The Experts below are selected from a list of 33153 Experts worldwide ranked by ideXlab platform
Sharon L Ford - One of the best experts on this subject based on the ideXlab platform.
-
42 apics deficiency reveals a role for a long noncoding rna in Dendritic Cell Function and autoimmunity
Cytokine, 2014Co-Authors: Colleen M Elso, Michelle P Ashton, Leanne Mackin, Edward P F Chu, Natalie Lisa Payne, Sharon L Ford, Iris K L Tan, Anthony T Papenfuss, Richard A KitchingAbstract:Although in vitro observations indicate that long noncoding RNAs (lncRNAs) regulate innate immune responses, their effect upon immune tolerance in vivo has not been defined. We have identified a novel gene of unknown Function for which sequence variation is associated with autoimmune diabetes in the nonobese diabetic (NOD) mouse strain. Bioinformatics and expression analyses indicate this gene encodes a lncRNA that is induced by Toll-like receptor (TLR) activation, localises to the nucleus and cytoplasm of Dendritic Cells, and binds to proteins within these Cellular compartments. Moreover, sequence variation for this gene is associated with altered TLR-mediated cytokine production. Hence this gene was named Apics for Attenuator of Pattern recognition receptor-Induced Cytokine Secretion. To further investigate the Function of this lncRNA, we established a C57BL/6 (B6) knockout mouse strain for Apics and discovered that Apics -deficient Dendritic Cells exhibit enhanced TLR-mediated cytokine production. Apics -deficient B6 mice also exhibit increased susceptibility to autoimmunity in two disease models: experimental autoimmune encephalomyelitis and experimental anti-neutrophil cytoplasmic antibody-associated vasculitis. Our study suggests that lncRNAs, such as Apics , can serve as TLR-inducible repressors that regulate the magnitude of innate immune responses to reduce the risk for developing autoimmune disease.
-
apics deficiency reveals a role for a long noncoding rna in Dendritic Cell Function and autoimmunity ba3p 203
Journal of Immunology, 2014Co-Authors: Thomas C Brodnicki, Michelle P Ashton, Colleen M Elso, Leanne Mackin, Edward P F Chu, Natalie Lisa Payne, Sharon L Ford, Iris K L Tan, Anthony T PapenfussAbstract:Although in vitro observations indicate that long noncoding RNAs (lncRNAs) regulate innate immune responses, their effect upon immune tolerance in vivo has not been defined. We have identified a novel gene of unknown Function for which sequence variation is associated with autoimmune diabetes in the nonobese diabetic (NOD) mouse strain. Bioinformatics and expression analyses indicate this gene encodes a lncRNA that is induced by Toll-like receptor (TLR) activation, localizes to the nucleus and cytoplasm of Dendritic Cells, and binds to proteins within these Cellular compartments. Moreover, sequence variation for this gene is associated with altered TLR-mediated cytokine production. Hence this gene was named Apics for Attenuator of Pattern recognition receptor-Induced Cytokine Secretion. To further investigate the Function of this lncRNA, we established a C57BL/6 (B6) knockout mouse strain for Apics and discovered that Apics-deficient Dendritic Cells exhibit enhanced TLR-mediated cytokine production. Apics-deficient B6 mice also exhibit increased susceptibility to autoimmunity in two disease models: experimental autoimmune encephalomyelitis and experimental anti-neutrophil cytoplasmic antibody-associated vasculitis. Our study suggests that lncRNAs, such as Apics, can serve as TLR-inducible repressors that regulate the magnitude of innate immune responses to reduce the risk for developing autoimmune disease.
Antonio Lanzavecchia - One of the best experts on this subject based on the ideXlab platform.
-
distinct patterns and kinetics of chemokine production regulate Dendritic Cell Function
European Journal of Immunology, 1999Co-Authors: Federica Sallusto, Belinda Palermo, Minja Miettinen, Ralf Burgstahler, Martin Lipp, Danielle Lenig, Sampsa Matikainen, Reinhold Forster, Ilkka Julkunen, Antonio LanzavecchiaAbstract:Dendritic Cells (DC) have been showed to both produce and respond to chemokines. To understand how this may impact on DC Function, we analyzed the kinetics of chemokine production and responsiveness during DC maturation. After stimulation with LPS, TNF-α or CD40 ligand, the inflammatory chemokines MIP-1α, MIP-1β and IL-8 were produced rapidly and at high levels, but only for a few hours, while RANTES and MCP-1 were produced in a sustained fashion. The constitutive chemokines TARC, MDC and PARC were expressed in immature DC and were up-regulated following maturation, while ELC was produced only at late time points. Activated macrophages produced a similar spectrum of chemokines, but did not produce TARC and ELC. In maturing DC chemokine production had different impact on chemokine receptor Function. While CCR1 and CCR5 were down-regulated by endogenous or exogenous chemokines, CCR7 levels gradually increased in maturing DC and showed a striking resistance to ligand-induced down-regulation, explaining how DC can sustain the response to SLC and ELC throughout the maturation process. The time-ordered production of inflammatory and constitutive chemokines provides DC with the capacity to self-regulate their migratory behavior as well as to recruit other Cells for the afferent and efferent limb of the immune response.
-
distinct patterns and kinetics of chemokine production regulate Dendritic Cell Function
European Journal of Immunology, 1999Co-Authors: Federica Sallusto, Belinda Palermo, Minja Miettinen, Ralf Burgstahler, Martin Lipp, Danielle Lenig, Sampsa Matikainen, Reinhold Forster, Ilkka Julkunen, Antonio LanzavecchiaAbstract:Dendritic Cells (DC) have been showed to both produce and respond to chemokines. To understand how this may impact on DC Function, we analyzed the kinetics of chemokine production and responsiveness during DC maturation. After stimulation with LPS, TNF-alpha or CD40 ligand, the inflammatory chemokines MIP-1alpha, MIP-1beta and IL-8 were produced rapidly and at high levels, but only for a few hours, while RANTES and MCP-1 were produced in a sustained fashion. The constitutive chemokines TARC, MDC and PARC were expressed in immature DC and were up-regulated following maturation, while ELC was produced only at late time points. Activated macrophages produced a similar spectrum of chemokines, but did not produce TARC and ELC. In maturing DC chemokine production had different impact on chemokine receptor Function. While CCR1 and CCR5 were down-regulated by endogenous or exogenous chemokines, CCR7 levels gradually increased in maturing DC and showed a striking resistance to ligand-induced down-regulation, explaining how DC can sustain the response to SLC and ELC throughout the maturation process. The time-ordered production of inflammatory and constitutive chemokines provides DC with the capacity to self-regulate their migratory behavior as well as to recruit other Cells for the afferent and efferent limb of the immune response.
Luca Battistini - One of the best experts on this subject based on the ideXlab platform.
-
immune regulatory neural stem precursor Cells protect from central nervous system autoimmunity by restraining Dendritic Cell Function
PLOS ONE, 2009Co-Authors: Stefano Pluchino, Lucia Zanotti, Elena Brambilla, Patrizia Roverequerini, Annalisa Capobianco, Clara Alfarocervello, Giuliana Salani, Chiara Cossetti, Giovanna Borsellino, Luca BattistiniAbstract:BACKGROUND: The systemic injection of neural stem/precursor Cells (NPCs) provides remarkable amelioration of the clinico-pathological features of experimental autoimmune encephalomyelitis (EAE). This is dependent on the capacity of transplanted NPCs to engage concurrent mechanisms of action within specific microenvironments in vivo. Among a wide range of therapeutic actions alternative to Cell replacement, neuroprotective and immune modulatory capacities of transplanted NPCs have been described. However, lacking is a detailed understanding of the mechanisms by which NPCs exert their therapeutic plasticity. This study was designed to identify the first candidate that exemplifies and sustains the immune modulatory capacity of transplanted NPCs. METHODOLOGY/PRINCIPAL FINDINGS: To achieve the exclusive targeting of the peripheral immune system, SJL mice with PLP-induced EAE were injected subcutaneously with NPCs and the treatment commenced prior to disease onset. NPC-injected EAE mice showed significant clinical improvement, as compared to controls. Exogenous NPCs lacking the expression of major neural antigens were reliably (and for long-term) found at the level of draining lymph nodes, while establishing sophisticated anatomical interactions with lymph node Cells. Importantly, injected NPCs were never found in organs other than lymph nodes, including the brain and the spinal cord. Draining lymph nodes from transplanted mice showed focal up-regulation of major developmental stem Cell regulators, such as BMP-4, Noggin and Sonic hedgehog. In lymph nodes, injected NPCs hampered the activation of myeloid Dendritic Cells (DCs) and steadily restrained the expansion of antigen-specific encephalitogenic T Cells. Both ex vivo and in vitro experiments identified a novel highly NPC-specific-BMP-4-dependent-mechanism hindering the DC maturation. CONCLUSION/SIGNIFICANCE: The study described herein, identifies the first member of the TGF beta/BMP family of stem Cell regulators as a novel tolerogenic factor released by NPCs. Full exploitation of this pathway as an efficient tool for vaccination therapy in autoimmune inflammatory conditions is underway.
-
immune regulatory neural stem precursor Cells protect from central nervous system autoimmunity by restraining Dendritic Cell Function
PLOS ONE, 2009Co-Authors: Stefano Pluchino, Lucia Zanotti, Elena Brambilla, Patrizia Roverequerini, Annalisa Capobianco, Clara Alfarocervello, Giuliana Salani, Chiara Cossetti, Giovanna Borsellino, Luca BattistiniAbstract:Background The systemic injection of neural stem/precursor Cells (NPCs) provides remarkable amelioration of the clinico-pathological features of experimental autoimmune encephalomyelitis (EAE). This is dependent on the capacity of transplanted NPCs to engage concurrent mechanisms of action within specific microenvironments in vivo. Among a wide range of therapeutic actions alternative to Cell replacement, neuroprotective and immune modulatory capacities of transplanted NPCs have been described. However, lacking is a detailed understanding of the mechanisms by which NPCs exert their therapeutic plasticity. This study was designed to identify the first candidate that exemplifies and sustains the immune modulatory capacity of transplanted NPCs. Methodology/Principal Findings To achieve the exclusive targeting of the peripheral immune system, SJL mice with PLP-induced EAE were injected subcutaneously with NPCs and the treatment commenced prior to disease onset. NPC-injected EAE mice showed significant clinical improvement, as compared to controls. Exogenous NPCs lacking the expression of major neural antigens were reliably (and for long-term) found at the level of draining lymph nodes, while establishing sophisticated anatomical interactions with lymph node Cells. Importantly, injected NPCs were never found in organs other than lymph nodes, including the brain and the spinal cord. Draining lymph nodes from transplanted mice showed focal up-regulation of major developmental stem Cell regulators, such as BMP-4, Noggin and Sonic hedgehog. In lymph nodes, injected NPCs hampered the activation of myeloid Dendritic Cells (DCs) and steadily restrained the expansion of antigen-specific encephalitogenic T Cells. Both ex vivo and in vitro experiments identified a novel highly NPC-specific–BMP-4-dependent–mechanism hindering the DC maturation. Conclusion/Significance The study described herein, identifies the first member of the TGF β/BMP family of stem Cell regulators as a novel tolerogenic factor released by NPCs. Full exploitation of this pathway as an efficient tool for vaccination therapy in autoimmune inflammatory conditions is underway.
Karina Yazdanbakhsh - One of the best experts on this subject based on the ideXlab platform.
-
altered heme mediated modulation of Dendritic Cell Function in sickle Cell alloimmunization
Haematologica, 2016Co-Authors: Emmanuelle Godefroy, Beau W Mitchell, Devin Cohen, Deepa Manwani, Stella T Chou, Karina YazdanbakhshAbstract:Transfusions are the main treatment for patients with sickle Cell disease. However, alloimmunization remains a major life-threatening complication for these patients, but the mechanism underlying pathogenesis of alloimmunization is not known. Because of chronic hemolytic state in sickle Cell disease, resulting in release of free heme and activation of inflammatory cascades, we tested the hypothesis that anti-inflammatory response to heme is compromised in alloimmunized sickle patients, heightening their risk of alloimmunization. Heme-exposed monocyte-derived Dendritic Cells from both non-alloimmunized sickle patients and healthy donors inhibited priming of pro-inflammatory CD4+ type 1 T Cells, and exhibited significantly reduced levels of the maturation marker CD83. In contrast, in alloimmunized patients, heme did not reverse priming of pro-inflammatory CD4+ Cells by monocyte-derived Dendritic Cells or their maturation. Furthermore, heme dampened NF-kappaB activation in non-alloimmunized, but not in alloimmunized monocyte-derived Dendritic Cells. Heme-mediated CD83 inhibition depended on Toll-like receptor 4 but not heme oxygenase 1. These data suggest that extraCellular heme limits CD83 expression on Dendritic Cells in non-alloimmunized sickle patients through a Toll-like receptor 4-mediated pathway, involving NF-kappaB, resulting in dampening of pro-inflammatory responses, but that in alloimmunized patients this pathway is defective, opening up new therapeutic strategies to prevent sickle Cell alloimmunization.
-
altered heme mediated modulation of Dendritic Cell Function in sickle Cell alloimmunization
Blood, 2015Co-Authors: Emmanuelle Godefroy, Beau W Mitchell, Devin Cohen, Deepa Manwani, Stella T Chou, Karina YazdanbakhshAbstract:Red blood Cell alloimmunization can be a life-threatening complication for patients with sickle Cell disease (SCD) receiving therapeutic transfusions. However, it remains unknown why only some (20-60%) SCD patients develop alloantibodies whereas others do not. Because of ongoing hemolysis in SCD, we have investigated the effects of toxic hemin on T Cell responses of patients with SCD on chronic transfusion therapy. We found impaired monocyte control of proinflammatory T Cells in response to hemin in alloimmunized SCD patients, partly due to defective levels of monocyte heme-oxygenase-1 (HO-1), an anti-inflammatory heme degrading enzyme that catabolizes heme into iron, biliverdin and carbon monoxide (CO). Monocytes are precursors of Dendritic Cells (DCs), which represent the antigen presenting Cells most able to initiate and regulate immune responses. However, little is known about the Functional properties of DCs in SCD patients. We therefore hypothesized that DCs of alloimmunized SCD patients would also have impaired response to hemin. Monocyte-derived DCs (moDCs) from healthy donor controls (n=11) and a cohort of SCD patients (aged 15-30 on chronic transfusion therapy every 3-4 weeks for at least two years using C,E,K phenotyped-matched, leukodepleted units) grouped either as "non-alloimmunized" (no history of antibody production, n=6), versus "alloimmunized" (with a history of having produced at least one alloantibody, n=7) were matured in the absence or presence of hemin (5uM and 20uM) with TLR agonists: LPS/IFNg (TLR4 agonist+STAT1 activation) or R848 (TLR7/8 agonist). Hemin-exposed mature and immature (no TLR agonist) moDCs were then assayed for HO-1 expression, cytokine production, co-stimulation, and T Cell priming. Interestingly, upon hemin exposure, immature moDCs from healthy donors and non-alloimmunized patients upregulated more HO-1 (1056±206 fold; mean fluorescent intensity (MFI): 12283±1818 at 20uM hemin) than alloimmunized patients (fold increase 494±49; MFI: 7422±959, p + T Cells (ie. priming), we performed mixed lymphocyte reactions: whereas hemin inhibited (roughly 30%) moDC-mediated priming of pro-inflammatory IFNg secreting T H 1 Cells in healthy donors and non-alloimmunized patients (%CD4 + IFNg + without hemin 58%±9% with 20uM hemin 41%±8%, p=0.005), T H 1 Cell responses were not suppressed in the alloimmunized group (without hemin: 52%±10% with 20uM hemin: 54%±10%, p=0.4). In summary, hemin-exposed moDCs from healthy donors and non-alloimmunized SCD patients suppress CD83 upregulation and inhibit ensuing T H 1 Cell responses, possibly through HO-1 induction and subsequent production of CO. In contrast, CD83 upregulation and proinflammatory T Cell priming are not inhibited by hemin in alloimmunized patients, probably representing a mechanism by which heme-associated inflammation is maintained in alloimmunized SCD, thereby increasing their risk of alloimmunization. Deciphering this mechanism not only offers a potential biomarker for alloimmunization, but also opens the way to designing innovative treatments for these patients. Disclosures No relevant conflicts of interest to declare.
Anthony T Papenfuss - One of the best experts on this subject based on the ideXlab platform.
-
42 apics deficiency reveals a role for a long noncoding rna in Dendritic Cell Function and autoimmunity
Cytokine, 2014Co-Authors: Colleen M Elso, Michelle P Ashton, Leanne Mackin, Edward P F Chu, Natalie Lisa Payne, Sharon L Ford, Iris K L Tan, Anthony T Papenfuss, Richard A KitchingAbstract:Although in vitro observations indicate that long noncoding RNAs (lncRNAs) regulate innate immune responses, their effect upon immune tolerance in vivo has not been defined. We have identified a novel gene of unknown Function for which sequence variation is associated with autoimmune diabetes in the nonobese diabetic (NOD) mouse strain. Bioinformatics and expression analyses indicate this gene encodes a lncRNA that is induced by Toll-like receptor (TLR) activation, localises to the nucleus and cytoplasm of Dendritic Cells, and binds to proteins within these Cellular compartments. Moreover, sequence variation for this gene is associated with altered TLR-mediated cytokine production. Hence this gene was named Apics for Attenuator of Pattern recognition receptor-Induced Cytokine Secretion. To further investigate the Function of this lncRNA, we established a C57BL/6 (B6) knockout mouse strain for Apics and discovered that Apics -deficient Dendritic Cells exhibit enhanced TLR-mediated cytokine production. Apics -deficient B6 mice also exhibit increased susceptibility to autoimmunity in two disease models: experimental autoimmune encephalomyelitis and experimental anti-neutrophil cytoplasmic antibody-associated vasculitis. Our study suggests that lncRNAs, such as Apics , can serve as TLR-inducible repressors that regulate the magnitude of innate immune responses to reduce the risk for developing autoimmune disease.
-
apics deficiency reveals a role for a long noncoding rna in Dendritic Cell Function and autoimmunity ba3p 203
Journal of Immunology, 2014Co-Authors: Thomas C Brodnicki, Michelle P Ashton, Colleen M Elso, Leanne Mackin, Edward P F Chu, Natalie Lisa Payne, Sharon L Ford, Iris K L Tan, Anthony T PapenfussAbstract:Although in vitro observations indicate that long noncoding RNAs (lncRNAs) regulate innate immune responses, their effect upon immune tolerance in vivo has not been defined. We have identified a novel gene of unknown Function for which sequence variation is associated with autoimmune diabetes in the nonobese diabetic (NOD) mouse strain. Bioinformatics and expression analyses indicate this gene encodes a lncRNA that is induced by Toll-like receptor (TLR) activation, localizes to the nucleus and cytoplasm of Dendritic Cells, and binds to proteins within these Cellular compartments. Moreover, sequence variation for this gene is associated with altered TLR-mediated cytokine production. Hence this gene was named Apics for Attenuator of Pattern recognition receptor-Induced Cytokine Secretion. To further investigate the Function of this lncRNA, we established a C57BL/6 (B6) knockout mouse strain for Apics and discovered that Apics-deficient Dendritic Cells exhibit enhanced TLR-mediated cytokine production. Apics-deficient B6 mice also exhibit increased susceptibility to autoimmunity in two disease models: experimental autoimmune encephalomyelitis and experimental anti-neutrophil cytoplasmic antibody-associated vasculitis. Our study suggests that lncRNAs, such as Apics, can serve as TLR-inducible repressors that regulate the magnitude of innate immune responses to reduce the risk for developing autoimmune disease.