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https://www.readbyqxmd.com/read/29772310/recombination-activity-of-human-rag2-mutations-and-correlation-with-the-clinical-phenotype
#1
Irit Tirosh, Yasuhiro Yamazaki, Francesco Frugoni, Francesca A Ververs, Eric J Allenspach, Yu Zhang, Siobhan Burns, Waleed Al-Herz, Lenora Noroski, Jolan E Walter, Andrew R Gennery, Mirjam van der Burg, Luigi D Notarangelo, Yu Nee Lee
BACKGROUND: Mutations in the Recombinase Activating Gene 1 and 2 (RAG1, RAG2) are associated with a broad range of clinical and immunological phenotypes in humans. OBJECTIVE: Using a flow cytometry-based assay, we aimed to measure the recombinase activity of naturally occurring RAG2 mutant proteins, and to correlate results with the severity of the clinical and immunological phenotype. METHODS: Abelson virus-transformed Rag2-/- pro-B cells engineered to contain an inverted GFP cassette flanked by recombination signal sequences (RSS) were transduced with retroviruses encoding either wild-type or 41 naturally occurring RAG2 variants...
May 14, 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29755449/immunization-elicits-antigen-specific-antibody-sequestration-in-dorsal-root-ganglia-sensory-neurons
#2
Manojkumar Gunasekaran, Prodyot K Chatterjee, Andrew Shih, Gavin H Imperato, Meghan Addorisio, Gopal Kumar, Annette Lee, John F Graf, Dan Meyer, Michael Marino, Christopher Puleo, Jeffrey Ashe, Maureen A Cox, Tak W Mak, Chad Bouton, Barbara Sherry, Betty Diamond, Ulf Andersson, Thomas R Coleman, Christine N Metz, Kevin J Tracey, Sangeeta S Chavan
The immune and nervous systems are two major organ systems responsible for host defense and memory. Both systems achieve memory and learning that can be retained, retrieved, and utilized for decades. Here, we report the surprising discovery that peripheral sensory neurons of the dorsal root ganglia (DRGs) of immunized mice contain antigen-specific antibodies. Using a combination of rigorous molecular genetic analyses, transgenic mice, and adoptive transfer experiments, we demonstrate that DRGs do not synthesize these antigen-specific antibodies, but rather sequester primarily IgG1 subtype antibodies...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29753156/antiviral-t-cells-for-adenovirus-in-the-pre-transplant-period-a-bridge-therapy-for-severe-combined-immunodeficiency
#3
Holly K Miller, Patrick J Hanley, Haili Lang, Christopher A Lazarski, Elizabeth A Chorvinsky, Sarah McCormack, Lauren Roesch, Shuroug Albihani, Marcus Dean, Fahmida Hoq, Roberta H Adams, Catherine Bollard, Michael D Keller
Viral infections can be life-threatening in patients with severe combined immunodeficiency (SCID) and other forms of profound primary immunodeficiency disorders both before and after hematopoietic stem cell transplant (HSCT). Adoptive immunotherapy with virus-specific T-cells (VST) has been utilized in many patients in the setting of HSCT, but has very rarely been attempted for treatment of viral infections before HSCT. Here we describe the use of VSTs in an infant with RAG1 SCID who had developed disseminated adenovirus which failed to improve on cidofovir...
May 9, 2018: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29746837/an-immunocompetent-mouse-model-of-zika-virus-infection
#4
Matthew J Gorman, Elizabeth A Caine, Konstantin Zaitsev, Matthew C Begley, James Weger-Lucarelli, Melissa B Uccellini, Shashank Tripathi, Juliet Morrison, Boyd L Yount, Kenneth H Dinnon, Claudia Rückert, Michael C Young, Zhe Zhu, Shelly J Robertson, Kristin L McNally, Jing Ye, Bin Cao, Indira U Mysorekar, Gregory D Ebel, Ralph S Baric, Sonja M Best, Maxim N Artyomov, Adolfo Garcia-Sastre, Michael S Diamond
Progress toward understanding Zika virus (ZIKV) pathogenesis is hindered by lack of immunocompetent small animal models, in part because ZIKV fails to effectively antagonize Stat2-dependent interferon (IFN) responses in mice. To address this limitation, we first passaged an African ZIKV strain (ZIKV-Dak-41525) through Rag1-/- mice to obtain a mouse-adapted virus (ZIKV-Dak-MA) that was more virulent than ZIKV-Dak-41525 in mice treated with an anti-Ifnar1 antibody. A G18R substitution in NS4B was the genetic basis for the increased replication, and resulted in decreased IFN-β production, diminished IFN-stimulated gene expression, and the greater brain infection observed with ZIKV-Dak-MA...
May 9, 2018: Cell Host & Microbe
https://www.readbyqxmd.com/read/29743177/hypomorphic-rag1-mutations-alter-the-pre-immune-repertoire-at-early-stages-of-lymphoid-development
#5
Lisa M Ott de Bruin, Marita Bosticardo, Alessandro Barbieri, Sherry G Lin, Jared H Rowe, Pietro L Poliani, Kimberly Ching, Daniel Eriksson, Nils Landegren, Olle Kämpe, John P Manis, Luigi D Notarangelo
Hypomorphic RAG1 mutations allowing residual T and B cell development have been found in patients presenting with delayed-onset combined immune deficiency with granulomas and/or autoimmunity (CID-G/AI) and abnormalities of the peripheral T and B cell repertoire. To examine how hypomorphic Rag1 mutations affect the earliest stages of lymphocyte development, we used CRISPR/Cas9 to generate mouse models with equivalent mutations found in patients with CID-G/AI. Immunological characterization showed partial development of T and B lymphocytes, with persistence of naïve cells, preserved serum immunoglobulin, but impaired antibody responses and presence of autoantibodies, thereby recapitulating the phenotype seen in patients with CID-G/AI...
May 9, 2018: Blood
https://www.readbyqxmd.com/read/29734775/characterization-of-an-n-terminal-non-core-domain-of-rag1-gene-disrupted-syrian-hamster-model-generated-by-crispr-cas9
#6
Jinxin Miao, Baoling Ying, Rong Li, Ann E Tollefson, Jacqueline F Spencer, William S M Wold, Seok-Hwan Song, Il-Keun Kong, Karoly Toth, Yaohe Wang, Zhongde Wang
The accumulating evidence demonstrates that Syrian hamsters have advantages as models for various diseases. To develop a Syrian hamster ( Mesocricetus auratus ) model of human immunodeficiency caused by RAG1 gene mutations, we employed the CRISPR/Cas9 system and introduced an 86-nucleotide frameshift deletion in the hamster RAG1 gene encoding part of the N-terminal non-core domain of RAG1. Histological and immunohistochemical analyses demonstrated that these hamsters (referred herein as RAG1-86nt hamsters) had atrophic spleen and thymus, and developed significantly less white pulp and were almost completely devoid of splenic lymphoid follicles...
May 6, 2018: Viruses
https://www.readbyqxmd.com/read/29723648/molecular-phylogeny-of-banjo-catfishes-ostaryophisi-siluriformes-aspredinidae-a-continental-radiation-in-south-american-freshwaters
#7
Tiago P Carvalho, H Mariangeles Arce, Roberto E Reis, Mark H Sabaj
The family Aspredinidae is a moderately diverse and broadly distributed group of freshwater fishes endemic to South America. Commonly known as Banjo Catfishes, Aspredinidae currently includes 44 valid species divided among 13 genera. The first species-comprehensive hypothesis on phylogenetic relationships among aspredinids is presented. The phylogeny is based on DNA sequence data for five gene fragments (mitochondrial 16S and COI; nuclear RAG1, MYH6 and SH3PX3) from 114 individuals representing 31 species in 12 aspredinid genera...
April 30, 2018: Molecular Phylogenetics and Evolution
https://www.readbyqxmd.com/read/29697763/pathogenicity-of-in-vivo-generated-intestinal-th17-lymphocytes-is-ifn%C3%AE-dependent
#8
Giulia Nizzoli, Claudia Burrello, Fulvia Milena Cribiù, Giulia Lovati, Giulia Ercoli, Fiorenzo Botti, Elena Trombetta, Laura Porretti, Katia Todoerti, Antonino Neri, Maria Rita Giuffrè, Jens Geginat, Maurizio Vecchi, Maria Rescigno, Moira Paroni, Flavio Caprioli, Federica Facciotti
Background and aims: Th17 cells are crucially involved in the immunopathogenesis of inflammatory bowel diseases in humans. Nevertheless, pharmacological blockade of IL17A, the Th17 signature cytokine, yielded negative results in patients with Crohn's disease (CD), and attempts to elucidate the determinants of Th17 cells pathogenicity in the gut have so far proved unsuccessful. Here, we aimed to identify and functionally validate the pathogenic determinants of intestinal IL-17-producing T cells...
April 25, 2018: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/29694887/the-nlrp3-inflammasome-suppresses-protective-immunity-to-gastrointestinal-helminth-infection
#9
Rafid Alhallaf, Zainab Agha, Catherine M Miller, Avril A B Robertson, Javier Sotillo, John Croese, Matthew A Cooper, Seth L Masters, Andreas Kupz, Nicholas C Smith, Alex Loukas, Paul R Giacomin
Inflammasomes promote immunity to microbial pathogens by regulating the function of IL-1-family cytokines such as IL-18 and IL-1β. However, the roles for inflammasomes during parasitic helminth infections remain unclear. We demonstrate that mice and humans infected with gastrointestinal nematodes display increased IL-18 secretion, which in Trichuris-infected or worm antigen-treated mice and in macrophages co-cultured with Trichuris antigens or exosome-like vesicles was dependent on the NLRP3 inflammasome. NLRP3-deficient mice displayed reduced pro-inflammatory type 1 cytokine responses and augmented protective type 2 immunity, which was reversed by IL-18 administration...
April 24, 2018: Cell Reports
https://www.readbyqxmd.com/read/29688994/generation-of-immunodeficient-rats-with-rag1-and-il2rg-gene-deletions-and-human-tissue-grafting-models
#10
Séverine Ménoret, Laure-Hélène Ouisse, Laurent Tesson, Frédéric Delbos, Delphine Garnier, Séverine Remy, Claire Usal, Jean-Paul Concordet, Carine Giovannangeli, Vanessa Chenouard, Lucas Brusselle, Emmanuel Merieau, Véronique Nerrière-Daguin, Franck Duteille, Frédérique Bellier-Waast, Alexandre Fraichard, Tuan H Nguyen, Ignacio Anegon
BACKGROUND: Immunodeficient mice are invaluable tools to analyze the long-term effects of potentially immunogenic molecules in the absence of adaptive immune responses. Nevertheless, there are models and experimental situations that would beneficiate of larger immunodeficient recipients. Rats are ideally suited to perform experiments in which larger size is needed and are still a small animal model suitable for rodent facilities. Additionally, rats reproduce certain human diseases better than mice, such as ankylosing spondylitis and Duchenne disease and these disease models would greatly benefit of immunodeficient rats to test different immunogenic treatments...
April 23, 2018: Transplantation
https://www.readbyqxmd.com/read/29687406/the-immune-response-to-picornavirus-infection-and-the-effect-of-immune-manipulation-on-acute-seizures
#11
Ana Beatriz DePaula-Silva, F Lynn Sonderegger, Jane E Libbey, Daniel J Doty, Robert S Fujinami
Viral infection of the central nervous system can result in encephalitis. About 20% of individuals who develop viral encephalitis go on to develop epilepsy. We have established an experimental model where virus infection of mice with Theiler's murine encephalomyelitis virus (TMEV) leads to acute seizures, followed by a latent period (no seizures/epileptogenesis phase) and then spontaneous recurrent seizures-epilepsy. Infiltrating macrophages (CD11b+ CD45hi ) present in the brain at day 3 post-infection are an important source of interleukin-6, which contributes to the development of acute seizures in the TMEV-induced seizure model...
April 23, 2018: Journal of Neurovirology
https://www.readbyqxmd.com/read/29685989/tcr%C3%AE-combinatorial-immunoreceptor-expression-by-neutrophils-correlates-with-parasite-burden-and-enhanced-phagocytosis-during-a-plasmodium-berghei-anka-malaria-infection
#12
Joanna K Chorazeczewski, Maya Aleshnick, Victoria Majam, Winter A Okoth, Regina Kurapova, Adovi Akue, Mark KuKuruga, Sanjai Kumar, Miranda S Oakley
Recent studies have demonstrated that a subpopulation of neutrophils express the TCRαβ combinatorial immunoreceptor in humans and mice. Here, we report that a Plasmodium berghei ANKA murine malaria infection induces expansion of TCRβ expressing CD11b+ Ly6G+ neutrophils in the spleen during the early phase of infection. Measurement of TCRβ transcript and protein levels of neutrophils in wildtype versus nude and Rag1 KO mice establishes that the observed expression is not a consequence of nonspecific antibody staining or passive receptor expression due to phagocytosis or trogocytosis of peripheral T cells...
April 23, 2018: Infection and Immunity
https://www.readbyqxmd.com/read/29662618/ectopic-expression-of-transcription-factor-batf3-induces-b-cell-lymphomas-in-a-murine-b-cell-transplantation-model
#13
Christian Weiser, Mina V Petkova, Benjamin Rengstl, Claudia Döring, Dorothee von Laer, Sylvia Hartmann, Ralf Küppers, Martin-Leo Hansmann, Sebastian Newrzela
The mechanisms involved in malignant transformation of mature B and T lymphocytes are still poorly understood. In a previous study, we compared gene expression profiles of the tumor cells of Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) to their normal cellular counterparts and found the basic leucine zipper protein ATF-like 3 (BATF3) to be significantly upregulated in the tumor cells of both entities. To assess the oncogenic potential of BATF3 in lymphomagenesis and to dissect the molecular interactions of BATF3 in lymphoma cells, we retrovirally transduced murine mature T and B cells with a BATF3-encoding viral vector and transplanted each population into Rag1-deficient recipients...
March 23, 2018: Oncotarget
https://www.readbyqxmd.com/read/29661927/t-independent-ifn%C3%AE-and-b-cells-cooperate-to-prevent-mortality-associated-with-disseminated-chlamydia-muridarum-genital-tract-infection
#14
Taylor B Poston, Catherine M O'Connell, Jenna Girardi, Jeanne E Sullivan, Uma M Nagarajan, Anthony Marinov, Amy M Scurlock, Toni Darville
CD4 T cells and antibody are required for optimal acquired immunity to C. muridarum genital tract infection, and T cell-mediated IFNγ production is necessary to clear infection in the absence of humoral immunity. However, the role of T cell-independent immune responses during primary infection remains unclear. We investigated this question by inoculating wild-type and immune-deficient mice with C. muridarum CM001, a clonal isolate capable of enhanced extragenital replication. Genital inoculation of wild-type mice resulted in transient dissemination to the lungs and spleen that then was rapidly cleared from these organs...
April 16, 2018: Infection and Immunity
https://www.readbyqxmd.com/read/29628308/cracking-the-dna-code-for-v-d-j-recombination
#15
Min-Sung Kim, Watchalee Chuenchor, Xuemin Chen, Yanxiang Cui, Xing Zhang, Z Hong Zhou, Martin Gellert, Wei Yang
To initiate V(D)J recombination for generating the adaptive immune response of vertebrates, RAG1/2 recombinase cleaves DNA at a pair of recombination signal sequences, the 12- and 23-RSS. We have determined crystal and cryo-EM structures of RAG1/2 with DNA in the pre-reaction and hairpin-forming complexes up to 2.75 Å resolution. Both protein and DNA exhibit structural plasticity and undergo dramatic conformational changes. Coding-flank DNAs extensively rotate, shift, and deform for nicking and hairpin formation...
March 29, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29625134/il-17-producing-st2-ilc2-plays-a-pathogenic-role-in-lung-inflammation
#16
Ting Cai, Jinxin Qiu, Yan Ji, Wenjing Li, Zhaoyun Ding, Caixia Suo, Jiali Chang, Jingjing Wang, Rui He, Youcun Qian, Xiaohuan Guo, Liang Zhou, Huiming Sheng, Lei Shen, Ju Qiu
BACKGROUND: IL-17 plays a pathogenic role in asthma. ST2- iILC2s (inflammatory group 2 innate lymphoid cells) driven by IL-25 can produce IL-17, while ST2+ nILC2s (natural ILC2s) produce few IL-17. OBJECTIVE: We characterized the ST2+ IL-17+ ILC2s during lung inflammation and determined the pathogenesis and molecular regulation of ST2+ IL-17+ ILC2s. METHODS: Lung inflammation was induced by papain or IL-33. IL-17 production by lung ILC2s from wild-type, Rag1-/- , Rorcgfp/gfp and Ahr-/- mice was examined by flow cytometry...
April 3, 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29618473/il-23r-deficiency-does-not-impact-atherosclerotic-plaque-development-in-mice
#17
Daniel Engelbertsen, Marie A C Depuydt, Robin A F Verwilligen, Sara Rattik, Erik Levinsohn, Andreas Edsfeldt, Felicia Kuperwaser, Petr Jarolim, Andrew H Lichtman
BACKGROUND: Interleukin-23 (IL-23) has been implicated in inflammatory and autoimmune diseases by skewing CD4+ T helper cells towards a pathogenic Th17 phenotype. In this study we investigated the presence of IL-23 receptor (IL-23R)-expressing cells in the atherosclerotic aorta and evaluated the effect of IL-23R deficiency on atherosclerosis development in mice. METHODS AND RESULTS: We used heterozygous Ldlr -/- Il23r e GFP / WT knock-in mice to identify IL-23R-expressing cells by flow cytometry and homozygous Ldlr -/- Il23r e GFP / eGFP ( Ldlr -/- Il23r -/- ) mice to investigate the effect of lack of IL-23R in atherosclerosis...
April 4, 2018: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29615958/lymphocytes-contribute-to-the-pathophysiology-of-neonatal-brain-injury
#18
Arshed Nazmi, Anna-Maj Albertsson, Eridan Rocha-Ferreira, Xiaoli Zhang, Regina Vontell, Aura Zelco, Mary Rutherford, Changlian Zhu, Gisela Nilsson, Carina Mallard, Henrik Hagberg, Jacqueline C Y Lai, Jianmei W Leavenworth, Xiaoyang Wang
Background: Periventricular leukomalacia (PVL) is the most common form of preterm brain injury affecting the cerebral white matter. This type of injury involves a multiphase process and is induced by many factors, including hypoxia-ischemia (HI) and infection. Previous studies have suggested that lymphocytes play a significant role in the pathogenesis of brain injury, and the aim of this study was to determine the contribution of lymphocyte subsets to preterm brain injury. Methods: Immunohistochemistry on brain sections from neonatal mice was performed to evaluate the extent of brain injury in wild-type and T cell and B cell-deficient neonatal mice ( Rag1 -/- mice) using a mouse model of HI-induced preterm brain injury...
2018: Frontiers in Neurology
https://www.readbyqxmd.com/read/29610161/topical-hypochlorite-and-skin-acidification-improves-erythroderma-of-omenn-syndrome
#19
Margaret Wat, Arielle Olicker, Howard Meyerson, Susan Nedorost, Amy S Paller, Kevin Cooper
We describe a case of Omenn syndrome displaying exudative erythroderma and other characteristic features, including alopecia, absent B and naïve T cells, hyper immunoglobulin E levels, and eosinophilia. A pathogenic recombination-activating RAG1 homozygous genetic mutation confirmed the diagnosis. She required frequent antibiotics at both treatment and prophylactic doses, which alone did not control her erythroderma, but her high risk of infection precluded the use of systemic agents such as cyclosporine, which would further suppress her already severely compromised immune system...
April 2018: Pediatrics
https://www.readbyqxmd.com/read/29607498/1-l-mt-an-ido-inhibitor-prevented-colitis-associated-cancer-by-inducing-cdc20-inhibition-mediated-mitotic-death-of-colon-cancer-cells
#20
Xiuting Liu, Wei Zhou, Xin Zhang, Yang Ding, Qianming Du, Rong Hu
Indoleamine 2,3-dioxygenase 1 (IDO1), known as IDO, catabolizes tryptophan through kynurenine pathway, whose activity is correlated with impaired clinical outcome of colorectal cancer. Here we showed that 1-L-MT, a canonical IDO inhibitor, suppressed proliferation of human colorectal cancer cells through inducing mitotic death. Our results showed that inhibition of IDO decreased the transcription of CDC20, which resulted in G2/M cycle arrest of HCT-116 and HT-29. Furthermore, 1-L-MT induced mitochondria injuries and caused apoptotic cancer cells...
April 1, 2018: International Journal of Cancer. Journal International du Cancer
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