The Journal of Experimental Medicine
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Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6
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(Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Machado, F. S., Esper, L., Dias, A., Madan, R., Gu, Y., Hildeman, D., Serhan, C. N., Karp, C. L., Aliberti, J. Tags: RETRACTION Source Type: journals
KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-CEmail this article to a colleague.
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Human killer cell immunoglobulin-like receptors (KIRs) are distinguished by expansion of activating KIR2DS, whose ligands and functions remain poorly understood. The oldest, most prevalent KIR2DS is KIR2DS4, which is represented by a variable balance between "full-length" and "deleted" forms. We find that full-length 2DS4 is a human histocompatibility leukocyte antigen (HLA) class I receptor that binds specifically to subsets of C1+ and C2+ HLA-C and to HLA-A*11, whereas deleted 2DS4 is nonfunctional. Activation of 2DS4+ NKL cells was achieved with A*1102 as ligand, which differs from A*1101 by unique substitution of lysin...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Graef, T., Moesta, A. K., Norman, P. J., Abi-Rached, L., Vago, L., Older Aguilar, A. M., Gleimer, M., Hammond, J. A., Guethlein, L. A., Bushnell, D. A., Robinson, P. J., Parham, P. Tags: Articles Source Type: journals
Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptorEmail this article to a colleague.
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Of the potent lipid inflammatory mediators comprising the cysteinyl leukotrienes (LTs; LTC4, LTD4, and LTE4), only LTE4 is stable and abundant in vivo. Although LTE4 shows negligible activity at the type 1 and 2 receptors for cys-LTs (CysLT1R and CysLT2R), it is a powerful inducer of mucosal eosinophilia and airway hyperresponsiveness in humans with asthma. We show that the adenosine diphosphate (ADP)–reactive purinergic (P2Y12) receptor is required for LTE4-mediated pulmonary inflammation. P2Y12 receptor expression permits LTE4 -induced activation of extracellular signal-regulated kinase in Chinese hamster ovary cel...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Paruchuri, S., Tashimo, H., Feng, C., Maekawa, A., Xing, W., Jiang, Y., Kanaoka, Y., Conley, P., Boyce, J. A. Tags: Articles Source Type: journals
A hypomorphic allele of ZAP-70 reveals a distinct thymic threshold for autoimmune disease versus autoimmune reactivityEmail this article to a colleague.
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ZAP-70 is critical for T cell receptor (TCR) signaling. Tyrosine to phenylalanine mutations of Y315 and Y319 in ZAP-70 suggest these residues function to recruit downstream effector molecules, but mutagenesis and crystallization studies reveal that these residues also play an important role in autoinhibition ZAP-70. To address the importance of the scaffolding function, we generated a zap70 mutant mouse (YYAA mouse) with Y315 and Y319 both mutated to alanines. These YYAA mice reveal that the scaffolding function is important for normal development and function. Moreover, the YYAA mice have many similarities to a previously...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Hsu, L.-Y., Tan, Y. X., Xiao, Z., Malissen, M., Weiss, A. Tags: Articles Source Type: journals
Therapy of experimental type 1 diabetes by isolated Sertoli cell xenografts aloneEmail this article to a colleague.
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We report that isolated neonatal porcine SC, administered alone in highly biocompatible microcapsules, led to diabetes prevention and reversion in the respective 88 and 81% of overtly diabetic (nonobese diabetic [NOD]) mice, with no need for additional β cell or insulin therapy. The effect was associated with restoration of systemic immune tolerance and detection of functional pancreatic islets that consisted of glucose-responsive and insulin-secreting cells. Curative effects by SC were strictly dependent on efficient tryptophan metabolism in the xenografts, leading to TGF-β–dependent emergence of autoantig...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Fallarino, F., Luca, G., Calvitti, M., Mancuso, F., Nastruzzi, C., Fioretti, M. C., Grohmann, U., Becchetti, E., Burgevin, A., Kratzer, R., van Endert, P., Boon, L., Puccetti, P., Calafiore, R. Tags: Articles Source Type: journals
Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasisEmail this article to a colleague.
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(Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Van Keymeulen, A., Mascre, G., Youseff, K. K., Harel, I., Michaux, C., De Geest, N., Szpalski, C., Achouri, Y., Bloch, W., Hassan, B. A., Blanpain, C. Tags: From the JCB Source Type: journals
Glyburide inhibits the Cryopyrin/Nalp3 inflammasomeEmail this article to a colleague.
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(Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Lamkanfi, M., Mueller, J. L., Vitari, A. C., Misaghi, S., Fedorova, A., Deshayes, K., Lee, W. P., Hoffman, H. M., Dixit, V. M. Tags: From the JCB Source Type: journals
CD1-restricted adaptive immune responses to Mycobacteria in human group 1 CD1 transgenic miceEmail this article to a colleague.
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Group 1 CD1 (CD1a, CD1b, and CD1c)–restricted T cells recognize mycobacterial lipid antigens and are found at higher frequencies in Mycobacterium tuberculosis (Mtb)–infected individuals. However, their role and dynamics during infection remain unknown because of the lack of a suitable small animal model. We have generated human group 1 CD1 transgenic (hCD1Tg) mice that express all three human group 1 CD1 isoforms and support the development of group 1 CD1–restricted T cells with diverse T cell receptor usage. Both mycobacterial infection and immunization with Mtb lipids elicit group 1 CD1–restricted...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Felio, K., Nguyen, H., Dascher, C. C., Choi, H.-J., Li, S., Zimmer, M. I., Colmone, A., Moody, D. B., Brenner, M. B., Wang, C.-R. Tags: Articles Source Type: journals
Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrowEmail this article to a colleague.
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This study provides the useful method needed to identify MSCs as defined in vivo entities. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Morikawa, S., Mabuchi, Y., Kubota, Y., Nagai, Y., Niibe, K., Hiratsu, E., Suzuki, S., Miyauchi-Hara, C., Nagoshi, N., Sunabori, T., Shimmura, S., Miyawaki, A., Nakagawa, T., Suda, T., Okano, H., Matsuzaki, Y. Tags: Articles Source Type: journals
T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrowEmail this article to a colleague.
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During a screen for ethylnitrosourea-induced mutations in mice affecting blood natural killer (NK) cells, we identified a strain, designated Duane, in which NK cells were reduced in blood and spleen but increased in lymph nodes (LNs) and bone marrow (BM). The accumulation of NK cells in LNs reflected a decreased ability to exit into lymph. This strain carries a point mutation within Tbx21 (T-bet), which generates a defective protein. Duane NK cells have a 30-fold deficiency in sphingosine-1-phosphate receptor 5 (S1P5) transcript levels, and S1P5-deficient mice exhibit an egress defect similar to Duane. Chromatin immunoprec...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Jenne, C. N., Enders, A., Rivera, R., Watson, S. R., Bankovich, A. J., Pereira, J. P., Xu, Y., Roots, C. M., Beilke, J. N., Banerjee, A., Reiner, S. L., Miller, S. A., Weinmann, A. S., Goodnow, C. C., Lanier, L. L., Cyster, J. G., Chun, J. Tags: Articles Source Type: journals
Mast cell-derived particles deliver peripheral signals to remote lymph nodesEmail this article to a colleague.
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During infection, signals from the periphery are known to reach draining lymph nodes (DLNs), but how these molecules, such as inflammatory cytokines, traverse the significant distances involved without dilution or degradation remains unclear. We show that peripheral mast cells, upon activation, release stable submicrometer heparin-based particles containing tumor necrosis factor and other proteins. These complexes enter lymphatic vessels and rapidly traffic to the DLNs. This physiological drug delivery system facilitates communication between peripheral sites of inflammation and remote secondary lymphoid tissues. (Source: ...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Kunder, C. A., St. John, A. L., Li, G., Leong, K. W., Berwin, B., Staats, H. F., Abraham, S. N. Tags: Articles Source Type: journals
Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytesEmail this article to a colleague.
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In normal T cell progenitors, phosphoinositide-dependent kinase l (PDK1)–mediated phosphorylation and activation of protein kinase B (PKB) is essential for the phosphorylation and inactivation of Foxo family transcription factors, and also controls T cell growth and proliferation. The current study has characterized the role of PDK1 in the pathology caused by deletion of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN). PDK1 is shown to be essential for lymphomagenesis caused by deletion of PTEN in T cell progenitors. However, PTEN deletion bypasses the normal PDK1-controlled sign...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Finlay, D. K., Sinclair, L. V., Feijoo, C., Waugh, C. M., Hagenbeek, T. J., Spits, H., Cantrell, D. A. Tags: Articles Source Type: journals
Subtilase cytotoxin cleaves newly synthesized BiP and blocks antibody secretion in B lymphocytesEmail this article to a colleague.
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Shiga-toxigenic Escherichia coli (STEC) use subtilase cytotoxin (SubAB) to interfere with adaptive immunity. Its inhibition of immunoglobulin secretion is both rapid and profound. SubAB favors cleavage of the newly synthesized immunoglobulin heavy chain–binding protein (BiP) to yield a C-terminal fragment that contains BiP’s substrate-binding domain. In the absence of its regulatory nucleotide-binding domain, the SubAB-cleaved C-terminal BiP fragment remains tightly bound to newly synthesized immunoglobulin light chains, resulting in retention of light chains in the endoplasmic reticulum (ER). Immunoglobulins a...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Hu, C.-C. A., Dougan, S. K., Winter, S. V., Paton, A. W., Paton, J. C., Ploegh, H. L. Tags: Articles Source Type: journals
Staphylococcus aureus synthesizes adenosine to escape host immune responsesEmail this article to a colleague.
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We examined the ability of S. aureus to escape phagocytic clearance in blood and identified adenosine synthase A (AdsA), a cell wall–anchored enzyme that converts adenosine monophosphate to adenosine, as a critical virulence factor. Staphylococcal synthesis of adenosine in blood, escape from phagocytic clearance, and subsequent formation of organ abscesses were all dependent on adsA and could be rescued by an exogenous supply of adenosine. An AdsA homologue was identified in the anthrax pathogen, and adenosine synthesis also enabled escape of Bacillus anthracis from phagocytic clearance. Collectively, these results s...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Thammavongsa, V., Kern, J. W., Missiakas, D. M., Schneewind, O. Tags: Articles Source Type: journals
Transforming growth factor {beta} is dispensable for the molecular orchestration of Th17 cell differentiationEmail this article to a colleague.
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We report that TGF-β does not directly promote Th17 cell differentiation but instead acts indirectly by blocking expression of the transcription factors signal transducer and activator of transcription (STAT) 4 and GATA-3, thus preventing Th1 and Th2 cell differentiation. In contrast, TGF-β had no effect on the expression of retinoic acid receptor–related orphan nuclear receptor t, a Th17-specific transcription factor. Interestingly, in Stat-6–/–T-bet–/– mice, which are unable to generate Th1 and Th2 cells, IL-6 alone was sufficient to induce robust differentiation of Th17 cells, whe...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Das, J., Ren, G., Zhang, L., Roberts, A. I., Zhao, X., Bothwell, A. L.M., Van Kaer, L., Shi, Y., Das, G. Tags: Articles Source Type: journals
Dependence of proliferative vascular smooth muscle cells on CD98hc (4F2hc, SLC3A2)Email this article to a colleague.
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Activation of vascular smooth muscle cells (VSMCs) to migrate and proliferate is essential for the formation of intimal hyperplasia. Hence, selectively targeting activated VSMCs is a potential strategy against vaso-occlusive disorders such as in-stent restenosis, vein-graft stenosis, and transplant vasculopathy. We show that CD98 heavy chain (CD98hc) is markedly up-regulated in neointimal and cultured VSMCs, and that activated but not quiescent VSMCs require CD98hc for survival. CD98hc mediates integrin signaling and localizes amino acid transporters to the plasma membrane. SMC-specific deletion of CD98hc did not affect no...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Fogelstrand, P., Feral, C. C., Zargham, R., Ginsberg, M. H. Tags: Articles Source Type: journals
Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasisEmail this article to a colleague.
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Blood coagulation starts immediately after damage to the vascular endothelium. This system is essential for minimizing blood loss from an injured blood vessel but also contributes to vascular thrombosis. Although it has long been thought that the intrinsic coagulation pathway is not important for clotting in vivo, recent data obtained with genetically altered mice indicate that contact phase proteins seem to be essential for thrombus formation. We show that recombinant Ixodes ricinus contact phase inhibitor (Ir-CPI), a Kunitz-type protein expressed by the salivary glands of the tick Ixodes ricinus, specifically interacts w...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Decrem, Y., Rath, G., Blasioli, V., Cauchie, P., Robert, S., Beaufays, J., Frere, J.-M., Feron, O., Dogne, J.-M., Dessy, C., Vanhamme, L., Godfroid, E. Tags: Articles Source Type: journals
Loss of matrix metalloproteinase 2 in platelets reduces arterial thrombosis in vivoEmail this article to a colleague.
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Platelet activation at a site of vascular injury is essential for the arrest of bleeding; however, excessive platelet activation at a site of arterial damage can result in the unwarranted formation of arterial thrombi, precipitating acute myocardial infarction, or ischemic stroke. Activation of platelets beyond the purpose of hemostasis may occur when substances facilitating thrombus growth and stability accumulate. Human platelets contain matrix metalloproteinase 2 (MMP-2) and release it upon activation. Active MMP-2 amplifies the platelet aggregation response to several agonists by potentiating phosphatidylinositol 3-kin...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Momi, S., Falcinelli, E., Giannini, S., Ruggeri, L., Cecchetti, L., Corazzi, T., Libert, C., Gresele, P. Tags: Articles Source Type: journals
Id2-, ROR{gamma}t-, and LT{beta}R-independent initiation of lymphoid organogenesis in ocular immunityEmail this article to a colleague.
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The eye is protected by the ocular immunosurveillance system. We show that tear duct–associated lymphoid tissue (TALT) is located in the mouse lacrimal sac and shares immunological characteristics with mucosa-associated lymphoid tissues (MALTs), including the presence of M cells and immunocompetent cells for antigen uptake and subsequent generation of mucosal immune responses against ocularly encountered antigens and bacteria such as Pseudomonas aeruginosa. Initiation of TALT genesis began postnatally; it occurred even in germ-free conditions and was independent of signaling through organogenesis regulators, includin...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Nagatake, T., Fukuyama, S., Kim, D.-Y., Goda, K., Igarashi, O., Sato, S., Nochi, T., Sagara, H., Yokota, Y., Jetten, A. M., Kaisho, T., Akira, S., Mimuro, H., Sasakawa, C., Fukui, Y., Fujihashi, K., Akiyama, T., Inoue, J.-i., Penninger, J. M., Kunisawa, J Tags: Articles Source Type: journals
Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected miceEmail this article to a colleague.
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Tertiary lymphoid organs (TLOs) are organized aggregates of B and T cells formed in postembryonic life in response to chronic immune responses to infectious agents or self-antigens. Although CD11c+ dendritic cells (DCs) are consistently found in regions of TLO, their contribution to TLO organization has not been studied in detail. We found that CD11chi DCs are essential for the maintenance of inducible bronchus-associated lymphoid tissue (iBALT), a form of TLO induced in the lungs after influenza virus infection. Elimination of DCs after the virus had been cleared from the lung resulted in iBALT disintegration and reductio...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: GeurtsvanKessel, C. H., Willart, M. A.M., Bergen, I. M., van Rijt, L. S., Muskens, F., Elewaut, D., Osterhaus, A. D.M.E., Hendriks, R., Rimmelzwaan, G. F., Lambrecht, B. N. Tags: Brief Definitive Reports Source Type: journals
Runx proteins regulate Foxp3 expressionEmail this article to a colleague.
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Runx proteins are essential for hematopoiesis and play an important role in T cell development by regulating key target genes, such as CD4 and CD8 as well as lymphokine genes, during the specialization of naive CD4 T cells into distinct T helper subsets. In regulatory T (T reg) cells, the signature transcription factor Foxp3 interacts with and modulates the function of several other DNA binding proteins, including Runx family members, at the protein level. We show that Runx proteins also regulate the initiation and the maintenance of Foxp3 gene expression in CD4 T cells. Full-length Runx promoted the de novo expression of ...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Bruno, L., Mazzarella, L., Hoogenkamp, M., Hertweck, A., Cobb, B. S., Sauer, S., Hadjur, S., Leleu, M., Naoe, Y., Telfer, J. C., Bonifer, C., Taniuchi, I., Fisher, A. G., Merkenschlager, M. Tags: Brief Definitive Reports Source Type: journals
Variants of CTGF are associated with hepatic fibrosis in Chinese, Sudanese, and Brazilians infected with SchistosomesEmail this article to a colleague.
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Abnormal fibrosis occurs during chronic hepatic inflammations and is the principal cause of death in hepatitis C virus and schistosome infections. Hepatic fibrosis (HF) may develop either slowly or rapidly in schistosome-infected subjects. This depends, in part, on a major genetic control exerted by genes of chromosome 6q23. A gene (connective tissue growth factor [CTGF]) is located in that region that encodes a strongly fibrogenic molecule. We show that the single nucleotide polymorphism (SNP) rs9402373 that lies close to CTGF is associated with severe HF (P = 2 x 10–6; odds ratio [OR] = 2.01; confidence interval of...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Dessein, A., Chevillard, C., Arnaud, V., Hou, X., Hamdoun, A. A., Dessein, H., He, H., Abdelmaboud, S. A., Luo, X., Li, J., Varoquaux, A., Mergani, A., Abdelwahed, M., Zhou, J., Monis, A., Pitta, M. G.R., Gasmelseed, N., Cabantous, S., Zhao, Y., Prata, A. Tags: Brief Definitive Reports Source Type: journals
Inhibition of MALT1 protease activity is selectively toxic for activated B cell-like diffuse large B cell lymphoma cellsEmail this article to a colleague.
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Diffuse large B cell lymphoma (DLBCL) is the most common type of lymphoma in humans. The aggressive activated B cell–like (ABC) subtype of DLBCL is characterized by constitutive NF-B activity and requires signals from CARD11, BCL10, and the paracaspase MALT1 for survival. CARD11, BCL10, and MALT1 are scaffold proteins that normally associate upon antigen receptor ligation. Signal-induced CARD11–BCL10–MALT1 (CBM) complexes couple upstream events to IB kinase (IKK)/NF-B activation. MALT1 also possesses a recently recognized proteolytic activity that cleaves and inactivates the negative NF-B regulator A20 an...
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Ferch, U., Kloo, B., Gewies, A., Pfander, V., Duwel, M., Peschel, C., Krappmann, D., Ruland, J. Tags: Brief Definitive Reports Source Type: journals
Masking MALT1: the paracaspase's potential for cancer therapyEmail this article to a colleague.
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A key feature of aggressive B cell lymphomas is constitutive NF-B activation, which requires signals from the CARD11–BCL-10–MALT1 (CMB) complex. The unique enzymatic activity of MALT1 degrades one of its binding partners, BCL-10, as well as the NF-B inhibitor A20. New data shows that targeting MALT1 protease activity may be a promising therapeutic strategy for treating aggressive B cell lymphomas. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Vucic, D., Dixit, V. M. Tags: Commentaries Source Type: journals
Salim "Slim" Abdool Karim: Attacking AIDS in South AfricaEmail this article to a colleague.
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(Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Maxmen, A. Tags: PEOPLE & IDEAS Source Type: journals
Pro-fibrotic SNPsEmail this article to a colleague.
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(Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Maxmen, A. Tags: In This Issue Source Type: journals
Runx: T reg cell keeper and creatorEmail this article to a colleague.
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(Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Maxmen, A. Tags: In This Issue Source Type: journals
How staph thwarts attackEmail this article to a colleague.
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(Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Maxmen, A. Tags: In This Issue Source Type: journals
Revising the Th17 recipeEmail this article to a colleague.
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(Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Maxmen, A. Tags: In This Issue Source Type: journals
Mast cells' message in a particleEmail this article to a colleague.
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(Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 26, 2009 Category: Internal Medicine Authors: Maxmen, A. Tags: In This Issue Source Type: journals
Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's diseaseEmail this article to a colleague.
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(Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Smith, A. M., Rahman, F. Z., Hayee, B., Graham, S. J., Marks, D. J.B., Sewell, G. W., Palmer, C. D., Wilde, J., Foxwell, B. M.J., Gloger, I. S., Sweeting, T., Marsh, M., Walker, A. P., Bloom, S. L., Segal, A. W. Tags: Corrections Source Type: journals
Blood leukocyte microarrays to diagnose systemic onset juvenile idiopathic arthritis and follow the response to IL-1 blockadeEmail this article to a colleague.
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(Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Allantaz, F., Chaussabel, D., Stichweh, D., Bennett, L., Allman, W., Mejias, A., Ardura, M., Chung, W., Smith, E., Wise, C., Palucka, K., Ramilo, O., Punaro, M., Banchereau, J., Pascual, V. Tags: Corrections Source Type: journals
Nonaminoglycoside compounds induce readthrough of nonsense mutationsEmail this article to a colleague.
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Large numbers of genetic disorders are caused by nonsense mutations for which compound-induced readthrough of premature termination codons (PTCs) might be exploited as a potential treatment strategy. We have successfully developed a sensitive and quantitative high-throughput screening (HTS) assay, protein transcription/translation (PTT)–enzyme-linked immunosorbent assay (ELISA), for identifying novel PTC-readthrough compounds using ataxia-telangiectasia (A-T) as a genetic disease model. This HTS PTT-ELISA assay is based on a coupled PTT that uses plasmid templates containing prototypic A-T mutated (ATM) mutations for...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Du, L., Damoiseaux, R., Nahas, S., Gao, K., Hu, H., Pollard, J. M., Goldstine, J., Jung, M. E., Henning, S. M., Bertoni, C., Gatti, R. A. Tags: Articles Source Type: journals
Distinct roles for E12 and E47 in B cell specification and the sequential rearrangement of immunoglobulin light chain lociEmail this article to a colleague.
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The E2A gene products, E12 and E47, are critical regulators of B cell development. However, it remains elusive whether E12 and E47 have overlapping and/or distinct functions during B lymphopoiesis. We have generated mice deficient for either E12 or E47 and examined their roles in B cell maturation. We show that E47 is essential for developmental progression at the prepro–B cell stage, whereas E12 is dispensable for early B cell development, commitment, and maintenance. In contrast, both E12 and E47 play critical roles in pre–B and immature B cells to promote immunoglobulin (Ig) germline transcription as well as...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Beck, K., Peak, M. M., Ota, T., Nemazee, D., Murre, C. Tags: Articles Source Type: journals
Self-class I MHC molecules support survival of naive CD8 T cells, but depress their functional sensitivity through regulation of CD8 expression levelsEmail this article to a colleague.
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In this study, we explored naive CD8 T cell survival and function in nonlymphopenic conditions by using bone marrow chimeric donors and hosts in which class I MHC expression is absent or limited to radiosensitive versus radioresistant cells. We found that long-term survival of naive CD8 T cells (but not CD4 T cells) was impaired in the absence of class I MHC. However, distinct from this effect, class I MHC deprivation also enhanced naive CD8 T cell responsiveness to low-affinity (but not high-affinity) peptide–MHC ligands. We found that this improved sensitivity was a consequence of up-regulated CD8 levels, which was...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Takada, K., Jameson, S. C. Tags: Articles Source Type: journals
Activating receptors promote NK cell expansion for maintenance, IL-10 production, and CD8 T cell regulation during viral infectionEmail this article to a colleague.
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Natural killer (NK) cells have the potential to deliver both direct antimicrobial effects and regulate adaptive immune responses, but NK cell yields have been reported to vary greatly during different viral infections. Activating receptors, including the Ly49H molecule recognizing mouse cytomegalovirus (MCMV), can stimulate NK cell expansion. To define Ly49H's role in supporting NK cell proliferation and maintenance under conditions of uncontrolled viral infection, experiments were performed in Ly49h–/–, perforin 1 (Prf1)–/–, and wild-type (wt) B6 mice. NK cell numbers were similar in uninfected mic...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Lee, S.-H., Kim, K.-S., Fodil-Cornu, N., Vidal, S. M., Biron, C. A. Tags: Articles Source Type: journals
The angiopietin-1-Tie2 pathway prevents rather than promotes pulmonary arterial hypertension in transgenic miceEmail this article to a colleague.
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The role of the angiopoietin-1 (Ang1)–Tie2 pathway in the pathogenesis of pulmonary arterial hypertension (PAH) is controversial. Although Ang1 is well known to prevent endothelial activation and injury in systemic vascular beds, this pathway has been suggested to mediate pulmonary vascular remodeling in PAH. Therefore, we used transgenic models to determine the effect of increased or decreased Tie2 activity on the development of PAH. We now report modest spontaneous elevation in right ventricular systolic pressure in Tie2-deficient mice (Tie2+/–) compared with wild-type (WT) littermate controls, which was exac...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Kugathasan, L., Ray, J. B., Deng, Y., Rezaei, E., Dumont, D. J., Stewart, D. J. Tags: Articles Source Type: journals
A murine DC-SIGN homologue contributes to early host defense against Mycobacterium tuberculosisEmail this article to a colleague.
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The C-type lectin dendritic cell–specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) mediates the innate immune recognition of microbial carbohydrates. We investigated the function of this molecule in the host response to pathogens in vivo, by generating mouse lines lacking the DC-SIGN homologues SIGNR1, SIGNR3, and SIGNR5. Resistance to Mycobacterium tuberculosis was impaired only in SIGNR3-deficient animals. SIGNR3 was expressed in lung phagocytes during infection, and interacted with M. tuberculosis bacilli and mycobacterial surface glycoconjugates to induce secretion of critical host defense...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Tanne, A., Ma, B., Boudou, F., Tailleux, L., Botella, H., Badell, E., Levillain, F., Taylor, M. E., Drickamer, K., Nigou, J., Dobos, K. M., Puzo, G., Vestweber, D., Wild, M. K., Marcinko, M., Sobieszczuk, P., Stewart, L., Lebus, D., Gicquel, B., Neyrolles Tags: Articles Source Type: journals
Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthmaEmail this article to a colleague.
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Polymorphisms in the interleukin-4 receptor chain (IL-4R) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4R has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target– and tissue-specific manne...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Tachdjian, R., Mathias, C., Al Khatib, S., Bryce, P. J., Kim, H. S., Blaeser, F., O'Connor, B. D., Rzymkiewicz, D., Chen, A., Holtzman, M. J., Hershey, G. K., Garn, H., Harb, H., Renz, H., Oettgen, H. C., Chatila, T. A. Tags: Articles Source Type: journals
Crohn's disease adherent-invasive Escherichia coli colonize and induce strong gut inflammation in transgenic mice expressing human CEACAMEmail this article to a colleague.
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Abnormal expression of CEACAM6 is observed at the apical surface of the ileal epithelium in Crohn's disease (CD) patients, and CD ileal lesions are colonized by pathogenic adherent-invasive Escherichia coli (AIEC). We investigated the ability of AIEC reference strain LF82 to colonize the intestinal mucosa and to induce inflammation in CEABAC10 transgenic mice expressing human CEACAMs. AIEC LF82 virulent bacteria, but not nonpathogenic E. coli K-12, were able to persist in the gut of CEABAC10 transgenic mice and to induce severe colitis with reduced survival rate, marked weight loss, increased rectal bleeding, presence of e...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Carvalho, F. A., Barnich, N., Sivignon, A., Darcha, C., Chan, C. H.F., Stanners, C. P., Darfeuille-Michaud, A. Tags: Articles Source Type: journals
Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin diseaseEmail this article to a colleague.
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Expression of enzymatically inactive caspase-8, or deletion of caspase-8 from basal epidermal keratinocytes, triggers chronic skin inflammation in mice. Unlike similar inflammation resulting from arrest of nuclear factor B activation in the epidermal cells, the effect induced by caspase-8 deficiency did not depend on TNF, IL-1, dermal macrophage function, or expression of the toll-like receptor adapter proteins MyD88 or TRIF. Both interferon regulatory factor (IRF) 3 and TANK-binding kinase were constitutively phosphorylated in the caspase-8–deficient epidermis, and knockdown of IRF3 in the epidermis-derived cells fr...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Kovalenko, A., Kim, J.-C., Kang, T.-B., Rajput, A., Bogdanov, K., Dittrich-Breiholz, O., Kracht, M., Brenner, O., Wallach, D. Tags: Articles Source Type: journals
XBP1 governs late events in plasma cell differentiation and is not required for antigen-specific memory B cell developmentEmail this article to a colleague.
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The unfolded protein response (UPR) is a stress response pathway that is driven by the increased load of unfolded proteins in the endoplasmic reticulum of highly secretory cells such as plasma cells (PCs). X box binding protein 1 (XBP1) is a transcription factor that mediates one branch of the UPR and is crucial for the development of antibody-secreting PCs. PCs represent only one class of terminally differentiated B cells, however, and little is known about the role for XBP1 in the other class: memory B cells. We have developed an XBP1fl/fl CD19+/cre conditional knockout (XBP1CD19) mouse to build upon our current understa...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Todd, D. J., McHeyzer-Williams, L. J., Kowal, C., Lee, A.-H., Volpe, B. T., Diamond, B., McHeyzer-Williams, M. G., Glimcher, L. H. Tags: Brief Definitive Reports Source Type: journals
GM-CSF regulates intimal cell proliferation in nascent atherosclerotic lesionsEmail this article to a colleague.
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The contribution of intimal cell proliferation to the formation of early atherosclerotic lesions is poorly understood. We combined 5-bromo-2'-deoxyuridine pulse labeling with sensitive en face immunoconfocal microscopy analysis, and quantified intimal cell proliferation and Ly-6Chigh monocyte recruitment in low density lipoprotein receptor–null mice. Cell proliferation begins in nascent lesions preferentially at their periphery, and proliferating cells accumulate in lesions over time. Although intimal cell proliferation increases in parallel to monocyte recruitment as lesions grow, proliferation continues when monocy...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Zhu, S.-N., Chen, M., Jongstra-Bilen, J., Cybulsky, M. I. Tags: Brief Definitive Reports Source Type: journals
Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokinesEmail this article to a colleague.
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This report shows that these conclusions provide a partial explanation at best. First, RA not only interfered with cytokine secretion but also with the ability of these cytokines to inhibit T reg cell conversion of naive T cells. Furthermore, RA enhanced conversion even in the absence of inhibitory cytokines. The latter effect depended on the RA receptor (RAR) but did not require Smad3, despite the fact that RA enhanced Smad3 expression. The RAR1 isoform was not essential for RA-dependent enhancement of transforming growth factor β–driven conversion, suggesting that conversion can also be mediated by RAR2. Inter...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Nolting, J., Daniel, C., Reuter, S., Stuelten, C., Li, P., Sucov, H., Kim, B.-G., Letterio, J. J., Kretschmer, K., Kim, H.-J., von Boehmer, H. Tags: Brief Definitive Reports Source Type: journals
TCR-dependent differentiation of thymic Foxp3+ cells is limited to small clonal sizesEmail this article to a colleague.
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Numerous studies have highlighted the importance of high-affinity interactions between T cell receptors (TCRs) and their ligands in the selection of Foxp3+ regulatory T cells (T reg cells). To determine the role of the TCR in directing T cells into the Foxp3+ lineage, we generated transgenic (Tg) mice expressing TCRs from Foxp3+ cells. Initial analyses of the TCR Tg mice crossed with RAG-deficient mice showed that the percentage of Foxp3+ cells was very low. However, intrathymic injection and bone marrow chimera experiments showed a saturable increase of the Foxp3+ population when T reg TCR Tg cells were present in low num...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Leung, M. W.L., Shen, S., Lafaille, J. J. Tags: Brief Definitive Reports Source Type: journals
TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasisEmail this article to a colleague.
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We report that resting and activated CD4+ T cells expressed high levels of IL-7 receptor a chain but very low levels of TSLP receptor (TSLPR) when compared with levels expressed in myeloid dendritic cells (mDCs). This was confirmed by immunohistology and flow cytometry analyses showing that only a subset of mDCs, with more activated phenotypes, expressed TSLPR in human tonsils in vivo. IL-7 induced strong STAT1, -3, and -5 activation and promoted the proliferation of naive CD4+ T cells in the presence of anti-CD3 and anti-CD28 monoclonal antibodies, whereas TSLP induced weak STAT5 activation, associated with marginally imp...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Lu, N., Wang, Y.-H., Wang, Y.-H., Arima, K., Hanabuchi, S., Liu, Y.-J. Tags: Brief Definitive Reports Source Type: journals
NOD2 regulates hematopoietic cell function during graft-versus-host diseaseEmail this article to a colleague.
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Nucleotide-binding oligomerization domain 2 (NOD2) polymorphisms are independent risk factors for Crohn's disease and graft-versus-host disease (GVHD). In Crohn's disease, the proinflammatory state resulting from NOD2 mutations have been associated with a loss of antibacterial function of enterocytes such as paneth cells. NOD2 has not been studied in experimental allogeneic bone marrow transplantation (allo-BMT). Using chimeric recipients with NOD2–/– hematopoietic cells, we demonstrate that NOD2 deficiency in host hematopoietic cells exacerbates GVHD. We found that proliferation and activation of donor T cells...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Penack, O., Smith, O. M., Cunningham-Bussel, A., Liu, X., Rao, U., Yim, N., Na, I.-K., Holland, A. M., Ghosh, A., Lu, S. X., Jenq, R. R., Liu, C., Murphy, G. F., Brandl, K., van den Brink, M. R.M. Tags: Brief Definitive Reports Source Type: journals
Epstein-Barr virus (EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from toll-like receptor 3Email this article to a colleague.
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Epstein-Barr virus–encoded small RNA (EBER) is nonpolyadenylated, noncoding RNA that forms stem-loop structure by intermolecular base-pairing, giving rise to double-stranded RNA (dsRNA)–like molecules, and exists abundantly in EBV-infected cells. Here, we report that EBER induces signaling from the Toll-like receptor 3 (TLR3), which is a sensor of viral double-stranded RNA (dsRNA) and induces type I IFN and proinflammatory cytokines. A substantial amount of EBER, which was sufficient to induce signaling from TLR3, was released from EBV-infected cells, and the majority of the released EBER existed as a complex w...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Iwakiri, D., Zhou, L., Samanta, M., Matsumoto, M., Ebihara, T., Seya, T., Imai, S., Fujieda, M., Kawa, K., Takada, K. Tags: Brief Definitive Reports Source Type: journals
The nuclear receptor PPAR{gamma} selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunityEmail this article to a colleague.
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T helper cells secreting interleukin (IL)-17 (Th17 cells) play a crucial role in autoimmune diseases like multiple sclerosis (MS). Th17 differentiation, which is induced by a combination of transforming growth factor (TGF)-β/IL-6 or IL-21, requires expression of the transcription factor retinoic acid receptor–related orphan receptor t (RORt). We identify the nuclear receptor peroxisome proliferator–activated receptor (PPAR) as a key negative regulator of human and mouse Th17 differentiation. PPAR activation in CD4+ T cells selectively suppressed Th17 differentiation, but not differentiation into Th1, Th2, ...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Klotz, L., Burgdorf, S., Dani, I., Saijo, K., Flossdorf, J., Hucke, S., Alferink, J., Novak, N., Beyer, M., Mayer, G., Langhans, B., Klockgether, T., Waisman, A., Eberl, G., Schultze, J., Famulok, M., Kolanus, W., Glass, C., Kurts, C., Knolle, P. A. Tags: Brief Definitive Reports Source Type: journals
Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosisEmail this article to a colleague.
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Atherosclerosis is an inflammatory vascular disease responsible for the first cause of mortality worldwide. Recent studies have clearly highlighted the critical role of the immunoinflammatory balance in the modulation of disease development and progression. However, the immunoregulatory pathways that control atherosclerosis remain largely unknown. We show that loss of suppressor of cytokine signaling (SOCS) 3 in T cells increases both interleukin (IL)-17 and IL-10 production, induces an antiinflammatory macrophage phenotype, and leads to unexpected IL-17–dependent reduction in lesion development and vascular inflamma...
Source: The Journal of Experimental Medicine - September 27, 2009 Category: Internal Medicine Authors: Taleb, S., Romain, M., Ramkhelawon, B., Uyttenhove, C., Pasterkamp, G., Herbin, O., Esposito, B., Perez, N., Yasukawa, H., Van Snick, J., Yoshimura, A., Tedgui, A., Mallat, Z. Tags: Brief Definitive Reports Source Type: journals
