The Experts below are selected from a list of 14163 Experts worldwide ranked by ideXlab platform
Shizuo Akira - One of the best experts on this subject based on the ideXlab platform.
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b cell intrinsic TLR7 signaling is essential for the development of spontaneous germinal centers
Journal of Immunology, 2014Co-Authors: Chetna Soni, Shizuo Akira, Eric B. Wong, Phillip P. Domeier, Tahsin N. Khan, Takashi Satoh, Zia Ur RahmanAbstract:Spontaneous germinal center (Spt-GC) B cells and follicular helper T cells generate high-affinity autoantibodies that are involved in the development of systemic lupus erythematosus. TLRs play a pivotal role in systemic lupus erythematosus pathogenesis. Although previous studies focused on the B cell-intrinsic role of TLR-MyD88 signaling on immune activation, autoantibody repertoire, and systemic inflammation, the mechanisms by which TLRs control the formation of Spt-GCs remain unclear. Using nonautoimmune C57BL/6 (B6) mice deficient in MyD88, TLR2, TLR3, TLR4, TLR7, or TLR9, we identified B cell-intrinsic TLR7 signaling as a prerequisite to Spt-GC formation without the confounding effects of autoimmune susceptibility genes and the overexpression of TLRs. TLR7 deficiency also rendered autoimmune B6.Sle1b mice unable to form Spt-GCs, leading to markedly decreased autoantibodies. Conversely, B6.yaa and B6.Sle1b.yaa mice expressing an extra copy of TLR7 and B6.Sle1b mice treated with a TLR7 agonist had increased Spt-GCs and follicular helper T cells. Further, TLR7/MyD88 deficiency led to compromised B cell proliferation and survival after B cell stimulation both in vitro and in vivo. In contrast, TLR9 inhibited Spt-GC development. Our findings demonstrate an absolute requirement for TLR7 and a negative regulatory function for TLR9 in Spt-GC formation under nonautoimmune and autoimmune conditions. Our data suggest that, under nonautoimmune conditions, Spt-GCs initiated by TLR7 produce protective Abs. However, in the presence of autoimmune susceptibility genes, TLR7-dependent Spt-GCs produce pathogenic autoantibodies. Thus, a single copy of TLR7 in B cells is the minimal requirement for breaking the GC-tolerance checkpoint.
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B Cell–Intrinsic TLR7 Signaling Is Essential for the Development of Spontaneous Germinal Centers
Journal of immunology (Baltimore Md. : 1950), 2014Co-Authors: Chetna Soni, Shizuo Akira, Eric B. Wong, Phillip P. Domeier, Tahsin N. Khan, Takashi Satoh, Zia Ur RahmanAbstract:Spontaneous germinal center (Spt-GC) B cells and follicular helper T cells generate high-affinity autoantibodies that are involved in the development of systemic lupus erythematosus. TLRs play a pivotal role in systemic lupus erythematosus pathogenesis. Although previous studies focused on the B cell-intrinsic role of TLR-MyD88 signaling on immune activation, autoantibody repertoire, and systemic inflammation, the mechanisms by which TLRs control the formation of Spt-GCs remain unclear. Using nonautoimmune C57BL/6 (B6) mice deficient in MyD88, TLR2, TLR3, TLR4, TLR7, or TLR9, we identified B cell-intrinsic TLR7 signaling as a prerequisite to Spt-GC formation without the confounding effects of autoimmune susceptibility genes and the overexpression of TLRs. TLR7 deficiency also rendered autoimmune B6.Sle1b mice unable to form Spt-GCs, leading to markedly decreased autoantibodies. Conversely, B6.yaa and B6.Sle1b.yaa mice expressing an extra copy of TLR7 and B6.Sle1b mice treated with a TLR7 agonist had increased Spt-GCs and follicular helper T cells. Further, TLR7/MyD88 deficiency led to compromised B cell proliferation and survival after B cell stimulation both in vitro and in vivo. In contrast, TLR9 inhibited Spt-GC development. Our findings demonstrate an absolute requirement for TLR7 and a negative regulatory function for TLR9 in Spt-GC formation under nonautoimmune and autoimmune conditions. Our data suggest that, under nonautoimmune conditions, Spt-GCs initiated by TLR7 produce protective Abs. However, in the presence of autoimmune susceptibility genes, TLR7-dependent Spt-GCs produce pathogenic autoantibodies. Thus, a single copy of TLR7 in B cells is the minimal requirement for breaking the GC-tolerance checkpoint.
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tlr2 engagement on cd8 t cells lowers the thresholdfor optimal antigen induced t cell activation
European Journal of Immunology, 2006Co-Authors: Anne Cottalorda, Shizuo Akira, Claire Verschelde, Antoine Marcais, Martine Tomkowiak, Philippe Musette, Satoshi Uematsu, Jacqueline Marvel, Nathalie BonnefoyberardAbstract:TLR have a crucial role in the detection of microbial infection in mammals. Until recently, most investigations on TLR have focused on cells of the innate immune system and on the role of TLR in the initiation of antigen-specific responses following recognition of microbial products by APC. Here, we report that murine T cells express TLR1, TLR2, TLR6, TLR7 and TLR9 mRNA. Using CD8 T cells from F5 TCR-transgenic mice, we demonstrate that the lipopeptide Pam3CysSK4 (Pam), a synthetic analog of bacterial and mycoplasmal lipoproteins that recognizes TLR1/2 complex, costimulates antigen-activated T cells. Costimulation with Pam permits an increased cell proliferation and survival associated with a sustained CD25 expression and an enhanced expression of Bcl-xL anti-apoptotic protein. In addition, we show that costimulation with Pam up-regulates IFN-γ production but also granzyme B secretion and cytotoxic activity of antigen-activated T cells, indicating that TLR2 engagement enhances the major effector functions of CD8 T cells. Finally, we demonstrate that TLR2 engagement on T cells lowers the activation threshold for costimulatory signals delivered by APC.
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toll like receptor expression in murine dc subsets lack of TLR7 expression by cd8α dc correlates with unresponsiveness to imidazoquinolines
European Journal of Immunology, 2003Co-Authors: Alexander D Edwards, Hideyuki Tomizawa, Sandra S Diebold, Emma Slack, Hiroaki Hemmi, Tsuneyasu Kaisho, Shizuo Akira, Caetano Reis E SousaAbstract:Toll-like receptors (TLR) recognize microbial and viral patterns and activate dendritic cells (DC). TLR distribution among human DC subsets is heterogeneous: plasmacytoid DC (PDC) express TLR1, 7 and 9, while other DC types do not express TLR9 but express other TLR. Here, we report that mRNA for most TLR is expressed at similar levels by murine splenic DC sub-types, including PDC, but that TLR3 is preferentially expressed by CD8α+ DC while TLR5 and TLR7 are selectively absent from the same subset. Consistent with the latter, TLR7 ligand activates CD8α– DC and PDC, but not CD8α+ DC as measured by survival ex vivo, up-regulation of surface markers and production of IL-12p40. These data suggest that the dichotomy in TLR expression between plasmacytoid and non-plasmacytoid DC is not conserved between species. However, lack of TLR7 expression could restrict the involvement of CD8α+ DC in recognition of certain mouse pathogens.
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Toll‐like receptor expression in murine DC subsets: lack of TLR7 expression by CD8α+ DC correlates with unresponsiveness to imidazoquinolines
European Journal of Immunology, 2003Co-Authors: Alexander D Edwards, Hideyuki Tomizawa, Sandra S Diebold, Emma Slack, Hiroaki Hemmi, Tsuneyasu Kaisho, Shizuo Akira, Caetano Reis E SousaAbstract:Toll-like receptors (TLR) recognize microbial and viral patterns and activate dendritic cells (DC). TLR distribution among human DC subsets is heterogeneous: plasmacytoid DC (PDC) express TLR1, 7 and 9, while other DC types do not express TLR9 but express other TLR. Here, we report that mRNA for most TLR is expressed at similar levels by murine splenic DC sub-types, including PDC, but that TLR3 is preferentially expressed by CD8α+ DC while TLR5 and TLR7 are selectively absent from the same subset. Consistent with the latter, TLR7 ligand activates CD8α– DC and PDC, but not CD8α+ DC as measured by survival ex vivo, up-regulation of surface markers and production of IL-12p40. These data suggest that the dichotomy in TLR expression between plasmacytoid and non-plasmacytoid DC is not conserved between species. However, lack of TLR7 expression could restrict the involvement of CD8α+ DC in recognition of certain mouse pathogens.
Maya Chrabieh - One of the best experts on this subject based on the ideXlab platform.
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inherited human irak 1 deficiency selectively impairs tlr signaling in fibroblasts
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Laura Israel, Erika Della Mina, Salim Bougarn, Ilaria Meloni, Alessandro Borghesi, Sabri Boughorbel, Hao Zhou, Maya ChrabiehAbstract:Most members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families transduce signals via a canonical pathway involving the MyD88 adapter and the interleukin-1 receptor-associated kinase (IRAK) complex. This complex contains four molecules, including at least two (IRAK-1 and IRAK-4) active kinases. In mice and humans, deficiencies of IRAK-4 or MyD88 abolish most TLR (except for TLR3 and some TLR4) and IL-1R signaling in both leukocytes and fibroblasts. TLR and IL-1R responses are weak but not abolished in mice lacking IRAK-1, whereas the role of IRAK-1 in humans remains unclear. We describe here a boy with X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1. Like many boys with MECP2 null mutations, this child died very early, at the age of 7 mo. Unlike most IRAK-4– or MyD88-deficient patients, he did not suffer from invasive bacterial diseases during his short life. The IRAK-1 protein was completely absent from the patient’s fibroblasts, which responded very poorly to all TLR2/6 (PAM2CSK4, LTA, FSL-1), TLR1/2 (PAM3CSK4), and TLR4 (LPS, MPLA) agonists tested but had almost unimpaired responses to IL-1β. By contrast, the patient’s peripheral blood mononuclear cells responded normally to all TLR1/2, TLR2/6, TLR4, TLR7, and TLR8 (R848) agonists tested, and to IL-1β. The death of this child precluded long-term evaluations of the clinical consequences of inherited IRAK-1 deficiency. However, these findings suggest that human IRAK-1 is essential downstream from TLRs but not IL-1Rs in fibroblasts, whereas it plays a redundant role downstream from both TLRs and IL-1Rs in leukocytes.
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igm igd cd27 b cells are markedly reduced in irak 4 myd88 and tirap but not unc 93b deficient patients
Blood, 2012Co-Authors: Sandra K. Weller, Mélanie Bonnet, Héloïse Delagreverie, Laura Israel, Maya Chrabieh, Chaim Roifman, Ben-zion Garty, Laszlo Marodi, Carlos Rodriguezgallego, Andrew C. IssekutzAbstract:We studied the distribution of peripheral B-cell subsets in patients deficient for key factors of the TLR-signaling pathways (MyD88, TIRAP/MAL, IL-1 receptor–associated kinase 4 [IRAK-4], TLR3, UNC-93B, TRIF). All TLRs, except TLR3, which signals through the TRIF adaptor, require MyD88 and IRAK-4 to mediate their function. TLR4 and the TLR2 heterodimers (with TLR1, TLR6, and possibly TLR10) require in addition the adaptor TIRAP, whereas UNC-93B is needed for the proper localization of intracellular TLR3, TLR7, TLR8, and TLR9. We found that IgM+IgD+CD27+ but not switched B cells were strongly reduced in MyD88-, IRAK-4-, and TIRAP-deficient patients. This defect did not appear to be compensated with age. However, somatic hypermutation of Ig genes and heavy-chain CDR3 size distribution of IgM+IgD+CD27+ B cells were not affected in these patients. In contrast, the numbers of IgM+IgD+CD27+ B cells were normal in the absence of TLR3, TRIF, and UNC-93B, suggesting that UNC-93B–dependent TLRs, and notably TLR9, are dispensable for the presence of this subset in peripheral blood. Interestingly, TLR10 was found to be expressed at greater levels in IgM+IgD+CD27+ compared with switched B cells in healthy patients. Hence, we propose a role for TIRAP-dependent TLRs, possibly TLR10 in particular, in the development and/or maintenance of IgM+IgD+CD27+ B cells in humans.
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IgM+IgD+CD27+ B cells are markedly reduced in IRAK-4-, MyD88- and TIRAP- but not UNC-93B-deficient patients
Blood, 2012Co-Authors: Sandra K. Weller, Mélanie Bonnet, Héloïse Delagreverie, Laura Israel, Maya Chrabieh, Chaim Roifman, Ben-zion Garty, Carlos Rodríguez-gallego, Laszlo Marodi, Andrew C. IssekutzAbstract:We studied the distribution of peripheral B-cell subsets in patients deficient for key factors of the TLR-signaling pathways (MyD88, TIRAP/MAL, IL-1 receptor–associated kinase 4 [IRAK-4], TLR3, UNC-93B, TRIF). All TLRs, except TLR3, which signals through the TRIF adaptor, require MyD88 and IRAK-4 to mediate their function. TLR4 and the TLR2 heterodimers (with TLR1, TLR6, and possibly TLR10) require in addition the adaptor TIRAP, whereas UNC-93B is needed for the proper localization of intracellular TLR3, TLR7, TLR8, and TLR9. We found that IgM+IgD+CD27+ but not switched B cells were strongly reduced in MyD88-, IRAK-4-, and TIRAP-deficient patients. This defect did not appear to be compensated with age. However, somatic hypermutation of Ig genes and heavy-chain CDR3 size distribution of IgM+IgD+CD27+ B cells were not affected in these patients. In contrast, the numbers of IgM+IgD+CD27+ B cells were normal in the absence of TLR3, TRIF, and UNC-93B, suggesting that UNC-93B–dependent TLRs, and notably TLR9, are dispensable for the presence of this subset in peripheral blood. Interestingly, TLR10 was found to be expressed at greater levels in IgM+IgD+CD27+ compared with switched B cells in healthy patients. Hence, we propose a role for TIRAP-dependent TLRs, possibly TLR10 in particular, in the development and/or maintenance of IgM+IgD+CD27+ B cells in humans.
Laura Israel - One of the best experts on this subject based on the ideXlab platform.
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inherited human irak 1 deficiency selectively impairs tlr signaling in fibroblasts
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Laura Israel, Erika Della Mina, Salim Bougarn, Ilaria Meloni, Alessandro Borghesi, Sabri Boughorbel, Hao Zhou, Maya ChrabiehAbstract:Most members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families transduce signals via a canonical pathway involving the MyD88 adapter and the interleukin-1 receptor-associated kinase (IRAK) complex. This complex contains four molecules, including at least two (IRAK-1 and IRAK-4) active kinases. In mice and humans, deficiencies of IRAK-4 or MyD88 abolish most TLR (except for TLR3 and some TLR4) and IL-1R signaling in both leukocytes and fibroblasts. TLR and IL-1R responses are weak but not abolished in mice lacking IRAK-1, whereas the role of IRAK-1 in humans remains unclear. We describe here a boy with X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1. Like many boys with MECP2 null mutations, this child died very early, at the age of 7 mo. Unlike most IRAK-4– or MyD88-deficient patients, he did not suffer from invasive bacterial diseases during his short life. The IRAK-1 protein was completely absent from the patient’s fibroblasts, which responded very poorly to all TLR2/6 (PAM2CSK4, LTA, FSL-1), TLR1/2 (PAM3CSK4), and TLR4 (LPS, MPLA) agonists tested but had almost unimpaired responses to IL-1β. By contrast, the patient’s peripheral blood mononuclear cells responded normally to all TLR1/2, TLR2/6, TLR4, TLR7, and TLR8 (R848) agonists tested, and to IL-1β. The death of this child precluded long-term evaluations of the clinical consequences of inherited IRAK-1 deficiency. However, these findings suggest that human IRAK-1 is essential downstream from TLRs but not IL-1Rs in fibroblasts, whereas it plays a redundant role downstream from both TLRs and IL-1Rs in leukocytes.
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igm igd cd27 b cells are markedly reduced in irak 4 myd88 and tirap but not unc 93b deficient patients
Blood, 2012Co-Authors: Sandra K. Weller, Mélanie Bonnet, Héloïse Delagreverie, Laura Israel, Maya Chrabieh, Chaim Roifman, Ben-zion Garty, Laszlo Marodi, Carlos Rodriguezgallego, Andrew C. IssekutzAbstract:We studied the distribution of peripheral B-cell subsets in patients deficient for key factors of the TLR-signaling pathways (MyD88, TIRAP/MAL, IL-1 receptor–associated kinase 4 [IRAK-4], TLR3, UNC-93B, TRIF). All TLRs, except TLR3, which signals through the TRIF adaptor, require MyD88 and IRAK-4 to mediate their function. TLR4 and the TLR2 heterodimers (with TLR1, TLR6, and possibly TLR10) require in addition the adaptor TIRAP, whereas UNC-93B is needed for the proper localization of intracellular TLR3, TLR7, TLR8, and TLR9. We found that IgM+IgD+CD27+ but not switched B cells were strongly reduced in MyD88-, IRAK-4-, and TIRAP-deficient patients. This defect did not appear to be compensated with age. However, somatic hypermutation of Ig genes and heavy-chain CDR3 size distribution of IgM+IgD+CD27+ B cells were not affected in these patients. In contrast, the numbers of IgM+IgD+CD27+ B cells were normal in the absence of TLR3, TRIF, and UNC-93B, suggesting that UNC-93B–dependent TLRs, and notably TLR9, are dispensable for the presence of this subset in peripheral blood. Interestingly, TLR10 was found to be expressed at greater levels in IgM+IgD+CD27+ compared with switched B cells in healthy patients. Hence, we propose a role for TIRAP-dependent TLRs, possibly TLR10 in particular, in the development and/or maintenance of IgM+IgD+CD27+ B cells in humans.
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IgM+IgD+CD27+ B cells are markedly reduced in IRAK-4-, MyD88- and TIRAP- but not UNC-93B-deficient patients
Blood, 2012Co-Authors: Sandra K. Weller, Mélanie Bonnet, Héloïse Delagreverie, Laura Israel, Maya Chrabieh, Chaim Roifman, Ben-zion Garty, Carlos Rodríguez-gallego, Laszlo Marodi, Andrew C. IssekutzAbstract:We studied the distribution of peripheral B-cell subsets in patients deficient for key factors of the TLR-signaling pathways (MyD88, TIRAP/MAL, IL-1 receptor–associated kinase 4 [IRAK-4], TLR3, UNC-93B, TRIF). All TLRs, except TLR3, which signals through the TRIF adaptor, require MyD88 and IRAK-4 to mediate their function. TLR4 and the TLR2 heterodimers (with TLR1, TLR6, and possibly TLR10) require in addition the adaptor TIRAP, whereas UNC-93B is needed for the proper localization of intracellular TLR3, TLR7, TLR8, and TLR9. We found that IgM+IgD+CD27+ but not switched B cells were strongly reduced in MyD88-, IRAK-4-, and TIRAP-deficient patients. This defect did not appear to be compensated with age. However, somatic hypermutation of Ig genes and heavy-chain CDR3 size distribution of IgM+IgD+CD27+ B cells were not affected in these patients. In contrast, the numbers of IgM+IgD+CD27+ B cells were normal in the absence of TLR3, TRIF, and UNC-93B, suggesting that UNC-93B–dependent TLRs, and notably TLR9, are dispensable for the presence of this subset in peripheral blood. Interestingly, TLR10 was found to be expressed at greater levels in IgM+IgD+CD27+ compared with switched B cells in healthy patients. Hence, we propose a role for TIRAP-dependent TLRs, possibly TLR10 in particular, in the development and/or maintenance of IgM+IgD+CD27+ B cells in humans.
Christian Fehrmann - One of the best experts on this subject based on the ideXlab platform.
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toll like receptor expression profile of human stem progenitor cells form the apical papilla
Journal of Endodontics, 2020Co-Authors: Christian Fehrmann, Christof E. Dörfer, Karim Fawzy M ElsayedAbstract:Abstract Introduction Stem/progenitor cells from the apical papilla (SCAPs) demonstrate remarkable regenerative and immunomodulatory properties. During their regenerative events, SCAPs, similar to other stem/progenitor cells, could interact with their local inflammatory microenvironment via their expressed toll-like receptors (TLRs). The present study aimed to describe for the first time the unique TLR expression profile of SCAPs. Methods Cells were isolated from the apical papilla of extracted wisdom teeth (n = 8), STRO-1 immunomagnetically sorted, and cultured to obtain single colony-forming units. The expression of CD14, 34, 45, 73, 90, and 105 were characterized on the SCAPs, and their multilineage differentiation potential was examined to prove their multipotent aptitude. After their incubation in basic or inflammatory medium (25 ng/mL interleukin 1 beta, 103 U/mL interferon gamma, 50 ng/mL tumor necrosis factor alpha, and 3 × 103 U/mL interferon alpha), a TLR expression profile for SCAPs under uninflamed as well as inflamed conditions was respectively generated. Results SCAPs demonstrated all predefined stem/progenitor cell characteristics. In basic medium, SCAPs expressed TLRs 1–10. The inflammatory microenvironment up-regulated the expression of TLR1, TLR2, TLR4, TLR5, TLR6, and TLR9 and down-regulated the expression of TLR3, TLR7, TLR8, and TLR10 in SCAPs under the inflamed condition. Conclusions The present study defines for the first time a distinctive TLR expression profile for SCAPs under uninflamed and inflamed conditions. This profile could greatly impact SCAP responsiveness to their inflammatory microenvironmental agents under regenerative conditions in vivo.
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Toll-like Receptor Expression Profile of Human Stem/Progenitor Cells Form the Apical Papilla.
Journal of Endodontics, 2020Co-Authors: Christian Fehrmann, Christof E. Dörfer, Karim M. Fawzy El-sayedAbstract:Abstract Introduction Stem/progenitor cells from the apical papilla (SCAPs) demonstrate remarkable regenerative and immunomodulatory properties. During their regenerative events, SCAPs, similar to other stem/progenitor cells, could interact with their local inflammatory microenvironment via their expressed toll-like receptors (TLRs). The present study aimed to describe for the first time the unique TLR expression profile of SCAPs. Methods Cells were isolated from the apical papilla of extracted wisdom teeth (n = 8), STRO-1 immunomagnetically sorted, and cultured to obtain single colony-forming units. The expression of CD14, 34, 45, 73, 90, and 105 were characterized on the SCAPs, and their multilineage differentiation potential was examined to prove their multipotent aptitude. After their incubation in basic or inflammatory medium (25 ng/mL interleukin 1 beta, 103 U/mL interferon gamma, 50 ng/mL tumor necrosis factor alpha, and 3 × 103 U/mL interferon alpha), a TLR expression profile for SCAPs under uninflamed as well as inflamed conditions was respectively generated. Results SCAPs demonstrated all predefined stem/progenitor cell characteristics. In basic medium, SCAPs expressed TLRs 1–10. The inflammatory microenvironment up-regulated the expression of TLR1, TLR2, TLR4, TLR5, TLR6, and TLR9 and down-regulated the expression of TLR3, TLR7, TLR8, and TLR10 in SCAPs under the inflamed condition. Conclusions The present study defines for the first time a distinctive TLR expression profile for SCAPs under uninflamed and inflamed conditions. This profile could greatly impact SCAP responsiveness to their inflammatory microenvironmental agents under regenerative conditions in vivo.
Andrew C. Issekutz - One of the best experts on this subject based on the ideXlab platform.
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igm igd cd27 b cells are markedly reduced in irak 4 myd88 and tirap but not unc 93b deficient patients
Blood, 2012Co-Authors: Sandra K. Weller, Mélanie Bonnet, Héloïse Delagreverie, Laura Israel, Maya Chrabieh, Chaim Roifman, Ben-zion Garty, Laszlo Marodi, Carlos Rodriguezgallego, Andrew C. IssekutzAbstract:We studied the distribution of peripheral B-cell subsets in patients deficient for key factors of the TLR-signaling pathways (MyD88, TIRAP/MAL, IL-1 receptor–associated kinase 4 [IRAK-4], TLR3, UNC-93B, TRIF). All TLRs, except TLR3, which signals through the TRIF adaptor, require MyD88 and IRAK-4 to mediate their function. TLR4 and the TLR2 heterodimers (with TLR1, TLR6, and possibly TLR10) require in addition the adaptor TIRAP, whereas UNC-93B is needed for the proper localization of intracellular TLR3, TLR7, TLR8, and TLR9. We found that IgM+IgD+CD27+ but not switched B cells were strongly reduced in MyD88-, IRAK-4-, and TIRAP-deficient patients. This defect did not appear to be compensated with age. However, somatic hypermutation of Ig genes and heavy-chain CDR3 size distribution of IgM+IgD+CD27+ B cells were not affected in these patients. In contrast, the numbers of IgM+IgD+CD27+ B cells were normal in the absence of TLR3, TRIF, and UNC-93B, suggesting that UNC-93B–dependent TLRs, and notably TLR9, are dispensable for the presence of this subset in peripheral blood. Interestingly, TLR10 was found to be expressed at greater levels in IgM+IgD+CD27+ compared with switched B cells in healthy patients. Hence, we propose a role for TIRAP-dependent TLRs, possibly TLR10 in particular, in the development and/or maintenance of IgM+IgD+CD27+ B cells in humans.
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IgM+IgD+CD27+ B cells are markedly reduced in IRAK-4-, MyD88- and TIRAP- but not UNC-93B-deficient patients
Blood, 2012Co-Authors: Sandra K. Weller, Mélanie Bonnet, Héloïse Delagreverie, Laura Israel, Maya Chrabieh, Chaim Roifman, Ben-zion Garty, Carlos Rodríguez-gallego, Laszlo Marodi, Andrew C. IssekutzAbstract:We studied the distribution of peripheral B-cell subsets in patients deficient for key factors of the TLR-signaling pathways (MyD88, TIRAP/MAL, IL-1 receptor–associated kinase 4 [IRAK-4], TLR3, UNC-93B, TRIF). All TLRs, except TLR3, which signals through the TRIF adaptor, require MyD88 and IRAK-4 to mediate their function. TLR4 and the TLR2 heterodimers (with TLR1, TLR6, and possibly TLR10) require in addition the adaptor TIRAP, whereas UNC-93B is needed for the proper localization of intracellular TLR3, TLR7, TLR8, and TLR9. We found that IgM+IgD+CD27+ but not switched B cells were strongly reduced in MyD88-, IRAK-4-, and TIRAP-deficient patients. This defect did not appear to be compensated with age. However, somatic hypermutation of Ig genes and heavy-chain CDR3 size distribution of IgM+IgD+CD27+ B cells were not affected in these patients. In contrast, the numbers of IgM+IgD+CD27+ B cells were normal in the absence of TLR3, TRIF, and UNC-93B, suggesting that UNC-93B–dependent TLRs, and notably TLR9, are dispensable for the presence of this subset in peripheral blood. Interestingly, TLR10 was found to be expressed at greater levels in IgM+IgD+CD27+ compared with switched B cells in healthy patients. Hence, we propose a role for TIRAP-dependent TLRs, possibly TLR10 in particular, in the development and/or maintenance of IgM+IgD+CD27+ B cells in humans.
