Sepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance. Phagocytic cells play a crucial part in the prevention of sepsis by clearing ...bacteria through host innate receptors. Here we show that the FcRγ adaptor, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing signal transduction subunit of the Fc receptor family, has a deleterious effect on sepsis. FcRγ−/− mice show increased survival during peritonitis, owing to markedly increased E. coli phagocytosis and killing and to lower production of the proinflammatory cytokine tumor necrosis factor (TNF)-α. The FcRγ-associated receptor that inhibits E. coli phagocytosis is FcγRIII (also called CD16), and its absence protects mice from sepsis. FcγRIII binds E. coli, and this interaction induces FcRγ phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation. Decreased PI3K activity inhibits E. coli phagocytosis and increases TNF-α production through Toll-like receptor 4. We identified the phagocytic receptor negatively regulated by FcRγ on macrophages as the class A scavenger receptor MARCO. E. coli-FcγRIII interaction induces the recruitment of SHP-1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding FcγRIII, E. coli triggers an inhibitory FcRγ pathway that both impairs MARCO-mediated bacterial clearance and activates TNF-α secretion.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Issue Title: Antibodies: Molecules, Receptors, Functions, and Therapeutic Usage The mechanism for anti-inflammatory action of intravenous immunoglobulin (IVIg) in the treatment of autoimmune and ...inflammatory diseases involves IgG Fc receptors (FcγR). Although the inhibitory FcγRIIB plays an important role in IVIg action, FcγRIIIA has recently been identified as another major anti-inflammatory actor. Interaction of FcγRIIIA with uncomplexed IgG1 or IVIg, or with bivalent anti-FcγRIII F(ab')^sub 2^ dampened calcium responses, ROS production, endocytosis and phagocytosis, induced by heterologous activating receptors. This inhibitory action required the inhibitory configuration of the ITAM motif (ITAMi) present within the FcγRIII-associated FcRγ subunit. This allowed SHP-1 recruitment and formation of intracellular inhibisome clusters containing FcγRIII and the targeted activating receptor. Therefore, IVIg functionally interact with FcγRIIIA inducing ITAMi signaling which can prevent development of autoimmune and inflammatory disorders independently of FcγRIIB. This new mechanism of action for IVIg reveals a therapeutic potential for FcγRIIIA targeting in inflammatory diseases.PUBLICATION ABSTRACT
T-cell polyspecificity, predicting that individual T cells recognize a continuum of related ligands, implies that multiple antigens can tolerize T cells specific for a given self-antigen. We ...previously showed in C57BL/6 mice that part of the CD4+ T-cell repertoire specific for myelin oligodendrocyte glycoprotein (MOG) 35-55 also recognizes the neuronal antigen neurofilament medium (NF-M) 15-35. Such bi-specific CD4+ T cells are frequent and produce inflammatory cytokines after stimulation. Since T cells recognizing two self-antigens would be expected to be tolerized more efficiently, this finding prompted us to study how polyspecificity impacts tolerance. We found that similar to MOG, NF-M is expressed in the thymus by medullary thymic epithelial cells, a tolerogenic population. Nevertheless, the frequency, phenotype, and capacity to transfer experimental autoimmune encephalomyelitis (EAE) of MOG35-55-reactive CD4+ T cells were increased in MOG-deficient but not in NF-M-deficient mice. We found that presentation of NF-M15-35 by I-Ab on dendritic cells is of short duration, suggesting unstable MHC class II binding. Consistently, introducing an MHC-anchoring residue into NF-M15-35 (NF-M15-35T20Y) increased its immunogenicity, activating a repertoire able to induce EAE. Our results show that in C57BL/6 mice bi-specific encephalitogenic T cells manage to escape tolerization due to inefficient exposure to two self-antigens.
T-cell polyspecificity, predicting that individual T cells recognize a continuum of related ligands, implies that multiple antigens can tolerize T cells specific for a given self-antigen. We ...previously showed in C57BL/6 mice that part of the CD4 super(+) T-cell repertoire specific for myelin oligodendrocyte glycoprotein (MOG) 35-55 also recognizes the neuronal antigen neurofilament medium (NF-M) 15-35. Such bi-specific CD4 super(+) T cells are frequent and produce inflammatory cytokines after stimulation. Since T cells recognizing two self-antigens would be expected to be tolerized more efficiently, this finding prompted us to study how polyspecificity impacts tolerance. We found that similar to MOG, NF-M is expressed in the thymus by medullary thymic epithelial cells, a tolerogenic population. Nevertheless, the frequency, phenotype, and capacity to transfer experimental autoimmune encephalomyelitis (EAE) of MOG sub(35-55)-reactive CD4 super(+) T cells were increased in MOG-deficient but not in NF-M-deficient mice. We found that presentation of NF-M sub(15-35) by I-A super(b) on dendritic cells is of short duration, suggesting unstable MHC class II binding. Consistently, introducing an MHC-anchoring residue into NF-M sub(15-35) (NF-M sub(15-35)T20Y) increased its immunogenicity, activating a repertoire able to induce EAE. Our results show that in C57BL/6 mice bi-specific encephalitogenic T cells manage to escape tolerization due to inefficient exposure to two self-antigens. In the absence of Myelin oligodendrocyte glycoprotein (MOG), CD4 T cells are not tolerized leading to increased Teff/Treg ratio, and enhanced inflammatory response in MOG super(-/-)NF-M super(-/-) animals. Absence of such tolerization results in increased encephalitogenic properties.
T‐cell polyspecificity, predicting that individual T cells recognize a continuum of related ligands, implies that multiple antigens can tolerize T cells specific for a given self‐antigen. We ...previously showed in C57BL/6 mice that part of the CD4+ T‐cell repertoire specific for myelin oligodendrocyte glycoprotein (MOG) 35–55 also recognizes the neuronal antigen neurofilament medium (NF‐M) 15–35. Such bi‐specific CD4+ T cells are frequent and produce inflammatory cytokines after stimulation. Since T cells recognizing two self‐antigens would be expected to be tolerized more efficiently, this finding prompted us to study how polyspecificity impacts tolerance. We found that similar to MOG, NF‐M is expressed in the thymus by medullary thymic epithelial cells, a tolerogenic population. Nevertheless, the frequency, phenotype, and capacity to transfer experimental autoimmune encephalomyelitis (EAE) of MOG35‐55‐reactive CD4+ T cells were increased in MOG‐deficient but not in NF‐M‐deficient mice. We found that presentation of NF‐M15‐35 by I‐Ab on dendritic cells is of short duration, suggesting unstable MHC class II binding. Consistently, introducing an MHC‐anchoring residue into NF‐M15‐35 (NF‐M15‐35T20Y) increased its immunogenicity, activating a repertoire able to induce EAE. Our results show that in C57BL/6 mice bi‐specific encephalitogenic T cells manage to escape tolerization due to inefficient exposure to two self‐antigens.
In the absence of Myelin oligodendrocyte glycoprotein (MOG), CD4 T cells are not tolerized leading to increased Teff/Treg ratio, and enhanced inflammatory response in MOG−/−NF‐M−/− animals. Absence of such tolerization results in increased encephalitogenic properties.
Inhibitory ITAMs: a matter of life and death da Silva, Fabiano Pinheiro; Aloulou, Meryem; Benhamou, Marc ...
Trends in immunology,
08/2008, Letnik:
29, Številka:
8
Journal Article
Recenzirano
The balance between activating and inhibitory signals is essential to control immune responses to microorganisms. Innate and adaptive immune responses are regulated by receptors that signal through ...either an immunoreceptor tyrosine-based activation motif (ITAM) or an immunoreceptor tyrosine-based inhibitory motif (ITIM). When clustered, these motifs are, respectively, responsible for activating and inhibitory signals. Recently, the concept of inhibitory ITAM (ITAMi ) has emerged as a new means to negatively control the immune response. In this Opinion, we will discuss the ability of Escherichia coli to evade the immune system by eliciting ITAMi function through FcγRIII (CD16) on phagocytes leading to uncontrolled systemic infection and sepsis. Elucidating such mechanisms will open opportunities for specific therapeutic manipulation of ITAMi -based signaling pathways.
Inhibitory signaling is an emerging function of ITAM-bearing immunoreceptors in the maintenance of homeostasis. Monovalent targeting of the IgA Fc receptor (FcalphaRI or CD89) by anti-FcalphaRI Fab ...triggers potent inhibitory ITAM (ITAM(i)) signaling through the associated FcRgamma chain (FcalphaRI-FcRgamma ITAM(i)) that prevents IgG phagocytosis and IgE-mediated asthma. It is not known whether FcalphaRI-FcRgamma ITAM(i) signaling controls receptors that do not function through an ITAM and whether this inhibition requires Src homology protein 1 phosphatase. We show in this study that FcalphaRI-Fcgamma ITAM(i) signals depend on Src homology protein 1 phosphatase to target multiple non-ITAM-bearing receptors such as chemotactic receptors, cytokine receptors, and TLRs. We found that anti-FcalphaRI Fab treatment in vivo reduced kidney inflammation in models of immune-mediated glomerulonephritis and nonimmune obstructive nephropathy by a mechanism that involved decreased inflammatory cell infiltration and fibrosis development. This treatment also prevented ex vivo LPS activation of monocytes from patients with lupus nephritis or vasculitis, as well as receptor activation through serum IgA complexes from IgA nephropathy patients. These findings point to a crucial role of FcalphaRI-FcRgamma ITAM(i) signaling in the control of multiple heterologous or autologous inflammatory responses. They also identify anti-FcalphaRI Fab as a new potential therapeutic tool for preventing progression of renal inflammatory diseases.
Abstract only
Pathogen‐induced immune dysregulation is largely responsible for the morbidity and mortality associated with sepsis. Sepsis also involves inefficient bacterial clearance by phagocytic ...cells. Here we show that FcRγ, the ITAM‐bearing signal transduction subunit of the Fc receptor family, plays a deleterious role in sepsis. FcRγ−/− mice show increased survival during peritonitis, due to markedly increased E. coli phagocytosis and killing and to lower production of the pro‐inflammatory cytokine TNFα. The FcRγ‐associated receptor that inhibits E. coli phagocytosis is FcγRIII (CD16), and its absence protects mice from sepsis. CD16 binds E. coli, and this interaction induces FcRγ phosphorylation, SHP‐1 recruitment and PI3‐K dephosphorylation. Decreased PI3‐K activity inhibits E. coli phagocytosis and increases TNFα production through TLR4. We identified the phagocytic receptor negatively regulated by FcRγ on macrophages as the class A scavenger receptor MARCO. E. coli‐CD16 interaction induces the recruitment of SHP‐1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding CD16, E. coli triggers an inhibitory FcRγ pathway that both impairs MARCO‐mediated bacterial clearance and activates TNFα secretion. This mechanism could be the target of new therapeutic approaches in sepsis. Granted by Inserm, ANR‐Mime and FAPESP.
Sepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance. Phagocytic cells play a crucial part in the prevention of sepsis by clearing ...bacteria through host innate receptors. Here we show that the FcRgamma adaptor, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing signal transduction subunit of the Fc receptor family, has a deleterious effect on sepsis. FcRgamma(-/-) mice show increased survival during peritonitis, owing to markedly increased E. coli phagocytosis and killing and to lower production of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. The FcRgamma-associated receptor that inhibits E. coli phagocytosis is FcgammaRIII (also called CD16), and its absence protects mice from sepsis. FcgammaRIII binds E. coli, and this interaction induces FcRgamma phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation. Decreased PI3K activity inhibits E. coli phagocytosis and increases TNF-alpha production through Toll-like receptor 4. We identified the phagocytic receptor negatively regulated by FcRgamma on macrophages as the class A scavenger receptor MARCO. E. coli-FcgammaRIII interaction induces the recruitment of SHP-1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding FcgammaRIII, E. coli triggers an inhibitory FcRgamma pathway that both impairs MARCO-mediated bacterial clearance and activates TNF-alpha secretion.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Sepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance. Phagocytic cells play a crucial part in the prevention of sepsis by clearing ...bacteria through host innate receptors. Here we show that the FcRg adaptor, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing signal transduction subunit of the Fc receptor family, has a deleterious effect on sepsis. FcRg super(-/-) mice show increased survival during peritonitis, owing to markedly increased E. coli phagocytosis and killing and to lower production of the proinflammatory cytokine tumor necrosis factor (TNF)-a. The FcRg-associated receptor that inhibits E. coli phagocytosis is FcgRIII (also called CD16), and its absence protects mice from sepsis. FcgRIII binds E. coli, and this interaction induces FcRg phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation. Decreased PI3K activity inhibits E. coli phagocytosis and increases TNF-a production through Toll-like receptor 4. We identified the phagocytic receptor negatively regulated by FcRg on macrophages as the class A scavenger receptor MARCO. E. coli-FcgRIII interaction induces the recruitment of SHP-1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding FcgRIII, E. coli triggers an inhibitory FcRg pathway that both impairs MARCO-mediated bacterial clearance and activates TNF-a secretion.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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