Regulatory networks induced by live parasites impair both Th1 and Th2 pathways in patent lymphatic filariasis: implications for parasite persistence.
Identifieur interne : 007864 ( Main/Exploration ); précédent : 007863; suivant : 007865Regulatory networks induced by live parasites impair both Th1 and Th2 pathways in patent lymphatic filariasis: implications for parasite persistence.
Auteurs : Subash Babu [États-Unis] ; Carla P. Blauvelt ; V. Kumaraswami ; Thomas B. NutmanSource :
- Journal of immunology (Baltimore, Md. : 1950) [ 0022-1767 ] ; 2006.
Descripteurs français
- KwdFr :
- Animaux, Anticorps bloquants (pharmacologie), Antigène CTLA-4, Antigènes CD, Antigènes de différenciation (immunologie), Antigènes de différenciation (métabolisme), Brugia malayi (croissance et développement), Brugia malayi (immunologie), Cellules cultivées, Cytokines (biosynthèse), Facteur de croissance transformant bêta (biosynthèse), Facteur de croissance transformant bêta (génétique), Facteur de transcription GATA-3 (antagonistes et inhibiteurs), Facteurs de transcription (antagonistes et inhibiteurs), Facteurs de transcription Forkhead (biosynthèse), Facteurs de transcription Forkhead (génétique), Filariose lymphatique (immunologie), Filariose lymphatique (parasitologie), Humains, Interactions hôte-parasite (immunologie), Lymphocytes auxiliaires Th1 (immunologie), Lymphocytes auxiliaires Th1 (métabolisme), Lymphocytes auxiliaires Th1 (parasitologie), Lymphocytes auxiliaires Th2 (immunologie), Lymphocytes auxiliaires Th2 (métabolisme), Lymphocytes auxiliaires Th2 (parasitologie), Protéines SOCS (biosynthèse), Protéines SOCS (génétique), Protéines à domaine boîte-T, Régulation négative (immunologie), Tolérance immunitaire (génétique), Transduction du signal (génétique), Transduction du signal (immunologie), Ubiquitin-protein ligases (antagonistes et inhibiteurs).
- MESH :
- antagonistes et inhibiteurs : Facteur de transcription GATA-3, Facteurs de transcription, Ubiquitin-protein ligases.
- biosynthèse : Cytokines, Facteur de croissance transformant bêta, Facteurs de transcription Forkhead, Protéines SOCS.
- croissance et développement : Brugia malayi.
- génétique : Facteur de croissance transformant bêta, Facteurs de transcription Forkhead, Protéines SOCS, Tolérance immunitaire, Transduction du signal.
- immunologie : Antigènes de différenciation, Brugia malayi, Filariose lymphatique, Interactions hôte-parasite, Lymphocytes auxiliaires Th1, Lymphocytes auxiliaires Th2, Régulation négative, Transduction du signal.
- métabolisme : Antigènes de différenciation, Lymphocytes auxiliaires Th1, Lymphocytes auxiliaires Th2.
- parasitologie : Filariose lymphatique, Lymphocytes auxiliaires Th1, Lymphocytes auxiliaires Th2.
- pharmacologie : Anticorps bloquants.
- Animaux, Antigène CTLA-4, Antigènes CD, Cellules cultivées, Humains, Protéines à domaine boîte-T.
English descriptors
- KwdEn :
- Animals, Antibodies, Blocking (pharmacology), Antigens, CD, Antigens, Differentiation (immunology), Antigens, Differentiation (metabolism), Brugia malayi (growth & development), Brugia malayi (immunology), CTLA-4 Antigen, Cells, Cultured, Cytokines (biosynthesis), Down-Regulation (immunology), Elephantiasis, Filarial (immunology), Elephantiasis, Filarial (parasitology), Forkhead Transcription Factors (biosynthesis), Forkhead Transcription Factors (genetics), GATA3 Transcription Factor (antagonists & inhibitors), Host-Parasite Interactions (immunology), Humans, Immune Tolerance (genetics), Signal Transduction (genetics), Signal Transduction (immunology), Suppressor of Cytokine Signaling Proteins (biosynthesis), Suppressor of Cytokine Signaling Proteins (genetics), T-Box Domain Proteins, Th1 Cells (immunology), Th1 Cells (metabolism), Th1 Cells (parasitology), Th2 Cells (immunology), Th2 Cells (metabolism), Th2 Cells (parasitology), Transcription Factors (antagonists & inhibitors), Transforming Growth Factor beta (biosynthesis), Transforming Growth Factor beta (genetics), Ubiquitin-Protein Ligases (antagonists & inhibitors).
- MESH :
- chemical , antagonists & inhibitors : GATA3 Transcription Factor, Transcription Factors, Ubiquitin-Protein Ligases.
- chemical , biosynthesis : Cytokines, Forkhead Transcription Factors, Suppressor of Cytokine Signaling Proteins, Transforming Growth Factor beta.
- chemical , genetics : Forkhead Transcription Factors, Suppressor of Cytokine Signaling Proteins, Transforming Growth Factor beta.
- chemical , immunology : Antigens, Differentiation.
- chemical , metabolism : Antigens, Differentiation.
- chemical , pharmacology : Antibodies, Blocking.
- genetics : Immune Tolerance, Signal Transduction.
- growth & development : Brugia malayi.
- immunology : Brugia malayi, Down-Regulation, Elephantiasis, Filarial, Host-Parasite Interactions, Signal Transduction, Th1 Cells, Th2 Cells.
- metabolism : Th1 Cells, Th2 Cells.
- parasitology : Elephantiasis, Filarial, Th1 Cells, Th2 Cells.
- Animals, Antigens, CD, CTLA-4 Antigen, Cells, Cultured, Humans, T-Box Domain Proteins.
Abstract
Patent lymphatic filariasis is characterized by a profound down-regulation of immune responses with both parasite Ag-specific tolerance and bystander suppression. Although this down-regulation is confined to the Th1 arm of the immune system in response to parasite Ag, we hypothesized a more generalized suppression in response to live parasites. Indeed, when we examined the cytokine profile of a cohort of filaria-infected (n = 10) and uninfected (n = 10) individuals in response to live infective-stage larvae or microfilariae of Brugia malayi, we found significant impairment of both Th1 and Th2 cytokines characterized by diminished production of IFN-gamma, TNF-alpha, IL-4, IL-5, and IL-10 in infected patients. The molecular basis of this impaired Th1/Th2 response was examined, and we identified three major networks of immunoregulation and tolerance. First, impaired induction of T-bet and GATA-3 mRNA underlies the Th1/Th2 deficiency in infected individuals. Second, regulatory networks, as evidenced by significantly increased expression of Foxp3 (natural regulatory T cell marker) and regulatory effectors such as TGF-beta, CTLA-4, PD-1, ICOS, and indoleamine 2,3-dioxygenase play an important role in immunosuppression. Third, the compromise of effector T cell function is mediated by the enhanced induction of anergy-inducing factors cbl-b, c-cbl (cbl is abbreviation for Casitas B lymphoma), Itch, and Nedd4. Indeed, blocking CTLA-4 or neutralizing TGF-beta restored the ability to mount Th1/Th2 responses to live parasites and reversed the induction of anergy-inducing factors. Hence, we conclude that a profound impairment of live parasite-specific Th1 and Th2 immune responses occurs in lymphatic filariasis that is governed at the transcriptional level by a complex interplay of inhibitory mediators.
PubMed: 16493086
Affiliations:
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inhibitors)</term><term>Host-Parasite Interactions (immunology)</term><term>Humans</term><term>Immune Tolerance (genetics)</term><term>Signal Transduction (genetics)</term><term>Signal Transduction (immunology)</term><term>Suppressor of Cytokine Signaling Proteins (biosynthesis)</term><term>Suppressor of Cytokine Signaling Proteins (genetics)</term><term>T-Box Domain Proteins</term><term>Th1 Cells (immunology)</term><term>Th1 Cells (metabolism)</term><term>Th1 Cells (parasitology)</term><term>Th2 Cells (immunology)</term><term>Th2 Cells (metabolism)</term><term>Th2 Cells (parasitology)</term><term>Transcription Factors (antagonists & inhibitors)</term><term>Transforming Growth Factor beta (biosynthesis)</term><term>Transforming Growth Factor beta (genetics)</term><term>Ubiquitin-Protein Ligases (antagonists & inhibitors)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Anticorps bloquants (pharmacologie)</term><term>Antigène CTLA-4</term><term>Antigènes CD</term><term>Antigènes de différenciation (immunologie)</term><term>Antigènes de différenciation (métabolisme)</term><term>Brugia malayi (croissance et développement)</term><term>Brugia malayi (immunologie)</term><term>Cellules cultivées</term><term>Cytokines (biosynthèse)</term><term>Facteur de croissance transformant bêta (biosynthèse)</term><term>Facteur de croissance transformant bêta (génétique)</term><term>Facteur de transcription GATA-3 (antagonistes et inhibiteurs)</term><term>Facteurs de transcription (antagonistes et inhibiteurs)</term><term>Facteurs de transcription Forkhead (biosynthèse)</term><term>Facteurs de transcription Forkhead (génétique)</term><term>Filariose lymphatique (immunologie)</term><term>Filariose lymphatique (parasitologie)</term><term>Humains</term><term>Interactions hôte-parasite (immunologie)</term><term>Lymphocytes auxiliaires Th1 (immunologie)</term><term>Lymphocytes auxiliaires Th1 (métabolisme)</term><term>Lymphocytes auxiliaires Th1 (parasitologie)</term><term>Lymphocytes auxiliaires Th2 (immunologie)</term><term>Lymphocytes auxiliaires Th2 (métabolisme)</term><term>Lymphocytes auxiliaires Th2 (parasitologie)</term><term>Protéines SOCS (biosynthèse)</term><term>Protéines SOCS (génétique)</term><term>Protéines à domaine boîte-T</term><term>Régulation négative (immunologie)</term><term>Tolérance immunitaire (génétique)</term><term>Transduction du signal (génétique)</term><term>Transduction du signal (immunologie)</term><term>Ubiquitin-protein ligases (antagonistes et inhibiteurs)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>GATA3 Transcription Factor</term><term>Transcription Factors</term><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Cytokines</term><term>Forkhead Transcription Factors</term><term>Suppressor of Cytokine Signaling 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transformant bêta</term><term>Facteurs de transcription Forkhead</term><term>Protéines SOCS</term></keywords><keywords scheme="MESH" qualifier="croissance et développement" xml:lang="fr"><term>Brugia malayi</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Immune Tolerance</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="growth & development" xml:lang="en"><term>Brugia malayi</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Facteur de croissance transformant bêta</term><term>Facteurs de transcription Forkhead</term><term>Protéines SOCS</term><term>Tolérance immunitaire</term><term>Transduction du signal</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Antigènes de différenciation</term><term>Brugia malayi</term><term>Filariose lymphatique</term><term>Interactions hôte-parasite</term><term>Lymphocytes auxiliaires Th1</term><term>Lymphocytes auxiliaires Th2</term><term>Régulation négative</term><term>Transduction du signal</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Brugia malayi</term><term>Down-Regulation</term><term>Elephantiasis, Filarial</term><term>Host-Parasite Interactions</term><term>Signal Transduction</term><term>Th1 Cells</term><term>Th2 Cells</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Th1 Cells</term><term>Th2 Cells</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Antigènes de différenciation</term><term>Lymphocytes auxiliaires Th1</term><term>Lymphocytes auxiliaires Th2</term></keywords><keywords scheme="MESH" qualifier="parasitologie" xml:lang="fr"><term>Filariose lymphatique</term><term>Lymphocytes auxiliaires Th1</term><term>Lymphocytes auxiliaires Th2</term></keywords><keywords scheme="MESH" qualifier="parasitology" xml:lang="en"><term>Elephantiasis, Filarial</term><term>Th1 Cells</term><term>Th2 Cells</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Anticorps bloquants</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Antigens, CD</term><term>CTLA-4 Antigen</term><term>Cells, Cultured</term><term>Humans</term><term>T-Box Domain Proteins</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Antigène CTLA-4</term><term>Antigènes CD</term><term>Cellules cultivées</term><term>Humains</term><term>Protéines à domaine boîte-T</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Patent lymphatic filariasis is characterized by a profound down-regulation of immune responses with both parasite Ag-specific tolerance and bystander suppression. Although this down-regulation is confined to the Th1 arm of the immune system in response to parasite Ag, we hypothesized a more generalized suppression in response to live parasites. Indeed, when we examined the cytokine profile of a cohort of filaria-infected (n = 10) and uninfected (n = 10) individuals in response to live infective-stage larvae or microfilariae of Brugia malayi, we found significant impairment of both Th1 and Th2 cytokines characterized by diminished production of IFN-gamma, TNF-alpha, IL-4, IL-5, and IL-10 in infected patients. The molecular basis of this impaired Th1/Th2 response was examined, and we identified three major networks of immunoregulation and tolerance. First, impaired induction of T-bet and GATA-3 mRNA underlies the Th1/Th2 deficiency in infected individuals. Second, regulatory networks, as evidenced by significantly increased expression of Foxp3 (natural regulatory T cell marker) and regulatory effectors such as TGF-beta, CTLA-4, PD-1, ICOS, and indoleamine 2,3-dioxygenase play an important role in immunosuppression. Third, the compromise of effector T cell function is mediated by the enhanced induction of anergy-inducing factors cbl-b, c-cbl (cbl is abbreviation for Casitas B lymphoma), Itch, and Nedd4. Indeed, blocking CTLA-4 or neutralizing TGF-beta restored the ability to mount Th1/Th2 responses to live parasites and reversed the induction of anergy-inducing factors. Hence, we conclude that a profound impairment of live parasite-specific Th1 and Th2 immune responses occurs in lymphatic filariasis that is governed at the transcriptional level by a complex interplay of inhibitory mediators.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Maryland</li></region></list><tree><noCountry><name sortKey="Blauvelt, Carla P" sort="Blauvelt, Carla P" uniqKey="Blauvelt C" first="Carla P" last="Blauvelt">Carla P. Blauvelt</name><name sortKey="Kumaraswami, V" sort="Kumaraswami, V" uniqKey="Kumaraswami V" first="V" last="Kumaraswami">V. Kumaraswami</name><name sortKey="Nutman, Thomas B" sort="Nutman, Thomas B" uniqKey="Nutman T" first="Thomas B" last="Nutman">Thomas B. Nutman</name></noCountry><country name="États-Unis"><region name="Maryland"><name sortKey="Babu, Subash" sort="Babu, Subash" uniqKey="Babu S" first="Subash" last="Babu">Subash Babu</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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