philip D. Hodgkin
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Article
| Open AccessProstaglandin E2 promotes Th1 differentiation via synergistic amplification of IL-12 signalling by cAMP and PI3-kinase
Activation of cAMP signalling by prostaglandin E2 (PGE2) has long been thought to suppress Tcell receptor activation and Th1 cell differentiation. Yao et al. reveal that dual stimulation of both cAMP and PI 3-kinase pathways by PGE2 synergistically promotes Th1 differentiation by amplifying IL-12 and IFN-γsignalling.
- Chengcan Yao
- , Takako Hirata
- & Shuh Narumiya
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Article
| Open AccessInhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD
Phosphodiesterase 4 inhibitors are under development as anti-inflammatory drugs, however, their mechanisms of action remain poorly understood. Komatsu et al. show that Rolipram, a specific inhibitor of PDE4, reduces inflammation in a model of middle ear infection by upregulating the deubiquitinase CYLD.
- Kensei Komatsu
- , Ji-Yun Lee
- & Jian-Dong Li
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FBXW7α attenuates inflammatory signalling by downregulating C/EBPδ and its target gene Tlr4
The innate immune sensor Toll-like receptor 4 controls inflammatory gene expression. Here the authors identify a network of positive and negative feedback loops involving the transcription factor C/EBPd and ubiquitin ligase substrate adaptor FBXW7a that regulate TLR4 levels and inflammatory signalling.
- Kuppusamy Balamurugan
- , Shikha Sharan
- & Esta Sterneck
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Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated β1/β2-integrin trafficking
Klf5 is a transcription factor that regulates self-renewal of pluripotent stem cells. Here the authors test the function of Klf5 in somatic stem cells, and discover that it controls stem cell homing and adhesion by regulating endocytosis of beta integrins.
- E. Taniguchi Ishikawa
- , K. H. Chang
- & J. A. Cancelas
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Article
| Open AccessA chronic model of arthritis supported by a strain-specific periarticular lymph node in BALB/c mice
Mouse models of arthritis generally do not result in both chronic disease and autoantibody production—two key features of the human disease. Here the authors obtain both features by combining two common protocols, and find that disease severity is associated with the presence of a previously unidentified lymph node.
- Uta Baddack
- , Sven Hartmann
- & Gerd Müller
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TRPM2 links oxidative stress to NLRP3 inflammasome activation
Activation of the NLRP3 inflammasome by particulate matter such as crystals is known to depend on the generation of reactive oxygen species. Zhong et al. now show that liposomes stimulate the same pathway, and oxidative stress activates NLRP3 by promoting calcium influx through TRPM2 channels.
- Zhenyu Zhong
- , Yougang Zhai
- & Liang Qiao
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Structural basis for recognition of autophagic receptor NDP52 by the sugar receptor galectin-8
When Salmonella invades human cells, galectin-8 binds host glycans exposed on damaged vesicles and recruits NDP52 to trigger autophagy of the invading microbe. Kim et al. reveal the structure of the NDP52–galectin-8 complex and the basis for its carbohydrate specificity.
- Byeong-Won Kim
- , Seung Beom Hong
- & Hyun Kyu Song
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Article
| Open AccessMouse urinary peptides provide a molecular basis for genotype discrimination by nasal sensory neurons
Major histocompatibility complex peptide ligands in mouse urine have been hypothesized to serve as signals for communication. In support of this hypothesis, Sturm and colleagues find that specific urinary peptides from genetically different mouse strains can be discriminated by nasal sensory neurons.
- Theo Sturm
- , Trese Leinders-Zufall
- & Hans-Georg Rammensee
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Article
| Open AccessA model of parity-dependent immunity to placental malaria
Exposure to malaria during pregnancy can result in its spread to the placenta; however, the risk of placental infection decreases with subsequent pregnancies. By constructing a mathematical model, the authors find that this is likely due to a reduction in the duration of infection rather than a reduced risk of transfer.
- Patrick G. T. Walker
- , Jamie T. Griffin
- & Azra C. Ghani
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Article
| Open AccessThe transcriptional repressor NKAP is required for the development of iNKT cells
The transcriptional repressor NKAP is required at an early stage of T cell development for the differentiation of αβ T cells. Thapa et al.now show that at a later stage, NKAP has a specific role in positive selection of double positive thymocytes into the iNKT cell lineage.
- Puspa Thapa
- , Joy Das
- & Virginia Smith Shapiro
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Article |
Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia
Parkinson’s disease is associated with the accumulation of abnormal aggregates of α-synuclein and microglial neuroinflammation. Kim et al. show that α-synuclein oliogomers released by neurons activate microglia by stimulating Toll-like receptor 2 signalling in these cells.
- Changyoun Kim
- , Dong-Hwan Ho
- & Seung-Jae Lee
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Aldara activates TLR7-independent immune defence
The skin cancer treatment Aldara generates psoriasis-like symptoms in mice, which are thought to be due to stimulation of TLR7 by the active ingredient imiquimod. The authors show that some of these inflammatory effects are independent of both imiquimod and TLR7, implicating an unexpected role for the vehicle.
- Anne Walter
- , Matthias Schäfer
- & Maries van den Broek
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Human haemodynamic frequency harmonics regulate the inflammatory phenotype of vascular endothelial cells
Natural variations in blood flow haemodynamics are associated with localized inflammation and atherosclerosis. Here the authors show that individual harmonics present within this complex signal have distinct impacts on the inflammatory phenotype in endothelial cells.
- Ryan E. Feaver
- , Bradley D. Gelfand
- & Brett R. Blackman
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Article
| Open AccessGRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance
The clearance of apoptotic cells by macrophages is important for tissue homoeostasis. Here Nakaya et al. reveal a role for GRK6 in the regulation of apoptotic engulfment and show that GRK6 deficiency in mice leads to autoimmune disease and iron accumulation in the spleen.
- Michio Nakaya
- , Mitsuru Tajima
- & Hitoshi Kurose
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Article
| Open AccessIGF-1 promotes the development and cytotoxic activity of human NK cells
Insulin-like growth factor (IGF)-1 regulates many physiological functions including growth and metabolism. Ni et al.show that human natural killer cells secrete IGF-1 and that IGF-1 enhances the development and cytotoxicity of these cells.
- Fang Ni
- , Rui Sun
- & Haiming Wei
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The microbiome extends to subepidermal compartments of normal skin
Microbes living in human skin are known to influence the immune system; however, the deeper layers in which immune cells reside were thought to be largely impervious to bacteria. Nakatsuji et al.show that the skin microbiome extends into the dermis, enabling contact with cells below the basement membrane.
- Teruaki Nakatsuji
- , Hsin-I. Chiang
- & Richard L. Gallo
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Synaptobrevin2 is the v-SNARE required for cytotoxic T-lymphocyte lytic granule fusion
Cytotoxic T lymphocytes kill target cells through the fusion of lytic granules at the immunological synapse. Using high-resolution microscopy techniques Matti et al.identify synaptobrevin2 as the vesicular SNARE protein required for this fusion reaction.
- Ulf Matti
- , Varsha Pattu
- & Jens Rettig
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Article
| Open AccessInterferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals
A variant in the IFITM3gene increases the risk of severe influenza, but homozygosity is rare in Caucasians. The authors show that the variant gene is homozygous in 25% of healthy Chinese people, and 69% of those with severe pandemic influenza, suggesting that this gene influences the epidemiology of influenza in South-East Asia.
- Yong-Hong Zhang
- , Yan Zhao
- & Tao Dong
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Germinal centre protein HGAL promotes lymphoid hyperplasia and amyloidosis via BCR-mediated Syk activation
The human germinal centre-associated lymphoma gene is expressed in germinal centre B-lymphocytes; however, its function is unknown. Here the authors show that human germinal centre-associated lymphoma activates Syk kinase, leading to lymphoid hyperplasia and systemic reactive amyloid A amyloidosis in transgenic mice.
- Isabel Romero-Camarero
- , Xiaoyu Jiang
- & Izidore S Lossos
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