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Jeyaseelan S Young SK Fessler MB Liu Y Malcolm KC Yamamoto M Akira S Worthen GS 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(5):3153-3160
Peripheral blood memory B cells latently infected with EBV bear somatic mutations and are typically isotype switched consistent with being classical Ag-selected memory B cells. In this work, we performed a comparative analysis of the expressed Ig genes between large sets of EBV-infected and uninfected peripheral blood B cells, isolated from the same infectious mononucleosis patients, to determine whether differences exist that could reveal the influence of EBV on the production and maintenance of these cells. We observed that EBV(+) cells on average accumulated more somatic hypermutations than EBV(-) cells. In addition, they had more replacement mutations and a higher replacement-silent ratio of mutations in their CDRs. We also found that EBV occupies a skewed niche within the memory compartment, due to its exclusion from the CD27(+)IgD(+)IgM(+) subset, but this skewing does not affect the overall structure of the compartment. These results indicate that EBV impacts the mutation and selection process of infected cells but that once they enter memory they cannot be distinguished from uninfected cells by host homeostasis mechanisms. 相似文献
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Changsheng Xing Mingjun Wang Adebusola A. Ajibade Peng Tan Chuntang Fu Lang Chen Motao Zhu Zhao-Zhe Hao Junjun Chu Xiao Yu Bingnan Yin Jiahui Zhu Wan-Jou Shen Tianhao Duan Helen Y. Wang Rong-Fu Wang 《Cell host & microbe》2021,29(6):959-974.e7
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Rhee EG Blattman JN Kasturi SP Kelley RP Kaufman DR Lynch DM La Porte A Simmons NL Clark SL Pulendran B Greenberg PD Barouch DH 《Journal of virology》2011,85(1):315-323
The innate immune pathways that contribute to the potent immunogenicity of recombinant adenovirus (rAd) vaccine vectors remain largely undefined. Previous studies assessing innate immunity triggered by vaccine vectors have largely focused on in vitro studies involving antigen-presenting cells and on early in vivo inflammatory responses. Here, we systematically explore the Toll-like receptor (TLR) signaling requirements for the generation of cellular immune responses by intramuscular immunization with common and alternative serotype rAd vectors in mice. Antigen-specific CD8(+) T-lymphocyte responses elicited by these rAd vectors were significantly diminished in MyD88(-/-) mice but not in TRIF(-/-) or TLR3(-/-) mice, suggesting the importance of MyD88-dependent TLR signaling. However, the absence of each individual TLR resulted in minimal to no effect on vaccine-elicited cellular immune responses. Moreover, responses were not diminished in IL-1R(-/-) or IL-18R(-/-) mice. These data suggest that rAd vectors engage multiple MyD88-dependent signaling pathways, none of which are individually critical; rather, they are integrated to contribute to the potent immunogenicity of rAd vectors. Stimulation of multiple innate immune mechanisms may prove a generalizable property of potent vaccines, and this strategy could be harnessed in the development of next-generation vaccine vectors and adjuvants. 相似文献
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Ding Y Chen D Tarcsafalvi A Su R Qin L Bromberg JS 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(3):1383-1391
IL-10 has proved to be a key cytokine in regulating inflammatory responses by controlling the production and function of various other cytokines. The suppressor of cytokine signaling (SOCS) gene products are a family of cytoplasmic molecules that are essential mediators for negatively regulating cytokine signaling. It has been previously shown that IL-10 induced SOCS3 expression and that forced constitutive expression of SOCS3 inhibits IL-10/STAT3 activation and LPS-induced macrophage activation. In this report, we show that, in addition to SOCS3 expression, IL-10 induces SOCS1 up-regulation in all cell lines tested, including Ba/F3 pro-B cells, MC/9 mast cells, M1 leukemia cells, U3A human fibroblasts, and primary mouse CD4(+) T cells. Induction of SOCS molecules is dependent on STAT3 activation by IL-10R1. Cell lines constitutively overexpressing SOCS proteins demonstrated that SOCS1 and SOCS3, but not SOCS2, are able to partially inhibit IL-10-mediated STAT3 activation and proliferative responses. Pretreatment of M1 cells with IFN-gamma resulted in SOCS1 induction and a reduction of IL-10-mediated STAT3 activation and cell growth inhibition. IL-10-induced SOCS is associated with the inhibition of IFN-gamma signaling in various cell types, and this inhibition is independent of C-terminal serine residues of the IL-10R, previously shown to be required for other anti-inflammatory responses. Thus, the present results show that both SOCS1 and SOCS3 are induced by IL-10 and may be important inhibitors of both IL-10 and IFN-gamma signaling. IL-10-induced SOCS1 may directly inhibit IL-10 IFN-gamma signaling, while inhibition of other proinflammatory cytokine responses may use additional IL-10R1-mediated mechanisms. 相似文献
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Nod1/RICK and TLR signaling regulate chemokine and antimicrobial innate immune responses in mesothelial cells 总被引:2,自引:0,他引:2
Park JH Kim YG Shaw M Kanneganti TD Fujimoto Y Fukase K Inohara N Núñez G 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(1):514-521
Mesothelial cells that line the serous cavities and outer surface of internal organs are involved in inflammatory responses induced by microbial stimuli and bacterial infection. Upon exposure to bacterial products, mesothelial cells secrete chemokines, but the signaling pathways by which these cells recognize bacteria to mediate innate immune responses remain largely unknown. We report that stimulation of primary peritoneal mesothelial cells via nucleotide-binding oligomerization domain (Nod)1, a member of the intracytoplasmic Nod-like receptor family, induced potent secretion of the chemokines CXCL1 and CCL2 as well as expression of inducible NO synthase and such responses required the kinase RICK. Mesothelial cells also produced chemokines in response to TLR2, TLR3, TLR4, and TLR5 agonists, but unlike that induced by Nod1 stimulation, the TLR-mediated responses were independent of RICK. Yet, Nod1 stimulation of mesothelial cells via RICK enhanced chemokine secretion induced by LPS or IFN-gamma and cooperated with IFN-gamma in the production of NO. The i.p. administration of KF1B, a synthetic Nod1 agonist, elicited chemokine production in the serum and peritoneal fluid as well as the recruitment of neutrophils into the peritoneal cavity of wild-type mice, but not RICK-deficient mice. Finally, infection of mesothelial cells with Listeria monocytogenes induced production of CXCL1 and this response was significantly reduced in Nod1- or RICK-deficient cells. These results define mesothelial cells as microbial sensors through TLRs and Nod-like receptors and identify Nod1 and RICK as important mediators of chemokine and antimicrobial responses in mesothelial cells. 相似文献
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Toll-like receptor 4 mediates innate immune responses to Haemophilus influenzae infection in mouse lung. 总被引:9,自引:0,他引:9
Xiaorong Wang Christian Moser Jean-Pierre Louboutin Elena S Lysenko Daniel J Weiner Jeffrey N Weiser James M Wilson 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(2):810-815
Toll-like receptors (TLRs) have been implicated in the regulation of host responses to microbial Ags. This study characterizes the role of TLR4 in the innate immune response to intrapulmonary administration of Haemophilus influenzae in the mouse. Two different strains of mice efficiently cleared aerosolized H. influenzae concurrent with a brisk elaboration of IL-1beta, IL-6, TNF-alpha, macrophage-inflammatory protein (MIP)-1alpha, and MIP-2 in bronchoalveolar lavage and a corresponding mobilization of intrapulmonary neutrophils. Congenic strains of mice deficient in TLR4 demonstrated a substantial delay in clearance of H. influenzae with diminished IL-1beta, IL-6, TNF-alpha, MIP-1alpha, and MIP-2 in bronchoalveolar lavage and a notable absence of intrapulmonary neutrophils. In TLR4-expressing animals, but not TLR4-deficient animals, TNF-alpha and MIP-1alpha expression was up-regulated in epithelial cells of the conducting airway in response to H. influenzae which was preceded by an apparent activation of the NF-kappaB pathway in these cells based on the findings of decreased overall IkappaB and an increase in its phosphorylated form. This study demonstrates a critical role of TLR4 in mediating an effective innate immune response to H. influenzae in the lung. This suggests that the airway epithelia might contribute to sensing of H. influenzae infection and signaling the innate immune response. 相似文献
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Lazarus JJ Meadows MJ Lintner RE Wooten RM 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(10):7076-7085
Borrelia burgdorferi is capable of persistently infecting a variety of hosts despite eliciting potent innate and adaptive immune responses. Preliminary studies indicated that IL-10-deficient (IL-10(-/-)) mice exhibit up to 10-fold greater clearance of B. burgdorferi from target tissues compared with wild-type mice, establishing IL-10 as the only cytokine currently known to have such a significant effect on spirochetal clearance. To further delineate these IL-10-mediated immune effects, kinetic studies indicated that spirochete dissemination to target tissues is similar in both wild-type and IL-10(-/-) mouse strains, and that enhanced clearance of B. burgdorferi in IL-10(-/-) mice is correlated with increased B. burgdorferi-specific Ab as early as 2 wk postinfection. Immunoblot analysis indicated that Abs produced by infected IL-10(-/-) and wild-type mice recognize similar ranges of spirochetal Ags. Immune sera from IL-10(-/-) and wild-type mice also exhibited similar bactericidal activity in vitro, and passive transfer of these immune sera into B. burgdorferi-infected SCID mice caused similar reductions of bacterial numbers in target tissues. Infectious dose studies indicated that 8-fold more B. burgdorferi were needed to efficiently infect naive IL-10(-/-) mice, suggesting these animals possess higher innate barriers to infection. Moreover, macrophages derived from IL-10(-/-) mice exhibit enhanced proinflammatory responses to B. burgdorferi stimulation compared with wild-type controls, and these responses are not significantly affected by the presence of immune serum. These findings confirm that B. burgdorferi clearance by innate immune responses is more efficient in the absence of IL-10, and these activities are not directly related to increased levels of B. burgdorferi-specific Ab. 相似文献
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Jack CS Arbour N Manusow J Montgrain V Blain M McCrea E Shapiro A Antel JP 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(7):4320-4330
The specific signals mediating the activation of microglia and astrocytes as a prelude to, or consequence of, CNS inflammation continue to be defined. We investigated TLRs as novel receptors mediating innate immune responses in human glial cells. We find that microglia express mRNA for TLRs 1-9, whereas astrocytes express robust TLR3, low-level TLR 1, 4, 5, and 9, and rare-to-undetectable TLR 2, 6, 7, 8, and 10 mRNA (quantitative real-time PCR). We focused on TLRs 3 and 4, which can signal through both the MyD88-dependent and -independent pathways, and on the MyD88-restricted TLR2. By flow cytometry, we established that microglia strongly express cell surface TLR2; TLR3 is expressed at higher levels intracellularly. Astrocytes express both cell surface and intracellular TLR3. All three TLRs trigger microglial activation upon ligation. TLR3 signaling induces the strongest proinflammatory polarizing response, characterized by secretion of high levels of IL-12, TNF-alpha, IL-6, CXCL-10, and IL-10, and the expression of IFN-beta. CXCL-10 and IL-10 secretion following TLR4 ligation are comparable to that of TLR3; however, other responses were lower or absent. TLR2-mediated responses are dominated by IL-6 and IL-10 secretion. Astrocytes respond to TLR3 ligation, producing IL-6, CXCL-10, and IFN-beta, implicating these cells as contributors to proinflammatory responses. Initial TLR-mediated glial activation also regulates consequent TLR expression; while TLR2 and TLR3 are subject to positive feedback, TLR4 is down-regulated in microglia. Astrocytes up-regulate all three TLRs following TLR3 ligation. Our data indicate that activation of innate immune responses in the CNS is not homogeneous but rather tailored according to cell type and environmental signal. 相似文献
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Yoshikawa M Nakajima T Tsukidate T Matsumoto K Iida M Otori N Haruna S Moriyama H Saito H 《Biochemical and biophysical research communications》2003,312(4):1248-1255
Two interleukin 13 receptors (IL-13Rs) have been identified as IL-13Ralpha1 and IL-13Ralpha2. IL-13Ralpha1 is composed of a heterodimer consisting of IL-13Ralpha1 and IL-4 receptor alpha (IL-4Ralpha) as a signaling subunit. In contrast, IL-13Ralpha2 is known as a decoy receptor for IL-13. In this study, we investigated the expression of IL-13Rs on human fibroblasts. IL-13Ralpha2 was significantly up-regulated after stimulation with tumor necrosis factor-alpha (TNF-alpha) and/or IL-4. In contrast, IL-13Ralpha1 was constitutively detectable and was not up-regulated. After the induction of IL-13alpha2 by IL-4, STAT6 phosphorylation through IL-13Ralpha1 by IL-13 was inhibited. We also detected large intracellular pools of IL-13Ralpha2 in fibroblasts quantitatively. Furthermore, mobilization of the IL-13Ralpha2 protein stores from the cytoplasm to the cell surface was prevented by an inhibitor of protein transport, brefeldin-A. These results indicate that TNF-alpha and IL-4 synergistically up-regulate the expression of IL-13Ralpha2 decoy receptor on human fibroblasts by inducing gene expression and mobilizing intracellular receptors, and thus may down-regulate the IL-13 signaling. 相似文献
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Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors 总被引:14,自引:0,他引:14
Adenovirus vectors induce acute inflammation of infected tissues due to activation of the innate immune system and expression of numerous chemokines and cytokines in transduced target cells. In contrast, adeno-associated virus (AAV) vectors are not associated with significant inflammation experimentally or clinically. We tested the ability of AAV vectors to induce the expression of chemokines in vitro and to activate the innate immune system in vivo. In human HeLa cells and murine renal epithelium-derived cells (REC cells) the adenovirus vector AdlacZ induced the expression of multiple inflammatory chemokines including RANTES, interferon-inducible protein 10 (IP-10), interleukin-8 (IL-8), MIP-1beta, and MIP-2 in a dose-dependent manner. The use of AAVlacZ did not induce the expression of these chemokines above baseline levels despite 40-fold-greater titers than AdlacZ and greater amounts of intracellular AAVlacZ genomes according to Southern and slot blot analysis. This finding confirmed that the lack of AAVlacZ induction of chemokine was not due to reduced transduction. In DBA/2 mice, the intravenous administration of 2.5 x 10(11) particles of AAVlacZ resulted in the rapid induction of liver tumor necrosis factor alpha (TNF-alpha), RANTES, IP-10, MIP-1beta, MCP-1, and MIP-2 mRNAs. However, 6 h following injection, chemokine mRNA levels returned to baseline. As expected, administration of 10-fold less AdlacZ caused an induction of liver TNF-alpha and chemokine mRNAs that persisted for more than 24 h posttransduction. Whereas intravenous administration of 2.5 x 10(11) particles of AAVlacZ triggered a transient infiltration of neutrophils and CD11b(+) cells into liver, this response stood in contrast to widespread inflammation and toxicity induced by AdlacZ. Kupffer cell depletion abolished AAVlacZ but not AdlacZ-induced chemokine expression and neutrophil infiltration. In summary, these results show that AAV vectors activate the innate immune system to a lesser extent than do adenovirus vectors and offer a possible explanation for the reduced inflammatory properties of AAV compared to adenovirus vectors. 相似文献
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Metazoans adapt to changing environmental conditions and to harmful challenges by attenuating growth and metabolic activities systemically. Recent studies in mice and flies indicate that endocrine signaling interactions between insulin/IGF signaling (IIS) and innate immune signaling pathways are critical for this adaptation, yet the temporal and spatial hierarchy of these signaling events remains elusive. Here, we identify and characterize a program of signaling interactions that regulates the systemic response of the Drosophila larva to localized DNA damage. We provide evidence that epidermal DNA damage induces an innate immune response that is kept in check by systemic repression of IIS activity. IIS repression induces NFκB/Relish signaling in the fat body, which is required for recovery of IIS activity in a second phase of the systemic response to DNA damage. This systemic response to localized DNA damage thus coordinates growth and metabolic activities across tissues, ensuring growth homeostasis and survival of the animal. 相似文献
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Adenovirus (AdV) is a common cause of respiratory illness in both children and adults. Respiratory symptoms can range from those of the common cold to severe pneumonia. Infection can also cause significant disease in the immunocompromised and among immunocompetent subjects in close quarters. Fortunately, infection with AdV in the normal host is generally mild. This is one reason why its initial use as a gene-therapy vector appeared to be so promising. Unfortunately, both innate and adaptive responses to the virus have limited the development of AdV vectors as a tool of gene therapy by increasing toxicity and limiting duration of transgene expression. This article will focus on the innate immune response to infection with wild-type AdV and exposure to AdV gene-therapy vectors. As much of the known information relates to the pulmonary inflammatory response, this organ system will be emphasized. This article will also discuss how that understanding has led to the creation of new vectors for use in gene therapy. 相似文献