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Journal of Experimental Medicine

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https://www.readbyqxmd.com/read/28739604/s1pr1-on-tumor-associated-macrophages-promotes-lymphangiogenesis-and-metastasis-via-nlrp3-il-1%C3%AE
#1
Benjamin Weichand, Rüdiger Popp, Sarah Dziumbla, Javier Mora, Elisabeth Strack, Eiman Elwakeel, Ann-Christin Frank, Klaus Scholich, Sandra Pierre, Shahzad N Syed, Catherine Olesch, Julia Ringleb, Bilge Ören, Claudia Döring, Rajkumar Savai, Michaela Jung, Andreas von Knethen, Bodo Levkau, Ingrid Fleming, Andreas Weigert, Bernhard Brüne
Metastasis is the primary cause of cancer death. The inflammatory tumor microenvironment contributes to metastasis, for instance, by recruiting blood and lymph vessels. Among tumor-infiltrating immune cells, tumor-associated macrophages (TAMs) take a center stage in promoting both tumor angiogenesis and metastatic spread. We found that genetic deletion of the S1P receptor 1 (S1pr1) alone in CD11b(hi) CD206(+) TAMs infiltrating mouse breast tumors prevents pulmonary metastasis and tumor lymphangiogenesis. Reduced lymphangiogenesis was also observed in the nonrelated methylcholanthrene-induced fibrosarcoma model...
July 24, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28739603/novel-in-vitro-booster-vaccination-to-rapidly-generate-antigen-specific-human-monoclonal-antibodies
#2
Irene Sanjuan Nandin, Carol Fong, Cecilia Deantonio, Juan A Torreno-Pina, Simone Pecetta, Paula Maldonado, Francesca Gasparrini, Jose Ordovas-Montanes, Samuel W Kazer, Svend Kjaer, Daryl W Borley, Usha Nair, Julia A Coleman, Daniel Lingwood, Alex K Shalek, Eric Meffre, Pascal Poignard, Dennis R Burton, Facundo D Batista
Vaccines remain the most effective tool to prevent infectious diseases. Here, we introduce an in vitro booster vaccination approach that relies on antigen-dependent activation of human memory B cells in culture. This stimulation induces antigen-specific B cell proliferation, differentiation of B cells into plasma cells, and robust antibody secretion after a few days of culture. We validated this strategy using cells from healthy donors to retrieve human antibodies against tetanus toxoid and influenza hemagglutinin (HA) from H1N1 and newly emergent subtypes such as H5N1 and H7N9...
July 24, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28733386/mir-99-regulates-normal-and-malignant-hematopoietic-stem-cell-self-renewal
#3
Mona Khalaj, Carolien M Woolthuis, Wenhuo Hu, Benjamin H Durham, S Haihua Chu, Sarah Qamar, Scott A Armstrong, Christopher Y Park
The microRNA-99 (miR-99) family comprises a group of broadly conserved microRNAs that are highly expressed in hematopoietic stem cells (HSCs) and acute myeloid leukemia stem cells (LSCs) compared with their differentiated progeny. Herein, we show that miR-99 regulates self-renewal in both HSCs and LSCs. miR-99 maintains HSC long-term reconstitution activity by inhibiting differentiation and cell cycle entry. Moreover, miR-99 inhibition induced LSC differentiation and depletion in an MLL-AF9-driven mouse model of AML, leading to reduction in leukemia-initiating activity and improved survival in secondary transplants...
July 21, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28724617/human-venous-valve-disease-caused-by-mutations-in-foxc2-and-gjc2
#4
Oliver Lyons, Prakash Saha, Christopher Seet, Adam Kuchta, Andrew Arnold, Steven Grover, Victoria Rashbrook, Amélie Sabine, Gema Vizcay-Barrena, Ash Patel, Francesca Ludwinski, Soundrie Padayachee, Tsutomu Kume, Brenda R Kwak, Glen Brice, Sahar Mansour, Pia Ostergaard, Peter Mortimer, Steve Jeffery, Nigel Brown, Taija Makinen, Tatiana V Petrova, Bijan Modarai, Alberto Smith
Venous valves (VVs) prevent venous hypertension and ulceration. We report that FOXC2 and GJC2 mutations are associated with reduced VV number and length. In mice, early VV formation is marked by elongation and reorientation ("organization") of Prox1(hi) endothelial cells by postnatal day 0. The expression of the transcription factors Foxc2 and Nfatc1 and the gap junction proteins Gjc2, Gja1, and Gja4 were temporospatially regulated during this process. Foxc2 and Nfatc1 were coexpressed at P0, and combined Foxc2 deletion with calcineurin-Nfat inhibition disrupted early Prox1(hi) endothelial organization, suggesting cooperative Foxc2-Nfatc1 patterning of these events...
July 19, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28724616/marburg-virus-survivor-immune-responses-are-th1-skewed-with-limited-neutralizing-antibody-responses
#5
Spencer W Stonier, Andrew S Herbert, Ana I Kuehne, Ariel Sobarzo, Polina Habibulin, Chen V Abramovitch Dahan, Rebekah M James, Moses Egesa, Stephen Cose, Julius Julian Lutwama, Leslie Lobel, John M Dye
Until recently, immune responses in filovirus survivors remained poorly understood. Early studies revealed IgM and IgG responses to infection with various filoviruses, but recent outbreaks have greatly expanded our understanding of filovirus immune responses. Immune responses in survivors of Ebola virus (EBOV) and Sudan virus (SUDV) infections have provided the most insight, with T cell responses as well as detailed antibody responses having been characterized. Immune responses to Marburg virus (MARV), however, remain almost entirely uncharacterized...
July 19, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28720569/platelets-as-autonomous-drones-for-hemostatic-and-immune-surveillance
#6
REVIEW
Jackson LiangYao Li, Alexander Zarbock, Andrés Hidalgo
Platelets participate in many important physiological processes, including hemostasis and immunity. However, despite their broad participation in these evolutionarily critical roles, the anucleate platelet is uniquely mammalian. In contrast with the large nucleated equivalents in lower vertebrates, we find that the design template for the evolutionary specialization of platelets shares remarkable similarities with human-engineered unmanned aerial vehicles in terms of overall autonomy, maneuverability, and expendability...
July 18, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28716882/protein-kinase-d-at-the-golgi-controls-nlrp3-inflammasome-activation
#7
Zhirong Zhang, Gergö Meszaros, Wan-Ting He, Yanfang Xu, Helena de Fatima Magliarelli, Laurent Mailly, Michael Mihlan, Yansheng Liu, Marta Puig Gámez, Alexander Goginashvili, Adrien Pasquier, Olga Bielska, Bénédicte Neven, Pierre Quartier, Rudolf Aebersold, Thomas F Baumert, Philippe Georgel, Jiahuai Han, Romeo Ricci
The inflammasomes are multiprotein complexes sensing tissue damage and infectious agents to initiate innate immune responses. Different inflammasomes containing distinct sensor molecules exist. The NLRP3 inflammasome is unique as it detects a variety of danger signals. It has been reported that NLRP3 is recruited to mitochondria-associated endoplasmic reticulum membranes (MAMs) and is activated by MAM-derived effectors. Here, we show that in response to inflammasome activators, MAMs localize adjacent to Golgi membranes...
July 17, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28710273/pd-l1-up-regulation-restrains-th17-cell-differentiation-in-stat3-loss-and-stat1-gain-of-function-patients
#8
Yuan Zhang, Chi A Ma, Monica G Lawrence, Timothy J Break, Michael P O'Connell, Jonathan J Lyons, Diego B López, John S Barber, Yongge Zhao, Daniel L Barber, Alexandra F Freeman, Steven M Holland, Michail S Lionakis, Joshua D Milner
Patients with hypomorphic mutations in STAT3 and patients with hypermorphic mutations in STAT1 share several clinical and cellular phenotypes suggesting overlapping pathophysiologic mechanisms. We, therefore, examined cytokine signaling and CD4(+) T cell differentiation in these cohorts to characterize common pathways. As expected, differentiation of Th17 cells was impaired in both cohorts. We found that STAT1 was hyperphosphorylated in response to cytokine stimulation in both cohorts and that STAT1-dependent PD-L1 up-regulation-known to inhibit Th17 differentiation in mouse models-was markedly enhanced as well...
July 14, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28701369/synergistic-cooperation-and-crosstalk-between-myd88-l265p-and-mutations-that-dysregulate-cd79b-and-surface-igm
#9
James Q Wang, Yogesh S Jeelall, Peter Humburg, Emma L Batchelor, Sarp M Kaya, Hee Min Yoo, Christopher C Goodnow, Keisuke Horikawa
CD79B and MYD88 mutations are frequently and simultaneously detected in B cell malignancies. It is not known if these mutations cooperate or how crosstalk occurs. Here we analyze the consequences of CD79B and MYD88(L265P) mutations individually and combined in normal activated mouse B lymphocytes. CD79B mutations alone increased surface IgM but did not enhance B cell survival, proliferation, or altered NF-κB responsive markers. Conversely, B cells expressing MYD88(L265P) decreased surface IgM coupled with accumulation of endoglycosidase H-sensitive IgM intracellularly, resembling the trafficking block in anergic B cells repeatedly stimulated by self-antigen...
July 12, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28701368/kunkel-lecture-fundamental-immunodeficiency-and-its-correction
#10
REVIEW
Carl Nathan
"Fundamental immunodeficiency" is the inability of the encoded immune system to protect an otherwise healthy host from every infection that could threaten its life. In contrast to primary immunodeficiencies, fundamental immunodeficiency is not rare but nearly universal. It results not from variation in a given host gene but from the rate and extent of variation in the genes of other organisms. The remedy for fundamental immunodeficiency is "adopted immunity," not to be confused with adaptive or adoptive immunity...
July 12, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28698287/blimp-1-dependent-and-independent-natural-antibody-production-by-b-1-and-b-1-derived-plasma-cells
#11
Hannah P Savage, Vanessa M Yenson, Sanjam S Sawhney, Betty J Mousseau, Frances E Lund, Nicole Baumgarth
Natural antibodies contribute to tissue homeostasis and protect against infections. They are secreted constitutively without external antigenic stimulation. The differentiation state and regulatory pathways that enable continuous natural antibody production by B-1 cells, the main cellular source in mice, remain incompletely understood. Here we demonstrate that natural IgM-secreting B-1 cells in the spleen and bone marrow are heterogeneous, consisting of (a) terminally differentiated B-1-derived plasma cells expressing the transcriptional regulator of differentiation, Blimp-1, (b) Blimp-1(+), and (c) Blimp-1(neg) phenotypic B-1 cells...
July 11, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28698286/tissue-microenvironment-dictates-the-fate-and-tumor-suppressive-function-of-type-3-ilcs
#12
Kathrin Nussbaum, Sara H Burkhard, Isabel Ohs, Florian Mair, Christoph S N Klose, Sebastian J Arnold, Andreas Diefenbach, Sonia Tugues, Burkhard Becher
Innate lymphoid cells (ILCs) have been classified into "functional subsets" according to their transcription factor and cytokine profiles. Although cytokines, such as IL-12 and IL-23, have been shown to shape plasticity of ILCs, little is known about how the tissue microenvironment influences the plasticity, phenotype, and function of these cells. Here, we show clearly demarcated tissue specifications of Rorc-dependent ILCs across lymphoid and nonlymphoid organs. Although intestinal Rorc fate map-positive (Rorc(fm+)) ILCs show a clear ILC3 phenotype, lymphoid tissue-derived Rorc(fm+) ILCs acquire an natural killer (NK) cell/ILC1-like phenotype...
July 11, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28698285/therapeutic-antibody-targeting-of-notch3-signaling-prevents-mural-cell-loss-in-cadasil
#13
Arturo I Machuca-Parra, Alexander A Bigger-Allen, Angie V Sanchez, Anissa Boutabla, Jonathan Cardona-Vélez, Dhanesh Amarnani, Magali Saint-Geniez, Christian W Siebel, Leo A Kim, Patricia A D'Amore, Joseph F Arboleda-Velasquez
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological syndrome characterized by small vessel disease (SVD), stroke, and vascular cognitive impairment and dementia caused by mutations in NOTCH3 No therapies are available for this condition. Loss of mural cells, which encompass pericytes and vascular smooth muscle cells, is a hallmark of CADASIL and other SVDs, including diabetic retinopathy, resulting in vascular instability. Here, we showed that Notch3 signaling is both necessary and sufficient to support mural cell coverage in arteries using genetic rescue in Notch3 knockout mice...
July 11, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28698284/breaching-peripheral-tolerance-promotes-the-production-of-hiv-1-neutralizing-antibodies
#14
Kristin M S Schroeder, Amanda Agazio, Pamela J Strauch, Sean T Jones, Scott B Thompson, Michael S Harper, Roberta Pelanda, Mario L Santiago, Raul M Torres
A subset of characterized HIV-1 broadly neutralizing antibodies (bnAbs) are polyreactive with additional specificities for self-antigens and it has been proposed immunological tolerance may present a barrier to their participation in protective humoral immunity. We address this hypothesis by immunizing autoimmune-prone mice with HIV-1 Envelope (Env) and characterizing the primary antibody response for HIV-1 neutralization. We find autoimmune mice generate neutralizing antibody responses to tier 2 HIV-1 strains with alum treatment alone in the absence of Env...
July 11, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28694388/annexin-a2-supports-pulmonary-microvascular-integrity-by-linking-vascular-endothelial-cadherin-and-protein-tyrosine-phosphatases
#15
Min Luo, Elle C Flood, Dena Almeida, LunBiao Yan, David A Berlin, Paul M Heerdt, Katherine A Hajjar
Relative or absolute hypoxia activates signaling pathways that alter gene expression and stabilize the pulmonary microvasculature. Alveolar hypoxia occurs in disorders ranging from altitude sickness to airway obstruction, apnea, and atelectasis. Here, we report that the phospholipid-binding protein, annexin A2 (ANXA2) functions to maintain vascular integrity in the face of alveolar hypoxia. We demonstrate that microvascular endothelial cells (ECs) from Anxa2(-/-) mice display reduced barrier function and excessive Src-related tyrosine phosphorylation of the adherens junction protein vascular endothelial cadherin (VEC)...
July 10, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28694387/inhibition-of-autophagy-limits-vertical-transmission-of-zika-virus-in-pregnant-mice
#16
Bin Cao, Lindsay A Parnell, Michael S Diamond, Indira U Mysorekar
Zika virus (ZIKV) infection during pregnancy leads to devastating fetal outcomes, including intrauterine growth restriction and microcephaly. Greater understanding of mechanisms underlying ZIKV maternal-fetal transmission is needed to develop new therapeutic interventions. Here, we define an important role for the autophagy pathway in ZIKV vertical transmission. ZIKV infection induced autophagic activity in human trophoblasts and pharmacological inhibition limited ZIKV infectivity. Furthermore, deficiency in an essential autophagy gene, Atg16l1, in mice limited ZIKV vertical transmission and placental and fetal damage and overall improved placental and fetal outcomes...
July 10, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28694386/a-type-2-cytokine-axis-for-thymus-emigration
#17
Andrea J White, Song Baik, Sonia M Parnell, Amanda M Holland, Frank Brombacher, William E Jenkinson, Graham Anderson
In the thymus, stromal microenvironments support a developmental program that generates mature T cells ready for thymic exit. The cellular and molecular specialization within thymic stromal cells that enables their regulation of specific stages of thymocyte development is poorly understood. Here, we show the thymic microenvironment expresses the type 2 IL-4R complex and is functionally responsive to its known ligands, IL-4 and IL-13. Absence of IL-4Rα limits thymocyte emigration, leading to an intrathymic accumulation of mature thymocytes within medullary perivascular spaces and reduced numbers of recent thymic emigrants...
July 10, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28694385/monocyte-derived-alveolar-macrophages-drive-lung-fibrosis-and-persist-in-the-lung-over-the-life-span
#18
Alexander V Misharin, Luisa Morales-Nebreda, Paul A Reyfman, Carla M Cuda, James M Walter, Alexandra C McQuattie-Pimentel, Ching-I Chen, Kishore R Anekalla, Nikita Joshi, Kinola J N Williams, Hiam Abdala-Valencia, Tyrone J Yacoub, Monica Chi, Stephen Chiu, Francisco J Gonzalez-Gonzalez, Khalilah Gates, Anna P Lam, Trevor T Nicholson, Philip J Homan, Saul Soberanes, Salina Dominguez, Vince K Morgan, Rana Saber, Alexander Shaffer, Monique Hinchcliff, Stacy A Marshall, Ankit Bharat, Sergejs Berdnikovs, Sangeeta M Bhorade, Elizabeth T Bartom, Richard I Morimoto, William E Balch, Jacob I Sznajder, Navdeep S Chandel, Gökhan M Mutlu, Manu Jain, Cara J Gottardi, Benjamin D Singer, Karen M Ridge, Neda Bagheri, Ali Shilatifard, G R Scott Budinger, Harris Perlman
Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution...
July 10, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28684431/convergent-roles-of-atf3-and-csl-in-chromatin-control-of-cancer-associated-fibroblast-activation
#19
Dong Eun Kim, Maria-Giuseppina Procopio, Soumitra Ghosh, Seung-Hee Jo, Sandro Goruppi, Francesco Magliozzi, Pino Bordignon, Victor Neel, Paolo Angelino, G Paolo Dotto
Cancer-associated fibroblasts (CAFs) are important for tumor initiation and promotion. CSL, a transcriptional repressor and Notch mediator, suppresses CAF activation. Like CSL, ATF3, a stress-responsive transcriptional repressor, is down-modulated in skin cancer stromal cells, and Atf3 knockout mice develop aggressive chemically induced skin tumors with enhanced CAF activation. Even at low basal levels, ATF3 converges with CSL in global chromatin control, binding to few genomic sites at a large distance from target genes...
July 6, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28666979/predicting-the-response-to-ctla-4-blockade-by-longitudinal-noninvasive-monitoring-of-cd8-t-cells
#20
Mohammad Rashidian, Jessica R Ingram, Michael Dougan, Anushka Dongre, Katherine A Whang, Camille LeGall, Juan J Cragnolini, Brian Bierie, Monica Gostissa, James Gorman, Gijsbert M Grotenbreg, Atul Bhan, Robert A Weinberg, Hidde L Ploegh
Immunotherapy using checkpoint-blocking antibodies against targets such as CTLA-4 and PD-1 can cure melanoma and non-small cell lung cancer in a subset of patients. The presence of CD8 T cells in the tumor correlates with improved survival. We show that immuno-positron emission tomography (immuno-PET) can visualize tumors by detecting infiltrating lymphocytes and, through longitudinal observation of individual animals, distinguish responding tumors from those that do not respond to therapy. We used (89)Zr-labeled PEGylated single-domain antibody fragments (VHHs) specific for CD8 to track the presence of intratumoral CD8(+) T cells in the immunotherapy-susceptible B16 melanoma model in response to checkpoint blockade...
June 30, 2017: Journal of Experimental Medicine
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