Leishmania major induces the rapid production of interleukin-4 (IL-4) in both susceptible BALB/c ... more Leishmania major induces the rapid production of interleukin-4 (IL-4) in both susceptible BALB/c and resistant B10.D2 mice. In both strains, IL-4 is produced by T cells which react to the parasite LACK (for Leishmania homolog of the receptor for activated C kinase) antigen. The rapid production of IL-4 in B10.D2 mice does not confer susceptibility but results in increased parasite burdens.
Allergology International xxx (2015) 1e3 http://dx.Please cite this article in press as: Kanda A,... more Allergology International xxx (2015) 1e3 http://dx.Please cite this article in press as: Kanda A, et al., Th2-activated eosinophils release Th1 cytokines that modulate allergic inflammation, Allergology International (2015), http://dx.Please cite this article in press as: Kanda A, et al., Th2-activated eosinophils release Th1 cytokines that modulate allergic inflammation, Allergology International (2015), http://dx.
Atopic dermatitis (AD) is a chronic allergic dermatosis characterized by epidermal thickening and... more Atopic dermatitis (AD) is a chronic allergic dermatosis characterized by epidermal thickening and dermal inflammatory infiltrates with a dominant Th2 profile during the acute phase, whereas a Th1 profile is characteristic of the chronic stage. Among chemokines and chemokine receptors associated with inflammation, increased levels of CX3CL1 (fractalkine) and its unique receptor, CX3CR1, have been observed in human AD. We have thus investigated their role and mechanism of action in experimental models of AD and psoriasis. AD pathology and immune responses, but not psoriasis, were profoundly decreased in CX3CR1-deficient mice and upon blocking CX3CL1-CX3CR1 interactions in wild-type mice. CX3CR1 deficiency affected neither antigen presentation nor T cell proliferation in vivo upon skin sensitization, but CX3CR1 expression by both Th2 and Th1 cells was required to induce AD. Surprisingly, unlike in allergic asthma, where CX3CL1 and CX3CR1 regulate the pathology by controlling effector C...
The protein surface in , A through C, is colored according to the calculated electrostatic potent... more The protein surface in , A through C, is colored according to the calculated electrostatic potential due to full charges on the protein; red when it is less than -5.0 kcal(mol * e)-1 and blue when it exceeds 5.0 kcal(mol * e)-1, where e is the unit charge. 39. The DNA model proved straightforward to construct by making simple rotations and translations of the helical axes that enabled the 5' to 3' and 3' to 5' phosphate backbone strands of each duplex section to be joined to those of adjacent sections. The covalent bond distances and angles are those of standard B-DNA (55), except for the E and 4 torsion angles adopted by the single linking phosphate group at the 90°bend in each chain, which have values of 2760 and 2220, respectively. These torsion angles are stereochemically reasonable and compare with values for E of 1700 and for 4 of 2570 in straight standard B-DNA (55).
Infection of BALB/c mice with Leishmania major results in the rapid accumulation of IL-4 transcri... more Infection of BALB/c mice with Leishmania major results in the rapid accumulation of IL-4 transcripts within CD4 ؉ T cells that react to the parasite Leishmania homologue of mammalian RACK1 (LACK) Ag. Because memory/effector cells secrete IL-4 more rapidly than naive cells, we sought to analyze the phenotype of these lymphocytes before infection. Indeed, a fraction of LACKspecific CD4 ؉ T cells expressed a typical CD62 ligand low CD44 high CD45RB low phenotype in uninfected mice. LACK-specific T cells were primed in gut-associated lymphoid tissues by cross-reactive microbial Ags as demonstrated by their reactivity with bacterial extracts and by the ability of APCs from the mesenteric LN of BALB/c mice to induce their proliferation. Also, mice in which the digestive tract has been decontaminated exhibited a reduced proportion of LACK-specific T cells expressing a memory/effector phenotype and did not exhibit the early accumulation of IL-4 transcripts induced by L. major. Thus, LACK-specific T cells represent a subset of CD4 ؉ T cells which have acquired the ability to rapidly secrete IL-4 as the result of their priming by cross-reactive microbial Ags. Tracking the fate of these cells may provide information about the regulation of cell-mediated immune responses to gut Ags in physiological and pathological situations.
Resistance and susceptibility to Leishmania major in mice are determined by multiple genes and co... more Resistance and susceptibility to Leishmania major in mice are determined by multiple genes and correlate with the preferential development of Th1 and Th2 responses, respectively. Here, we found that CD11b ϩ dendritic cells (DCs) prime parasite-specific CD4 ϩ T cells in both susceptible BALB/c (H2-d) and resistant B10.D2 (H2-d) mice. However, BALB/c and B10.D2 DCs from L. major -infected mice differ in their ability to polarize naive T cells into Th1 or Th2 effector cells. This difference is cell-intrinsic, is not restricted to H2-d mice, and is observed with both parasite-specific and allospecific CD4 ϩ T cells. Thus, strain-specific differences within CD11b ϩ DCs influence the ability of inbred mice to mount polarized CD4 ϩ T cell responses.
Eosinophils are key players in T(H)2-driven pathologies, such as allergic lung inflammation. Afte... more Eosinophils are key players in T(H)2-driven pathologies, such as allergic lung inflammation. After IL-5- and eotaxin-mediated tissue recruitment, they release several cytotoxic and inflammatory mediators. However, their exact contribution to asthma remains controversial. Indeed, in human subjects anti-IL-5 treatment inhibits eosinophilia but not antigen-induced airway hyperresponsiveness (AHR). Likewise, lung fibrosis is abrogated in 2 strains of eosinophil-deficient mice, whereas AHR is inhibited in only one of them. Finally, eosinophils have been shown to attract T(H)2 lymphocytes at the inflammatory site. The ability of eosinophils to promote AHR and lung inflammation independently of lymphocytes was investigated. Adoptive transfers of resting or activated eosinophils from IL-5 transgenic mice were performed into naive BALB/c mice, mice with severe combined immunodeficiency, and IFN-gamma-deficient BALB/c recipients. Adoptively transferred eosinophils induced lung inflammation, fibrosis, collagen deposition, and AHR not only in BALB/c mice but also in recipient mice with severe combined immunodeficiency. Surprisingly, IFN-gamma expression was increased in lungs from eosinophil-transferred animals. Furthermore, IFN-gamma neutralization in recipients partially inhibited eosinophil-induced AHR. Moreover, IFN-gamma-deficient eosinophils or eosinophils treated with a blocking anti-IFN-gamma receptor antibody failed to induce AHR in IFN-gamma-deficient recipients. Finally, in vitro and at low concentrations, IFN-gamma increased eosinophil peroxidase release, potentiated chemotaxis, and prolonged survival, suggesting the existence of an autocrine mechanism. These results support the important and previously unsuspected contribution of eosinophils to lung inflammation independently of lymphocytes through production of IFN-gamma, the prototypical T(H)1 cytokine.
IgE and orchestrate the recruitment and activation of the primary effector cells, the mast cells,... more IgE and orchestrate the recruitment and activation of the primary effector cells, the mast cells, and eosinophils. Despite recent advances in understanding the pathology of asthma, little is known about the mechanisms leading to the chronicity of airway inflammation resulting
Recent reports have suggested that after infection of BALB/c mice with Leishmania major, CD4+ T c... more Recent reports have suggested that after infection of BALB/c mice with Leishmania major, CD4+ T cells responding to a single antigen, LACK (Leishmania homologue of receptors for activated C kinase), drive the differentiation of other responding T cells to the Th2 phenotype and so allow lesion development to occur. Transgenic mice expressing LACK in the thymus are tolerant to LACK and thus resolve infection with L. major. The oral administration of soluble protein to mice has been shown to result in the peripheral tolerance of antigen-specific CD4+ T cells. We therefore sought to tolerize LACK reactive T cells in non-transgenic BALB/c mice in order to determine the effectiveness of this tolerization approach as an alternative to standard vaccination protocols against L. major infection. Surprisingly, oral or nasal administration of up to 8 mg of recombinant LACK did not affect the outcome of infection. We therefore conjugated LACK to cholera toxin beta subunit (CTB-LACK) which has previously been shown to improve the effectiveness of oral tolerance to conjugated antigens. Nasal administration of as little as 12 microg of CTB-LACK effectively diminished the capacity of mice to mount a subsequent proliferative response to LACK and further delayed the onset of lesion development in infected mice. However, pretreatment with CTB-LACK did not prevent the eventual onset and progression of disease in these mice. An examination of cytokine responsiveness to LACK after tolerization with CTB-LACK revealed that while the Th1 response to LACK was suppressed, Th2 cytokine production was unaffected. Similar experiments using an ovalbumin-CTB conjugate suggested that this selective tolerance of Th1 cells was not specific to the LACK protein but may be an effect common to CTB-conjugated proteins.
Interleukin-33 (IL-33) is thought to be released during cellular death as an alarmin cytokine dur... more Interleukin-33 (IL-33) is thought to be released during cellular death as an alarmin cytokine during the acute phase of disease, but its regulation in vivo is poorly understood. We investigated the expression of IL-33 in two mouse models of acute hepatitis by administering either carbon tetrachloride (CCl 4 ) or concanavalin A (ConA). IL-33 was overexpressed in both models but with a stronger induction in ConA-induced hepatitis. IL-33 was weakly expressed in vascular and sinusoidal endothelial cells from normal liver and was clearly induced in CCl 4 -treated mice. Surprisingly, we found that hepatocytes strongly expressed IL-33 exclusively in the ConA model. CD1d knock-out mice, which are deficient in NKT cells and resistant to ConA-induced hepatitis, no longer expressed IL-33 in hepatocytes following ConA administration. Interestingly, invariant NKT (iNKT) cells adoptively transferred into ConA-treated CD1d KO mouse restored IL-33 expression in hepatocytes. This strongly suggests that NKT cells are responsible for the induction of IL-33 in hepatocytes.
... J. Immunol. 8/11. Muhammad I. Arshad 1 ,; Michel Rauch 1 ,; Annie L'Helgoualc&am... more ... J. Immunol. 8/11. Muhammad I. Arshad 1 ,; Michel Rauch 1 ,; Annie L'Helgoualc'h 1 ,; Valérie Julia 2 ,; Maria C. Leite-de-Moraes 3 ,; Catherine Lucas-Clerc 4 ,; Claire Piquet-Pellorce 1 ,; ... 3 CNRS UMR 8147, Hôpital Necker Enfants Malades, Université Paris Descartes, Paris, France ...
increased in SpA (22.6%) versus HC (13.6%) (P = 0.048). This was mainly in the naive (28.0% versu... more increased in SpA (22.6%) versus HC (13.6%) (P = 0.048). This was mainly in the naive (28.0% versus 12.8%, P = 0.009) and the IgD + /CD27-subset (18.4% versus 10.5%, P = 0.006). Expression of the costimulatory molecules CD80 and CD86 was lower in CD5 + versus CD5 − B cells both in SpA and HC (P b 0.05). Expression of CD69 was elevated in CD5 + versus CD5 − B cells both in SpA and in HC (P b 0.05). After T celldependent and -independent stimulation, CD5 + naive B cells downregulated CD80 expression (P b 0.05), whereas CD5 − B cells upregulated CD80 expression (P b 0.05). Conclusion: These data show an increase of CD5 + B cells in SpA, which could have an anergic phenotype. In mice, these cells reside in the peritoneum. Additional characterization of this cell population is interesting, since SpA is associated with inflammatory bowel disease in humans.
Leishmania major induces the rapid production of interleukin-4 (IL-4) in both susceptible BALB/c ... more Leishmania major induces the rapid production of interleukin-4 (IL-4) in both susceptible BALB/c and resistant B10.D2 mice. In both strains, IL-4 is produced by T cells which react to the parasite LACK (for Leishmania homolog of the receptor for activated C kinase) antigen. The rapid production of IL-4 in B10.D2 mice does not confer susceptibility but results in increased parasite burdens.
Allergology International xxx (2015) 1e3 http://dx.Please cite this article in press as: Kanda A,... more Allergology International xxx (2015) 1e3 http://dx.Please cite this article in press as: Kanda A, et al., Th2-activated eosinophils release Th1 cytokines that modulate allergic inflammation, Allergology International (2015), http://dx.Please cite this article in press as: Kanda A, et al., Th2-activated eosinophils release Th1 cytokines that modulate allergic inflammation, Allergology International (2015), http://dx.
Atopic dermatitis (AD) is a chronic allergic dermatosis characterized by epidermal thickening and... more Atopic dermatitis (AD) is a chronic allergic dermatosis characterized by epidermal thickening and dermal inflammatory infiltrates with a dominant Th2 profile during the acute phase, whereas a Th1 profile is characteristic of the chronic stage. Among chemokines and chemokine receptors associated with inflammation, increased levels of CX3CL1 (fractalkine) and its unique receptor, CX3CR1, have been observed in human AD. We have thus investigated their role and mechanism of action in experimental models of AD and psoriasis. AD pathology and immune responses, but not psoriasis, were profoundly decreased in CX3CR1-deficient mice and upon blocking CX3CL1-CX3CR1 interactions in wild-type mice. CX3CR1 deficiency affected neither antigen presentation nor T cell proliferation in vivo upon skin sensitization, but CX3CR1 expression by both Th2 and Th1 cells was required to induce AD. Surprisingly, unlike in allergic asthma, where CX3CL1 and CX3CR1 regulate the pathology by controlling effector C...
The protein surface in , A through C, is colored according to the calculated electrostatic potent... more The protein surface in , A through C, is colored according to the calculated electrostatic potential due to full charges on the protein; red when it is less than -5.0 kcal(mol * e)-1 and blue when it exceeds 5.0 kcal(mol * e)-1, where e is the unit charge. 39. The DNA model proved straightforward to construct by making simple rotations and translations of the helical axes that enabled the 5' to 3' and 3' to 5' phosphate backbone strands of each duplex section to be joined to those of adjacent sections. The covalent bond distances and angles are those of standard B-DNA (55), except for the E and 4 torsion angles adopted by the single linking phosphate group at the 90°bend in each chain, which have values of 2760 and 2220, respectively. These torsion angles are stereochemically reasonable and compare with values for E of 1700 and for 4 of 2570 in straight standard B-DNA (55).
Infection of BALB/c mice with Leishmania major results in the rapid accumulation of IL-4 transcri... more Infection of BALB/c mice with Leishmania major results in the rapid accumulation of IL-4 transcripts within CD4 ؉ T cells that react to the parasite Leishmania homologue of mammalian RACK1 (LACK) Ag. Because memory/effector cells secrete IL-4 more rapidly than naive cells, we sought to analyze the phenotype of these lymphocytes before infection. Indeed, a fraction of LACKspecific CD4 ؉ T cells expressed a typical CD62 ligand low CD44 high CD45RB low phenotype in uninfected mice. LACK-specific T cells were primed in gut-associated lymphoid tissues by cross-reactive microbial Ags as demonstrated by their reactivity with bacterial extracts and by the ability of APCs from the mesenteric LN of BALB/c mice to induce their proliferation. Also, mice in which the digestive tract has been decontaminated exhibited a reduced proportion of LACK-specific T cells expressing a memory/effector phenotype and did not exhibit the early accumulation of IL-4 transcripts induced by L. major. Thus, LACK-specific T cells represent a subset of CD4 ؉ T cells which have acquired the ability to rapidly secrete IL-4 as the result of their priming by cross-reactive microbial Ags. Tracking the fate of these cells may provide information about the regulation of cell-mediated immune responses to gut Ags in physiological and pathological situations.
Resistance and susceptibility to Leishmania major in mice are determined by multiple genes and co... more Resistance and susceptibility to Leishmania major in mice are determined by multiple genes and correlate with the preferential development of Th1 and Th2 responses, respectively. Here, we found that CD11b ϩ dendritic cells (DCs) prime parasite-specific CD4 ϩ T cells in both susceptible BALB/c (H2-d) and resistant B10.D2 (H2-d) mice. However, BALB/c and B10.D2 DCs from L. major -infected mice differ in their ability to polarize naive T cells into Th1 or Th2 effector cells. This difference is cell-intrinsic, is not restricted to H2-d mice, and is observed with both parasite-specific and allospecific CD4 ϩ T cells. Thus, strain-specific differences within CD11b ϩ DCs influence the ability of inbred mice to mount polarized CD4 ϩ T cell responses.
Eosinophils are key players in T(H)2-driven pathologies, such as allergic lung inflammation. Afte... more Eosinophils are key players in T(H)2-driven pathologies, such as allergic lung inflammation. After IL-5- and eotaxin-mediated tissue recruitment, they release several cytotoxic and inflammatory mediators. However, their exact contribution to asthma remains controversial. Indeed, in human subjects anti-IL-5 treatment inhibits eosinophilia but not antigen-induced airway hyperresponsiveness (AHR). Likewise, lung fibrosis is abrogated in 2 strains of eosinophil-deficient mice, whereas AHR is inhibited in only one of them. Finally, eosinophils have been shown to attract T(H)2 lymphocytes at the inflammatory site. The ability of eosinophils to promote AHR and lung inflammation independently of lymphocytes was investigated. Adoptive transfers of resting or activated eosinophils from IL-5 transgenic mice were performed into naive BALB/c mice, mice with severe combined immunodeficiency, and IFN-gamma-deficient BALB/c recipients. Adoptively transferred eosinophils induced lung inflammation, fibrosis, collagen deposition, and AHR not only in BALB/c mice but also in recipient mice with severe combined immunodeficiency. Surprisingly, IFN-gamma expression was increased in lungs from eosinophil-transferred animals. Furthermore, IFN-gamma neutralization in recipients partially inhibited eosinophil-induced AHR. Moreover, IFN-gamma-deficient eosinophils or eosinophils treated with a blocking anti-IFN-gamma receptor antibody failed to induce AHR in IFN-gamma-deficient recipients. Finally, in vitro and at low concentrations, IFN-gamma increased eosinophil peroxidase release, potentiated chemotaxis, and prolonged survival, suggesting the existence of an autocrine mechanism. These results support the important and previously unsuspected contribution of eosinophils to lung inflammation independently of lymphocytes through production of IFN-gamma, the prototypical T(H)1 cytokine.
IgE and orchestrate the recruitment and activation of the primary effector cells, the mast cells,... more IgE and orchestrate the recruitment and activation of the primary effector cells, the mast cells, and eosinophils. Despite recent advances in understanding the pathology of asthma, little is known about the mechanisms leading to the chronicity of airway inflammation resulting
Recent reports have suggested that after infection of BALB/c mice with Leishmania major, CD4+ T c... more Recent reports have suggested that after infection of BALB/c mice with Leishmania major, CD4+ T cells responding to a single antigen, LACK (Leishmania homologue of receptors for activated C kinase), drive the differentiation of other responding T cells to the Th2 phenotype and so allow lesion development to occur. Transgenic mice expressing LACK in the thymus are tolerant to LACK and thus resolve infection with L. major. The oral administration of soluble protein to mice has been shown to result in the peripheral tolerance of antigen-specific CD4+ T cells. We therefore sought to tolerize LACK reactive T cells in non-transgenic BALB/c mice in order to determine the effectiveness of this tolerization approach as an alternative to standard vaccination protocols against L. major infection. Surprisingly, oral or nasal administration of up to 8 mg of recombinant LACK did not affect the outcome of infection. We therefore conjugated LACK to cholera toxin beta subunit (CTB-LACK) which has previously been shown to improve the effectiveness of oral tolerance to conjugated antigens. Nasal administration of as little as 12 microg of CTB-LACK effectively diminished the capacity of mice to mount a subsequent proliferative response to LACK and further delayed the onset of lesion development in infected mice. However, pretreatment with CTB-LACK did not prevent the eventual onset and progression of disease in these mice. An examination of cytokine responsiveness to LACK after tolerization with CTB-LACK revealed that while the Th1 response to LACK was suppressed, Th2 cytokine production was unaffected. Similar experiments using an ovalbumin-CTB conjugate suggested that this selective tolerance of Th1 cells was not specific to the LACK protein but may be an effect common to CTB-conjugated proteins.
Interleukin-33 (IL-33) is thought to be released during cellular death as an alarmin cytokine dur... more Interleukin-33 (IL-33) is thought to be released during cellular death as an alarmin cytokine during the acute phase of disease, but its regulation in vivo is poorly understood. We investigated the expression of IL-33 in two mouse models of acute hepatitis by administering either carbon tetrachloride (CCl 4 ) or concanavalin A (ConA). IL-33 was overexpressed in both models but with a stronger induction in ConA-induced hepatitis. IL-33 was weakly expressed in vascular and sinusoidal endothelial cells from normal liver and was clearly induced in CCl 4 -treated mice. Surprisingly, we found that hepatocytes strongly expressed IL-33 exclusively in the ConA model. CD1d knock-out mice, which are deficient in NKT cells and resistant to ConA-induced hepatitis, no longer expressed IL-33 in hepatocytes following ConA administration. Interestingly, invariant NKT (iNKT) cells adoptively transferred into ConA-treated CD1d KO mouse restored IL-33 expression in hepatocytes. This strongly suggests that NKT cells are responsible for the induction of IL-33 in hepatocytes.
... J. Immunol. 8/11. Muhammad I. Arshad 1 ,; Michel Rauch 1 ,; Annie L'Helgoualc&am... more ... J. Immunol. 8/11. Muhammad I. Arshad 1 ,; Michel Rauch 1 ,; Annie L'Helgoualc'h 1 ,; Valérie Julia 2 ,; Maria C. Leite-de-Moraes 3 ,; Catherine Lucas-Clerc 4 ,; Claire Piquet-Pellorce 1 ,; ... 3 CNRS UMR 8147, Hôpital Necker Enfants Malades, Université Paris Descartes, Paris, France ...
increased in SpA (22.6%) versus HC (13.6%) (P = 0.048). This was mainly in the naive (28.0% versu... more increased in SpA (22.6%) versus HC (13.6%) (P = 0.048). This was mainly in the naive (28.0% versus 12.8%, P = 0.009) and the IgD + /CD27-subset (18.4% versus 10.5%, P = 0.006). Expression of the costimulatory molecules CD80 and CD86 was lower in CD5 + versus CD5 − B cells both in SpA and HC (P b 0.05). Expression of CD69 was elevated in CD5 + versus CD5 − B cells both in SpA and in HC (P b 0.05). After T celldependent and -independent stimulation, CD5 + naive B cells downregulated CD80 expression (P b 0.05), whereas CD5 − B cells upregulated CD80 expression (P b 0.05). Conclusion: These data show an increase of CD5 + B cells in SpA, which could have an anergic phenotype. In mice, these cells reside in the peritoneum. Additional characterization of this cell population is interesting, since SpA is associated with inflammatory bowel disease in humans.
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