Publications
2018
Sawaf Matthieu, Fauny Jean-Daniel, Felten Renaud, Sagez Flora, Gottenberg Jacques-Eric, Dumortier Hélène, Monneaux Fanny
Defective BTLA functionality is rescued by restoring lipid metabolism in lupus CD4+ Ŧ cells Journal Article
In: JCI insight, vol. 3, no. 13, 2018, ISSN: 2379-3708.
Abstract | Links | BibTeX | Tags: 80 and over, Adolescent, Adult, Aged, Autoimmune Diseases, Autoimmunity, CD4-Positive T-Lymphocytes, Cell Proliferation, CTLA-4 Antigen, Dumortier, Female, France, Humans, I2CT, Imagerie, Immunologic, Immunology, Lipid Metabolism, lupus, Lupus Erythematosus, Lymphocyte Activation, Male, Middle Aged, Monneaux, Programmed Cell Death 1 Receptor, Receptors, Signal Transduction, Systemic, Team-Dumortier, Young Adult
@article{sawaf_defective_2018,
title = {Defective BTLA functionality is rescued by restoring lipid metabolism in lupus CD4+ Ŧ cells},
author = {Matthieu Sawaf and Jean-Daniel Fauny and Renaud Felten and Flora Sagez and Jacques-Eric Gottenberg and Hélène Dumortier and Fanny Monneaux},
doi = {10.1172/jci.insight.99711},
issn = {2379-3708},
year = {2018},
date = {2018-01-01},
journal = {JCI insight},
volume = {3},
number = {13},
abstract = {Coinhibitory receptors play an important role in the prevention of autoimmune diseases, such as systemic lupus erythematosus (SLE), by limiting T cell activation. B and T lymphocyte attenuator (BTLA) is an inhibitory receptor, similar to cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD1), that negatively regulates the immune response. The role of BTLA in the pathogenesis of autoimmune diseases in humans and, more specifically, in SLE is largely unknown. We investigated BTLA expression on various T cell subsets, and we did not observe significant variations of BTLA expression between lupus patients and healthy controls. However, the enhancement of BTLA expression after activation was significantly lower in SLE patients compared with that in healthy controls. Furthermore, we found an impaired capacity of BTLA to inhibit T cell activation in SLE due to a poor BTLA recruitment to the immunological synapse following T cell stimulation. Finally, we demonstrated that defective BTLA function can be corrected by restoring intracellular trafficking and by normalizing the lipid metabolism in lupus CD4+ T cells. Collectively, our results evidence that the BTLA signaling pathway is altered in SLE T cells and highlight the potential of targeting this pathway for the development of new therapeutic strategies in lupus.},
keywords = {80 and over, Adolescent, Adult, Aged, Autoimmune Diseases, Autoimmunity, CD4-Positive T-Lymphocytes, Cell Proliferation, CTLA-4 Antigen, Dumortier, Female, France, Humans, I2CT, Imagerie, Immunologic, Immunology, Lipid Metabolism, lupus, Lupus Erythematosus, Lymphocyte Activation, Male, Middle Aged, Monneaux, Programmed Cell Death 1 Receptor, Receptors, Signal Transduction, Systemic, Team-Dumortier, Young Adult},
pubstate = {published},
tppubtype = {article}
}
2016
Sawaf Matthieu, Dumortier Hélène, Monneaux Fanny
Follicular Helper Ŧ Cells in Systemic Lupus Erythematosus: Why Should They Be Considered as Interesting Therapeutic Targets? Journal Article
In: Journal of Immunology Research, vol. 2016, pp. 5767106, 2016, ISSN: 2314-7156.
Abstract | Links | BibTeX | Tags: Adult, Autoantibodies, B-Lymphocytes, Cell Differentiation, Dumortier, Germinal Center, Helper-Inducer, Humans, I2CT, Lupus Erythematosus, Molecular Targeted Therapy, Monneaux, Plasma Cells, Systemic, T-Lymphocytes, Team-Dumortier
@article{sawaf_follicular_2016,
title = {Follicular Helper Ŧ Cells in Systemic Lupus Erythematosus: Why Should They Be Considered as Interesting Therapeutic Targets?},
author = {Matthieu Sawaf and Hélène Dumortier and Fanny Monneaux},
doi = {10.1155/2016/5767106},
issn = {2314-7156},
year = {2016},
date = {2016-01-01},
journal = {Journal of Immunology Research},
volume = {2016},
pages = {5767106},
abstract = {Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by B cell hyperactivity leading to the production of autoantibodies, some of which having a deleterious effect. Reducing autoantibody production thus represents a way of controlling lupus pathogenesis, and a better understanding of the molecular and cellular factors involved in the differentiation of B cells into plasma cells could allow identifying new therapeutic targets. Follicular helper T cells (TFH) represent a distinct subset of CD4(+) T cells specialized in providing help to B cells. They are required for the formation of germinal centers and the generation of long-lived serological memory and, as such, are suspected to play a central role in SLE. Recent advances in the field of TFH biology have allowed the identification of important molecular factors involved in TFH differentiation, regulation, and function. Interestingly, some of these TFH-related molecules have been described to be dysregulated in lupus patients. In the present review, we give an overview of the aberrant expression and/or function of such key players in lupus, and we highlight their potential as therapeutic targets.},
keywords = {Adult, Autoantibodies, B-Lymphocytes, Cell Differentiation, Dumortier, Germinal Center, Helper-Inducer, Humans, I2CT, Lupus Erythematosus, Molecular Targeted Therapy, Monneaux, Plasma Cells, Systemic, T-Lymphocytes, Team-Dumortier},
pubstate = {published},
tppubtype = {article}
}
2013
Coz Carole Le, Joublin Aurélie, Pasquali Jean-Louis, Korganow Anne-Sophie, Dumortier Hélène, Monneaux Fanny
Circulating TFH subset distribution is strongly affected in lupus patients with an active disease Journal Article
In: PloS One, vol. 8, no. 9, pp. e75319, 2013, ISSN: 1932-6203.
Abstract | Links | BibTeX | Tags: Adult, Aged, B-Lymphocytes, Case-Control Studies, CD4 Lymphocyte Count, CD5 Antigens, CXCR5, Cytokines, Dumortier, Female, Flow Cytometry, Helper-Inducer, Humans, I2CT, Immunoglobulin E, Immunologic Memory, Immunophenotyping, Interleukin-21, Lupus Erythematosus, Male, Middle Aged, Monneaux, Phenotype, Receptors, Systemic, T-Lymphocytes, Team-Dumortier, Th2 Cells, Young Adult
@article{le_coz_circulating_2013,
title = {Circulating TFH subset distribution is strongly affected in lupus patients with an active disease},
author = {Carole Le Coz and Aurélie Joublin and Jean-Louis Pasquali and Anne-Sophie Korganow and Hélène Dumortier and Fanny Monneaux},
doi = {10.1371/journal.pone.0075319},
issn = {1932-6203},
year = {2013},
date = {2013-01-01},
journal = {PloS One},
volume = {8},
number = {9},
pages = {e75319},
abstract = {Follicular helper T cells (TFH) represent a distinct subset of CD4(+) T cells specialized in providing help to B lymphocytes, which may play a central role in autoimmune diseases having a major B cell component such as systemic lupus erythematosus. Recently, TFH subsets that share common phenotypic and functional characteristics with TFH cells from germinal centers, have been described in the peripheral blood from healthy individuals. The aim of this study was to analyze the distribution of such populations in lupus patients. Circulating TFH cell subsets were defined by multicolor flow cytometry as TFH17 (CXCR3(-)CCR6(+)), TFH1 (CXCR3 (+) CCR6(-)) or TFH2 (CXCR3(-)CCR6(-)) cells among CXCR5 (+) CD45RA(-)CD4(+) T cells in the peripheral blood of 23 SLE patients and 23 sex and age-matched healthy controls. IL-21 receptor expression by B cells was analyzed by flow cytometry and the serum levels of IL-21 and Igs were determined by ELISA tests. We found that the TFH2 cell subset frequency is strongly and significantly increased in lupus patients with an active disease (SLEDAI scoretextgreater8), while the TFH1 cell subset percentage is greatly decreased. The TFH2 and TFH1 cell subset frequency alteration is associated with the presence of high Ig levels and autoantibodies in patient's sera. Moreover, the TFH2 cell subset enhancement correlates with an increased frequency of double negative memory B cells (CD27(-)IgD(-)CD19(+) cells) expressing the IL-21R. Finally, we found that IgE levels in lupus patients' sera correlate with disease activity and seem to be associated with high TFH2 cell subset frequency. In conclusion, our study describes for the first time the distribution of circulating TFH cell subsets in lupus patients. Interestingly, we found an increased frequency of TFH2 cells, which correlates with disease activity. Our results suggest that this subset might play a key role in lupus pathogenesis.},
keywords = {Adult, Aged, B-Lymphocytes, Case-Control Studies, CD4 Lymphocyte Count, CD5 Antigens, CXCR5, Cytokines, Dumortier, Female, Flow Cytometry, Helper-Inducer, Humans, I2CT, Immunoglobulin E, Immunologic Memory, Immunophenotyping, Interleukin-21, Lupus Erythematosus, Male, Middle Aged, Monneaux, Phenotype, Receptors, Systemic, T-Lymphocytes, Team-Dumortier, Th2 Cells, Young Adult},
pubstate = {published},
tppubtype = {article}
}
2012
Thomann Jean-Sébastien, Monneaux Fanny, Creusat Gaëlle, Spanedda Maria Vittoria, Heurtault Béatrice, Habermacher Chloé, Schuber Francis, Bourel-Bonnet Line, Frisch Benoît
Novel glycolipid TLR2 ligands of the type Pam2Cys-α-Gal: synthesis and biological properties Journal Article
In: European Journal of Medicinal Chemistry, vol. 51, pp. 174–183, 2012, ISSN: 1768-3254.
Abstract | Links | BibTeX | Tags: Adjuvants, Animals, Cell Line, Chemistry Techniques, Female, Galactose, Glycolipids, Humans, I2CT, Immunologic, ligands, Mice, Monneaux, Structure-Activity Relationship, Synthetic, Team-Dumortier, Toll-Like Receptor 2
@article{thomann_novel_2012,
title = {Novel glycolipid TLR2 ligands of the type Pam2Cys-α-Gal: synthesis and biological properties},
author = {Jean-Sébastien Thomann and Fanny Monneaux and Gaëlle Creusat and Maria Vittoria Spanedda and Béatrice Heurtault and Chloé Habermacher and Francis Schuber and Line Bourel-Bonnet and Benoît Frisch},
doi = {10.1016/j.ejmech.2012.02.039},
issn = {1768-3254},
year = {2012},
date = {2012-05-01},
journal = {European Journal of Medicinal Chemistry},
volume = {51},
pages = {174--183},
abstract = {A more complete understanding of the mechanism of action of TLR agonists has fueled the investigation of new synthetic immunoadjuvants. In this context, we designed and synthesized glycolipids of the type Pam(2)Cys-α-Galactose as novel immunoadjuvants. Their synthesis required modifying a hydrophobic tBoc-[2,3-bispalmitoyloxy-(2R)-propyl]-R-cysteinyl moiety, i.e. the minimal structure required for TLR2 agonist activity, by addition of a hydrophilic head, either an α-Galactosylpyranose or an α-Galactosylfuranose to gain respectively Pam(2)CGalp and Pam(2)CGalf. While preparing a carbohydrate building block, an unexpected stereoselectivity was observed during a halide ion-catalytic process on a protected galactofuranose: the alpha anomer was obtained with surprisingly high selectivity (α/β ratiotextgreater9) and with good isolated yield (51%). The TLR2 binding properties of Pam(2)CGalp and Pam(2)CGalf were then fully evaluated. Their efficiency in triggering the proliferation of BALB/c mouse splenocytes was also compared to that of Pam(2)CAG and Pam(3)CAG, two well-established ligands of TLRs. Moreover, the maturation state of murine dendritic cells previously incubated with either Pam(2)CGalp or Pam(2)CGalf was monitored by flow cytometry and compared to that induced by lipopolysaccharide. Pam(2)CGalp and Pam(2)CGalf were found to be equivalent TLR2 agonists, and induced splenocyte proliferation and DC maturation. With very similar activity, Pam(2)CGalp and Pam(2)CGalf were also 10-fold to 100-fold better than Pam(2)CAG and Pam(3)CAG at inducing B cell proliferation. This represents the first time a glucidic head has been added to the tBoc-[2,3-bispalmitoyloxy-(2R)-propyl]-R-cysteinyl moiety whilst maintaining the immunomodulating activity. This should greatly enrich the data available on Pam(2)C structure/activity relationships.},
keywords = {Adjuvants, Animals, Cell Line, Chemistry Techniques, Female, Galactose, Glycolipids, Humans, I2CT, Immunologic, ligands, Mice, Monneaux, Structure-Activity Relationship, Synthetic, Team-Dumortier, Toll-Like Receptor 2},
pubstate = {published},
tppubtype = {article}
}
Keravis Thérèse, Monneaux Fanny, Yougbaré Issaka, Gazi Lucien, Bourguignon Jean-Jacques, Muller Sylviane, Lugnier Claire
Disease progression in MRL/lpr lupus-prone mice is reduced by NCS 613, a specific cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitor Journal Article
In: PloS One, vol. 7, no. 1, pp. e28899, 2012, ISSN: 1932-6203.
Abstract | Links | BibTeX | Tags: Adenine, Animals, Cyclic AMP, Cyclic Nucleotide Phosphodiesterases, Disease Progression, Female, Humans, I2CT, Inbred CBA, Inbred MRL lpr, Isoenzymes, Kidney, Lipopolysaccharides, Lupus Erythematosus, Mice, Monneaux, Pentoxifylline, Phosphodiesterase 4 Inhibitors, Proteinuria, Survival Rate, Systemic, Team-Dumortier, Tumor Necrosis Factor-alpha, Type 4, Xanthines
@article{keravis_disease_2012,
title = {Disease progression in MRL/lpr lupus-prone mice is reduced by NCS 613, a specific cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitor},
author = {Thérèse Keravis and Fanny Monneaux and Issaka Yougbaré and Lucien Gazi and Jean-Jacques Bourguignon and Sylviane Muller and Claire Lugnier},
doi = {10.1371/journal.pone.0028899},
issn = {1932-6203},
year = {2012},
date = {2012-01-01},
journal = {PloS One},
volume = {7},
number = {1},
pages = {e28899},
abstract = {Systemic lupus erythematosus is a polymorphic and multigenic inflammatory autoimmune disease. Cyclic AMP (cAMP) modulates inflammation and the inhibition of cyclic nucleotide phosphodiesterase type 4 (PDE4), which specifically hydrolyzes cAMP, inhibits TNFα secretion. This study was aimed at investigating the evolution of PDE activity and expression levels during the course of the disease in MRL/lpr lupus-prone mice, and to evaluate in these mice the biological and clinical effects of treatments with pentoxifylline, denbufylline and NCS 613 PDE inhibitors. This study reveals that compared to CBA/J control mice, kidney PDE4 activity of MRL/lpr mice increases with the disease progression. Furthermore, it showed that the most potent and selective PDE4 inhibitor NCS 613 is also the most effective molecule in decreasing proteinuria and increasing survival rate of MRL/lpr mice. NCS 613 is a potent inhibitor, which is more selective for the PDE4C subtype (IC₅₀= 1.4 nM) than the other subtypes (PDE4A, IC₅₀= 44 nM; PDE4B, IC₅₀= 48 nM; and PDE4D, IC₅₀= 14 nM). Interestingly, its affinity for the High Affinity Rolipram Binding Site is relatively low (K(i) = 148 nM) in comparison to rolipram (K(i) = 3 nM). Finally, as also observed using MRL/lpr peripheral blood lymphocytes (PBLs), NCS 613 inhibits basal and LPS-induced TNFα secretion from PBLs of lupus patients, suggesting a therapeutic potential of NCS 613 in systemic lupus. This study reveals that PDE4 represent a potential therapeutic target in lupus disease.},
keywords = {Adenine, Animals, Cyclic AMP, Cyclic Nucleotide Phosphodiesterases, Disease Progression, Female, Humans, I2CT, Inbred CBA, Inbred MRL lpr, Isoenzymes, Kidney, Lipopolysaccharides, Lupus Erythematosus, Mice, Monneaux, Pentoxifylline, Phosphodiesterase 4 Inhibitors, Proteinuria, Survival Rate, Systemic, Team-Dumortier, Tumor Necrosis Factor-alpha, Type 4, Xanthines},
pubstate = {published},
tppubtype = {article}
}
2011
Banchet-Cadeddu Aline, Martinez Agathe, Guillarme Stéphane, Parietti Véronique, Monneaux Fanny, Hénon Eric, Renault Jean-Hugues, Nuzillard Jean-Marc, Haudrechy Arnaud
Use of the NEO strategy (Nucleophilic addition/Epoxide Opening) for the synthesis of a new C-galactoside ester analogue of KRN 7000 Journal Article
In: Bioorganic & Medicinal Chemistry Letters, vol. 21, no. 8, pp. 2510–2514, 2011, ISSN: 1464-3405.
Abstract | Links | BibTeX | Tags: Animals, Cell Proliferation, Cells, Cultured, Esters, Galactosides, Galactosylceramides, Glycolipids, I2CT, Interferon-gamma, Interleukin-4, Mice, Monneaux, Team-Dumortier
@article{banchet-cadeddu_use_2011,
title = {Use of the NEO strategy (Nucleophilic addition/Epoxide Opening) for the synthesis of a new C-galactoside ester analogue of KRN 7000},
author = {Aline Banchet-Cadeddu and Agathe Martinez and Stéphane Guillarme and Véronique Parietti and Fanny Monneaux and Eric Hénon and Jean-Hugues Renault and Jean-Marc Nuzillard and Arnaud Haudrechy},
doi = {10.1016/j.bmcl.2011.02.044},
issn = {1464-3405},
year = {2011},
date = {2011-04-01},
journal = {Bioorganic & Medicinal Chemistry Letters},
volume = {21},
number = {8},
pages = {2510--2514},
abstract = {Our goal in the search for potentially bioactive analogues of KRN 7000 was to design an easy synthetic approach to a library of analogues using a strategy recently developed in our laboratory based on a Nucleophilic addition followed by an Epoxide Opening (the NEO strategy). Through the use of a common pivotal structure, a new C-galactoside ester analogue (23) was synthesized which showed an encouraging T(H)2 biased response during preliminary biological tests.},
keywords = {Animals, Cell Proliferation, Cells, Cultured, Esters, Galactosides, Galactosylceramides, Glycolipids, I2CT, Interferon-gamma, Interleukin-4, Mice, Monneaux, Team-Dumortier},
pubstate = {published},
tppubtype = {article}
}
Banchet-Cadeddu Aline, Hénon Eric, Dauchez Manuel, Renault Jean-Hugues, Monneaux Fanny, Haudrechy Arnaud
The stimulating adventure of KRN 7000 Journal Article
In: Organic & Biomolecular Chemistry, vol. 9, no. 9, pp. 3080–3104, 2011, ISSN: 1477-0539.
Abstract | Links | BibTeX | Tags: Adjuvants, Animals, Antigen, Antigens, CD1d, Galactosylceramides, Helper-Inducer, Humans, I2CT, Immunologic, Monneaux, Receptors, T-Cell, T-Lymphocytes, Team-Dumortier
@article{banchet-cadeddu_stimulating_2011,
title = {The stimulating adventure of KRN 7000},
author = {Aline Banchet-Cadeddu and Eric Hénon and Manuel Dauchez and Jean-Hugues Renault and Fanny Monneaux and Arnaud Haudrechy},
doi = {10.1039/c0ob00975j},
issn = {1477-0539},
year = {2011},
date = {2011-01-01},
journal = {Organic & Biomolecular Chemistry},
volume = {9},
number = {9},
pages = {3080--3104},
abstract = {Associated with the CD1d protein, KRN 7000, a potent synthetic α-galactosylceramide, is known to activate the invariant NKT immune cells. This stimulation then leads to the production of different cytokines modulating a T(H)1/T(H)2 immune response balance involved in protection against several pathologies such as autoimmune diseases and cancers. Various efforts have been made toward the synthesis of simple and more functionalized analogues in order to selectively induce T(H)1 or T(H)2-type cytokine production. Since the discovery of KRN 7000, structure-activity relationships, crystallographic and modelling studies have pointed to the potential of several GalCer analogues in term of selective bioactivity, and have highlighted interesting elements in order to better understand the recognition and activation mechanisms of immune iNKT cells. By presenting an up-to-date library of analogues, collecting recent breakthroughs done in crystallography and molecular modelling, and relating them to the available biological results, we hope that this review will highlight and help the scientific community in their KRN research.},
keywords = {Adjuvants, Animals, Antigen, Antigens, CD1d, Galactosylceramides, Helper-Inducer, Humans, I2CT, Immunologic, Monneaux, Receptors, T-Cell, T-Lymphocytes, Team-Dumortier},
pubstate = {published},
tppubtype = {article}
}
2010
Parietti Véronique, Chifflot Hélène, Sibilia Jean, Muller Sylviane, Monneaux Fanny
Rituximab treatment overcomes reduction of regulatory iNKT cells in patients with rheumatoid arthritis Journal Article
In: Clinical Immunology (Orlando, Fla.), vol. 134, no. 3, pp. 331–339, 2010, ISSN: 1521-7035.
Abstract | Links | BibTeX | Tags: Adult, Age Factors, Aged, Antibodies, Antirheumatic Agents, arthritis, Female, Flow Cytometry, Humans, I2CT, Longitudinal Studies, Male, Middle Aged, Monneaux, Monoclonal, Murine-Derived, Natural Killer T-Cells, Nonparametric, rheumatoid, Rituximab, Sex Factors, Statistics, Team-Dumortier, Young Adult
@article{parietti_rituximab_2010,
title = {Rituximab treatment overcomes reduction of regulatory iNKT cells in patients with rheumatoid arthritis},
author = {Véronique Parietti and Hélène Chifflot and Jean Sibilia and Sylviane Muller and Fanny Monneaux},
doi = {10.1016/j.clim.2009.11.007},
issn = {1521-7035},
year = {2010},
date = {2010-01-01},
journal = {Clinical Immunology (Orlando, Fla.)},
volume = {134},
number = {3},
pages = {331--339},
abstract = {Invariant natural killer T (iNKT) cells are a subset of T cells that recognize glycolipid antigens presented by the CD1d molecule. Accumulating evidences showed that iNKT cells are implicated in the regulatory mechanisms that control autoimmunity. We evaluated the number of circulating iNKT cells in patients with rheumatoid arthritis (RA) by flow cytometry and performed a longitudinal analysis of iNKT cell frequency in RA patients who were given an anti-CD20 therapy. Significantly lower iNKT cell numbers were measured in the blood from RA patients compared to healthy individuals (ptextless0.0001) and low iNKT cell frequencies were rather associated with an active disease. In RA patients who received rituximab treatment, iNKT cell number was increased in relation to the clinical outcome. We demonstrated that the number of iNKT cells is altered in RA patients and that following rituximab therapy, clinical remission of RA is associated with an increase of iNKT cell frequency.},
keywords = {Adult, Age Factors, Aged, Antibodies, Antirheumatic Agents, arthritis, Female, Flow Cytometry, Humans, I2CT, Longitudinal Studies, Male, Middle Aged, Monneaux, Monoclonal, Murine-Derived, Natural Killer T-Cells, Nonparametric, rheumatoid, Rituximab, Sex Factors, Statistics, Team-Dumortier, Young Adult},
pubstate = {published},
tppubtype = {article}
}
2009
Chamouard Patrick, Monneaux Fanny, Richert Zoe, Voegeli Anne-Claire, Lavaux Thomas, Gaub Marie Pierre, Baumann René, Oudet Pierre, Muller Sylviane
Diminution of Circulating CD4+CD25 high Ŧ cells in naïve Crohn's disease Journal Article
In: Digestive Diseases and Sciences, vol. 54, no. 10, pp. 2084–2093, 2009, ISSN: 1573-2568.
Abstract | Links | BibTeX | Tags: Adult, Aged, Blood Cell Count, CD4 Antigens, Colitis, Crohn Disease, Female, Flow Cytometry, Humans, I2CT, Interleukin-2 Receptor alpha Subunit, Lymphocyte Subsets, Male, Middle Aged, Monneaux, Regulatory, T-Lymphocytes, Team-Dumortier, Ulcerative
@article{chamouard_diminution_2009,
title = {Diminution of Circulating CD4+CD25 high Ŧ cells in naïve Crohn's disease},
author = {Patrick Chamouard and Fanny Monneaux and Zoe Richert and Anne-Claire Voegeli and Thomas Lavaux and Marie Pierre Gaub and René Baumann and Pierre Oudet and Sylviane Muller},
doi = {10.1007/s10620-008-0590-6},
issn = {1573-2568},
year = {2009},
date = {2009-10-01},
journal = {Digestive Diseases and Sciences},
volume = {54},
number = {10},
pages = {2084--2093},
abstract = {Crohn's disease is considered to be caused either by an excess of T-cell effector functions and/or by a defective regulatory T-cell compartment. The aim of this study was to assess in Crohn's disease the frequency of circulating CD4(+)CD25(high) T cells that possess regulatory T-cell functions and CD4(+)CD25(low) T cells that contain activated T cells. Flow cytometry of peripheral blood was used to assess CD4(+)CD25(high) and CD4(+)CD25(low) T-cell frequencies in a cohort of 66 patients with Crohn's disease in comparison to 19 patients with ulcerative colitis and 31 healthy individuals enrolled as controls. The CD4(+)CD25(high) T-cell frequency was significantly lowered in naïve Crohn's disease (P = 0.013) and in ulcerative colitis (P = 0.001). CD4(+)CD25(low) T-cell frequency was increased in Crohn's disease (P = 0.0001) and in ulcerative colitis (P = 0.0002). Both CD4(+)CD25(high) and CD4(+)CD25(low) T-cell frequencies are altered in naïve Crohn's disease resulting in an imbalance between both populations and a relative contraction of the CD4(+)CD25(high) T-cell population.},
keywords = {Adult, Aged, Blood Cell Count, CD4 Antigens, Colitis, Crohn Disease, Female, Flow Cytometry, Humans, I2CT, Interleukin-2 Receptor alpha Subunit, Lymphocyte Subsets, Male, Middle Aged, Monneaux, Regulatory, T-Lymphocytes, Team-Dumortier, Ulcerative},
pubstate = {published},
tppubtype = {article}
}
Monneaux Fanny, Muller Sylviane
Molecular therapies for systemic lupus erythematosus: clinical trials and future prospects Journal Article
In: Arthritis Research & Therapy, vol. 11, no. 3, pp. 234, 2009, ISSN: 1478-6362.
Abstract | Links | BibTeX | Tags: Animals, Clinical Trials as Topic, Forecasting, Genetic Therapy, Humans, I2CT, Lupus Erythematosus, Monneaux, Systemic, Team-Dumortier
@article{monneaux_molecular_2009,
title = {Molecular therapies for systemic lupus erythematosus: clinical trials and future prospects},
author = {Fanny Monneaux and Sylviane Muller},
doi = {10.1186/ar2711},
issn = {1478-6362},
year = {2009},
date = {2009-01-01},
journal = {Arthritis Research & Therapy},
volume = {11},
number = {3},
pages = {234},
abstract = {The prognosis of patients with systemic lupus erythematosus has greatly improved since treatment regimens combining corticosteroids and immunosuppressive medications have been widely adopted in therapeutic strategies given to these patients. Immune suppression is evidently efficient but also leads to higher susceptibility to infectious and malignant diseases. Toxic effects and sometimes unexpectedly dramatic complications of current therapies have been progressively reported. Identifying novel molecular targets therefore remains an important issue in the treatment of lupus. The aim of this review article is to highlight emerging pharmacological options and new therapeutic avenues for lupus with a particular focus on non-antibody molecular strategies.},
keywords = {Animals, Clinical Trials as Topic, Forecasting, Genetic Therapy, Humans, I2CT, Lupus Erythematosus, Monneaux, Systemic, Team-Dumortier},
pubstate = {published},
tppubtype = {article}
}
2008
Parietti Véronique, Monneaux Fanny, Décossas Marion, Muller Sylviane
Function of CD4+,CD25+ Treg cells in MRL/lpr mice is compromised by intrinsic defects in antigen-presenting cells and effector Ŧ cells Journal Article
In: Arthritis and Rheumatism, vol. 58, no. 6, pp. 1751–1761, 2008, ISSN: 0004-3591.
Abstract | Links | BibTeX | Tags: Animal, Animals, Antigen-Presenting Cells, Antigens, B7-1 Antigen, B7-2 Antigen, CD, Cell Communication, Cells, Coculture Techniques, CTLA-4 Antigen, Cultured, Disease Models, Female, I2CT, Interleukin-1, Interleukin-2 Receptor alpha Subunit, Lupus Erythematosus, Mice, Monneaux, Regulatory, Systemic, T-Lymphocyte Subsets, T-Lymphocytes, Team-Dumortier
@article{parietti_function_2008,
title = {Function of CD4+,CD25+ Treg cells in MRL/lpr mice is compromised by intrinsic defects in antigen-presenting cells and effector Ŧ cells},
author = {Véronique Parietti and Fanny Monneaux and Marion Décossas and Sylviane Muller},
doi = {10.1002/art.23464},
issn = {0004-3591},
year = {2008},
date = {2008-06-01},
journal = {Arthritis and Rheumatism},
volume = {58},
number = {6},
pages = {1751--1761},
abstract = {OBJECTIVE: Naturally occurring CD4+,CD25+ Treg cells are central in the maintenance of peripheral tolerance. Impaired activity and/or a lower frequency of these cells is involved in the emergence of autoimmunity. We undertook this study to analyze relative proportions and functional alterations of Treg cells in MRL/lpr mice.
METHODS: The frequency of CD4+,CD25+ T cells in the peripheral blood of healthy and autoimmune mice was compared by flow cytometry. The capacity of CD4+,CD25+ T cells to inhibit the proliferation and cytokine secretion of CD4+,CD25- T cells was assessed after polyclonal activation.
RESULTS: MRL/lpr mice exhibited a normal percentage of CD4+,CD25 high T cells, and forkhead box P3 messenger RNA and protein expression in Treg cells was not altered. However, MRL/lpr Treg cells displayed a reduced capacity to suppress proliferation and to inhibit interferon-gamma secretion by syngeneic effector CD4+,CD25- T cells, as compared with syngeneic cocultures of CBA/J T cells. Moreover, effector MRL/lpr CD4+,CD25- T cells were substantially less susceptible to suppression even when cultured with CBA/J or MRL/lpr Treg cells. Crossover experiments led us to conclude that in MRL/lpr mice, each partner engaged in T cell regulation displays altered functions. Molecules involved in suppressive mechanisms (CTLA-4 and CD80/CD86) are underexpressed, and antigen-presenting cells (APCs) produce raised levels of interleukin-6, which is known to abrogate suppression.
CONCLUSION: Our results suggest that although the frequency and phenotype of Treg cells in MRL/lpr mice are similar to those in normal mice, Treg cells in MRL/lpr mice are not properly stimulated by APCs and are unable to suppress proinflammatory cytokine secretion from effector T cells.},
keywords = {Animal, Animals, Antigen-Presenting Cells, Antigens, B7-1 Antigen, B7-2 Antigen, CD, Cell Communication, Cells, Coculture Techniques, CTLA-4 Antigen, Cultured, Disease Models, Female, I2CT, Interleukin-1, Interleukin-2 Receptor alpha Subunit, Lupus Erythematosus, Mice, Monneaux, Regulatory, Systemic, T-Lymphocyte Subsets, T-Lymphocytes, Team-Dumortier},
pubstate = {published},
tppubtype = {article}
}
METHODS: The frequency of CD4+,CD25+ T cells in the peripheral blood of healthy and autoimmune mice was compared by flow cytometry. The capacity of CD4+,CD25+ T cells to inhibit the proliferation and cytokine secretion of CD4+,CD25- T cells was assessed after polyclonal activation.
RESULTS: MRL/lpr mice exhibited a normal percentage of CD4+,CD25 high T cells, and forkhead box P3 messenger RNA and protein expression in Treg cells was not altered. However, MRL/lpr Treg cells displayed a reduced capacity to suppress proliferation and to inhibit interferon-gamma secretion by syngeneic effector CD4+,CD25- T cells, as compared with syngeneic cocultures of CBA/J T cells. Moreover, effector MRL/lpr CD4+,CD25- T cells were substantially less susceptible to suppression even when cultured with CBA/J or MRL/lpr Treg cells. Crossover experiments led us to conclude that in MRL/lpr mice, each partner engaged in T cell regulation displays altered functions. Molecules involved in suppressive mechanisms (CTLA-4 and CD80/CD86) are underexpressed, and antigen-presenting cells (APCs) produce raised levels of interleukin-6, which is known to abrogate suppression.
CONCLUSION: Our results suggest that although the frequency and phenotype of Treg cells in MRL/lpr mice are similar to those in normal mice, Treg cells in MRL/lpr mice are not properly stimulated by APCs and are unable to suppress proinflammatory cytokine secretion from effector T cells.
Muller Sylviane, Monneaux Fanny, Schall Nicolas, Rashkov Rasho K, Oparanov Boycho A, Wiesel Philippe, Geiger Jean-Marie, Zimmer Robert
Spliceosomal peptide P140 for immunotherapy of systemic lupus erythematosus: results of an early phase II clinical trial Journal Article
In: Arthritis and Rheumatism, vol. 58, no. 12, pp. 3873–3883, 2008, ISSN: 0004-3591.
Abstract | Links | BibTeX | Tags: Adolescent, Adult, Aged, Antibodies, Antinuclear, C-Reactive Protein, DNA, Female, Humans, I2CT, Immunotherapy, Lupus Erythematosus, Male, Middle Aged, Monneaux, Peptide Fragments, Peptides, Severity of Illness Index, Spliceosomes, Systemic, Team-Dumortier, Treatment Outcome, Young Adult
@article{muller_spliceosomal_2008,
title = {Spliceosomal peptide P140 for immunotherapy of systemic lupus erythematosus: results of an early phase II clinical trial},
author = {Sylviane Muller and Fanny Monneaux and Nicolas Schall and Rasho K Rashkov and Boycho A Oparanov and Philippe Wiesel and Jean-Marie Geiger and Robert Zimmer},
doi = {10.1002/art.24027},
issn = {0004-3591},
year = {2008},
date = {2008-01-01},
journal = {Arthritis and Rheumatism},
volume = {58},
number = {12},
pages = {3873--3883},
abstract = {OBJECTIVE: To assess the safety, tolerability, and efficacy of spliceosomal peptide P140 (IPP-201101; sequence 131-151 of the U1-70K protein phosphorylated at Ser140), which is recognized by lupus CD4+ T cells, in the treatment of patients with systemic lupus erythematosus (SLE).
METHODS: An open-label, dose-escalation phase II study was conducted in two centers in Bulgaria. Twenty patients (2 male and 18 female) with moderately active SLE received 3 subcutaneous (SC) administrations of a clinical batch of P140 peptide at 2-week intervals. Clinical evaluation was performed using approved scales. A panel of autoantibodies, including antinuclear antibodies, antibodies to extractable nuclear antigens (U1 RNP, SmD1, Ro/SSA, La/SSB), and antibodies to double-stranded DNA (anti-dsDNA), chromatin, cardiolipin, and peptides of the U1-70K protein, was tested by enzyme-linked immunosorbent assay (ELISA). The plasma levels of C-reactive protein, total Ig, IgG, IgG subclasses, IgM, IgA, and IgE, and of the cytokines interleukin-2 and tumor necrosis factor alpha were measured by ELISA and nephelometry.
RESULTS: IgG anti-dsDNA antibody levels decreased by at least 20% in 7 of 10 patients who received 3 x 200 microg IPP-201101 (group 1), but only in 1 patient in the group receiving 3 x 1,000 microg IPP-201101 (group 2). Physician's global assessment of disease activity scores and scores on the SLE Disease Activity Index were significantly decreased in group 1. The changes occurred progressively in the population of responders, increased in magnitude during the treatment period, and were sustained. No clinical or biologic adverse effects were observed in the individuals, except for some local irritation at the highest concentration.
CONCLUSION: IPP-201101 was found to be safe and well tolerated by subjects. Three SC doses of IPP-201101 at 200 microg significantly improved the clinical and biologic status of lupus patients.},
keywords = {Adolescent, Adult, Aged, Antibodies, Antinuclear, C-Reactive Protein, DNA, Female, Humans, I2CT, Immunotherapy, Lupus Erythematosus, Male, Middle Aged, Monneaux, Peptide Fragments, Peptides, Severity of Illness Index, Spliceosomes, Systemic, Team-Dumortier, Treatment Outcome, Young Adult},
pubstate = {published},
tppubtype = {article}
}
METHODS: An open-label, dose-escalation phase II study was conducted in two centers in Bulgaria. Twenty patients (2 male and 18 female) with moderately active SLE received 3 subcutaneous (SC) administrations of a clinical batch of P140 peptide at 2-week intervals. Clinical evaluation was performed using approved scales. A panel of autoantibodies, including antinuclear antibodies, antibodies to extractable nuclear antigens (U1 RNP, SmD1, Ro/SSA, La/SSB), and antibodies to double-stranded DNA (anti-dsDNA), chromatin, cardiolipin, and peptides of the U1-70K protein, was tested by enzyme-linked immunosorbent assay (ELISA). The plasma levels of C-reactive protein, total Ig, IgG, IgG subclasses, IgM, IgA, and IgE, and of the cytokines interleukin-2 and tumor necrosis factor alpha were measured by ELISA and nephelometry.
RESULTS: IgG anti-dsDNA antibody levels decreased by at least 20% in 7 of 10 patients who received 3 x 200 microg IPP-201101 (group 1), but only in 1 patient in the group receiving 3 x 1,000 microg IPP-201101 (group 2). Physician's global assessment of disease activity scores and scores on the SLE Disease Activity Index were significantly decreased in group 1. The changes occurred progressively in the population of responders, increased in magnitude during the treatment period, and were sustained. No clinical or biologic adverse effects were observed in the individuals, except for some local irritation at the highest concentration.
CONCLUSION: IPP-201101 was found to be safe and well tolerated by subjects. Three SC doses of IPP-201101 at 200 microg significantly improved the clinical and biologic status of lupus patients.
Dieker J, Cisterna B, Monneaux F, Decossas M, van der Vlag J, Biggiogera M, Muller S
Apoptosis-linked changes in the phosphorylation status and subcellular localization of the spliceosomal autoantigen U1-70K Journal Article
In: Cell Death and Differentiation, vol. 15, no. 4, pp. 793–804, 2008, ISSN: 1350-9047.
Abstract | Links | BibTeX | Tags: Apoptosis, Autoantigens, Autoimmunity, Caspase 3, Chromatin, HeLa Cells, Humans, I2CT, Jurkat Cells, Lupus Erythematosus, Monneaux, Phosphorylation, Post-Translational, Protein Phosphatase 1, Protein Processing, Protein Transport, Recombinant Proteins, Ribonucleoprotein, RNA Splicing, Serine, Spliceosomes, Systemic, Team-Dumortier, Time Factors, U1 Small Nuclear
@article{dieker_apoptosis-linked_2008,
title = {Apoptosis-linked changes in the phosphorylation status and subcellular localization of the spliceosomal autoantigen U1-70K},
author = {J Dieker and B Cisterna and F Monneaux and M Decossas and J van der Vlag and M Biggiogera and S Muller},
doi = {10.1038/sj.cdd.4402312},
issn = {1350-9047},
year = {2008},
date = {2008-01-01},
journal = {Cell Death and Differentiation},
volume = {15},
number = {4},
pages = {793--804},
abstract = {Apoptosis consists of highly regulated pathways involving post-translational modifications and cleavage of proteins leading to sequential inactivation of the main cellular processes. Here, we focused on the apoptotic processing of one of the essential components of the mRNA splicing machinery, the U1-70K snRNP protein. We found that at an early stage of apoptosis, before the cleavage of the C-terminal part of the protein by caspase-3, the basal phosphorylation of the Ser140 residue located within the RNA recognition motif, increases very significantly. A caspase-dependent, PP1-mediated dephosphorylation of other serine residues takes place in a subset of U1-70K proteins. The U1-70K protein phosphorylated at Ser140 is clustered in heterogeneous ectopic RNP-derived structures, which are finally extruded in apoptotic bodies. The elaborate processing of the spliceosomal U1-70K protein we identified might play an important role in the regulated breakdown of the mRNA splicing machinery during early apoptosis. In addition, these specific changes in the phosphorylation/dephosphorylation balance and the subcellular localization of the U1-70K protein might explain why the region encompassing the Ser140 residue becomes a central autoantigen during the autoimmune disease systemic lupus erythematosus.},
keywords = {Apoptosis, Autoantigens, Autoimmunity, Caspase 3, Chromatin, HeLa Cells, Humans, I2CT, Jurkat Cells, Lupus Erythematosus, Monneaux, Phosphorylation, Post-Translational, Protein Phosphatase 1, Protein Processing, Protein Transport, Recombinant Proteins, Ribonucleoprotein, RNA Splicing, Serine, Spliceosomes, Systemic, Team-Dumortier, Time Factors, U1 Small Nuclear},
pubstate = {published},
tppubtype = {article}
}
2007
Monneaux Fanny, Muller Sylviane
Peptide-based therapy in lupus: promising data Journal Article
In: Advances in Experimental Medicine and Biology, vol. 601, pp. 105–112, 2007, ISSN: 0065-2598.
Abstract | Links | BibTeX | Tags: Adrenal Cortex Hormones, Animals, Autoantigens, Autoimmune Diseases, Cyclophosphamide, Epitopes, Humans, I2CT, Immune System, Immunosuppressive Agents, inflammation, Lupus Erythematosus, Monneaux, Peptides, Systemic, T-Lymphocytes, Team-Dumortier
@article{monneaux_peptide-based_2007,
title = {Peptide-based therapy in lupus: promising data},
author = {Fanny Monneaux and Sylviane Muller},
doi = {10.1007/978-0-387-72005-0_11},
issn = {0065-2598},
year = {2007},
date = {2007-01-01},
journal = {Advances in Experimental Medicine and Biology},
volume = {601},
pages = {105--112},
abstract = {Systemic lupus erythematosus (SLE) is a multisystem chronic inflammatory disease of multifactorial aetiology, characterized by inflammation and damage of various tissues and organs. Current treatments of the disease are mainly based on immunosuppressive drugs such as corticosteroids and cyclophosphamide. Although these treatments have reduced mortality and morbidity, they cause a non-specific immune suppression. To avoid these side effects, our efforts should focus on the development of alternative therapeutic strategies, which consist, for example in specific T cell targeting using autoantigen-derived peptides identified as sequences encompassing major epitopes.},
keywords = {Adrenal Cortex Hormones, Animals, Autoantigens, Autoimmune Diseases, Cyclophosphamide, Epitopes, Humans, I2CT, Immune System, Immunosuppressive Agents, inflammation, Lupus Erythematosus, Monneaux, Peptides, Systemic, T-Lymphocytes, Team-Dumortier},
pubstate = {published},
tppubtype = {article}
}
Parietti Véronique, Chifflot Hélène, Muller Sylviane, Monneaux Fanny
Regulatory Ŧ cells and systemic lupus erythematosus Journal Article
In: Annals of the New York Academy of Sciences, vol. 1108, pp. 64–75, 2007, ISSN: 0077-8923.
Abstract | Links | BibTeX | Tags: Animals, Autoimmunity, Humans, I2CT, Immune Tolerance, Lupus Erythematosus, Monneaux, Regulatory, Systemic, T-Lymphocyte Subsets, T-Lymphocytes, Team-Dumortier
@article{parietti_regulatory_2007,
title = {Regulatory Ŧ cells and systemic lupus erythematosus},
author = {Véronique Parietti and Hélène Chifflot and Sylviane Muller and Fanny Monneaux},
doi = {10.1196/annals.1422.007},
issn = {0077-8923},
year = {2007},
date = {2007-01-01},
journal = {Annals of the New York Academy of Sciences},
volume = {1108},
pages = {64--75},
abstract = {Regulatory T cells, especially CD4+CD25+ T cells, "natural killer" T cells and gammadelta T cells, are central in the maintenance of peripheral tolerance and the protection from the development of autoimmune diseases. Numerical or functional modifications of these cell populations were demonstrated to lead to the breakdown of tolerance and the emergence of autoimmunity. Involvement of regulatory T cells in the pathogenesis of systemic autoimmune diseases, such as systemic lupus erythematosus, might be of first importance. In murine models and patients with lupus, these regulatory T cells seem to be reduced in number. Functional deficiencies have also been described in a few studies. A better knowledge of regulatory T cell functional properties in systemic autoimmune diseases is essential to manipulate these cells and hopefully to restore immune tolerance.},
keywords = {Animals, Autoimmunity, Humans, I2CT, Immune Tolerance, Lupus Erythematosus, Monneaux, Regulatory, Systemic, T-Lymphocyte Subsets, T-Lymphocytes, Team-Dumortier},
pubstate = {published},
tppubtype = {article}
}
Monneaux F, Muller S
[The spliceosome and its interest for lupus therapy] Journal Article
In: La Revue De Medecine Interne, vol. 28, no. 10, pp. 725–728, 2007, ISSN: 0248-8663.
Abstract | Links | BibTeX | Tags: Amino Acid Motifs, Animals, Antibodies, CD4-Positive T-Lymphocytes, Conserved Sequence, DNA, Epitopes, Haplotypes, Humans, I2CT, Immune Tolerance, Inbred MRL lpr, Inbred NZB, Lupus Erythematosus, Mice, Monneaux, Phosphoserine, Protein, Recombinant, Ribonucleoprotein, Sequence Analysis, Serine, Spliceosomes, Systemic, Team-Dumortier, U1 Small Nuclear
@article{monneaux_spliceosome_2007,
title = {[The spliceosome and its interest for lupus therapy]},
author = {F Monneaux and S Muller},
doi = {10.1016/j.revmed.2007.05.003},
issn = {0248-8663},
year = {2007},
date = {2007-01-01},
journal = {La Revue De Medecine Interne},
volume = {28},
number = {10},
pages = {725--728},
abstract = {INTRODUCTION: The spliceosome, which is a particle containing a molecule of U-RNA and proteins that are specific to each U ribonuclear particle (U-snRNP) or common to every U-snRNPs, is one of the numerous nuclear targets recognized by the antibodies (Abs) and CD4+ T cells from patients with systemic lupus erythematosus and lupus mice.
EXEGESIS: We recently characterized a peptide from the spliceosomal protein U1-70K (sequence 131-151), which is recognized by the Abs and CD4+ T cells from lupus mice and patients. This peptide contains a conserved RNP1 motif, which is also present in other spliceosomal proteins targeted by the Abs from individuals with lupus. We further showed that peptide 131-151 containing a phosphoserine at position 140 (peptide P140) possessed tolerogenic properties in lupus mice and was recognized by the Abs and CD4+ T cells from lupus patients.
CONCLUSION: Thanks to its RNP1 motif, the peptide P140 might play an important role in the initiation and perpetuation steps of the humoral and cellular immune response diversification in lupus individuals. Therapeutic and particularly immunomodulating properties of P140 peptide are being evaluated in humans (a phase III clinical trial will be undertaken in the next weeks).},
keywords = {Amino Acid Motifs, Animals, Antibodies, CD4-Positive T-Lymphocytes, Conserved Sequence, DNA, Epitopes, Haplotypes, Humans, I2CT, Immune Tolerance, Inbred MRL lpr, Inbred NZB, Lupus Erythematosus, Mice, Monneaux, Phosphoserine, Protein, Recombinant, Ribonucleoprotein, Sequence Analysis, Serine, Spliceosomes, Systemic, Team-Dumortier, U1 Small Nuclear},
pubstate = {published},
tppubtype = {article}
}
EXEGESIS: We recently characterized a peptide from the spliceosomal protein U1-70K (sequence 131-151), which is recognized by the Abs and CD4+ T cells from lupus mice and patients. This peptide contains a conserved RNP1 motif, which is also present in other spliceosomal proteins targeted by the Abs from individuals with lupus. We further showed that peptide 131-151 containing a phosphoserine at position 140 (peptide P140) possessed tolerogenic properties in lupus mice and was recognized by the Abs and CD4+ T cells from lupus patients.
CONCLUSION: Thanks to its RNP1 motif, the peptide P140 might play an important role in the initiation and perpetuation steps of the humoral and cellular immune response diversification in lupus individuals. Therapeutic and particularly immunomodulating properties of P140 peptide are being evaluated in humans (a phase III clinical trial will be undertaken in the next weeks).
Woods Anne, Monneaux Fanny, Soulas-Sprauel Pauline, Muller Sylviane, Martin Thierry, Korganow Anne-Sophie, Pasquali Jean-Louis
Influenza virus-induced type I interferon leads to polyclonal B-cell activation but does not break down B-cell tolerance Journal Article
In: Journal of Virology, vol. 81, no. 22, pp. 12525–12534, 2007, ISSN: 0022-538X.
Abstract | Links | BibTeX | Tags: Animals, Antibody Formation, Autoantibodies, Autoantigens, Autoimmunity, B-Lymphocytes, Humans, I2CT, Immune Tolerance, Immunoglobulin M, Inbred Strains, Influenza A virus, Interferon Type I, Lymphocyte Activation, Mice, Monneaux, Rheumatoid Factor, Team-Dumortier, transgenic
@article{woods_influenza_2007,
title = {Influenza virus-induced type I interferon leads to polyclonal B-cell activation but does not break down B-cell tolerance},
author = {Anne Woods and Fanny Monneaux and Pauline Soulas-Sprauel and Sylviane Muller and Thierry Martin and Anne-Sophie Korganow and Jean-Louis Pasquali},
doi = {10.1128/JVI.00839-07},
issn = {0022-538X},
year = {2007},
date = {2007-01-01},
journal = {Journal of Virology},
volume = {81},
number = {22},
pages = {12525--12534},
abstract = {The link between infection and autoimmunity is not yet well understood. This study was designed to evaluate if an acute viral infection known to induce type I interferon production, like influenza, can by itself be responsible for the breakdown of immune tolerance and for autoimmunity. We first tested the effects of influenza virus on B cells in vitro. We then infected different transgenic mice expressing human rheumatoid factors (RF) in the absence or in the constitutive presence of the autoantigen (human immunoglobulin G [IgG]) and young lupus-prone mice [(NZB x NZW)F(1)] with influenza virus and looked for B-cell activation. In vitro, the virus induces B-cell activation through type I interferon production by non-B cells but does not directly stimulate purified B cells. In vivo, both RF and non-RF B cells were activated in an autoantigen-independent manner. This activation was abortive since IgM and IgM-RF production levels were not increased in infected mice compared to uninfected controls, whether or not anti-influenza virus human IgG was detected and even after viral rechallenge. As in RF transgenic mice, acute viral infection of (NZB x NZW)F(1) mice induced only an abortive activation of B cells and no increase in autoantibody production compared to uninfected animals. Taken together, these experiments show that virus-induced acute type I interferon production is not able by itself to break down B-cell tolerance in both normal and autoimmune genetic backgrounds.},
keywords = {Animals, Antibody Formation, Autoantibodies, Autoantigens, Autoimmunity, B-Lymphocytes, Humans, I2CT, Immune Tolerance, Immunoglobulin M, Inbred Strains, Influenza A virus, Interferon Type I, Lymphocyte Activation, Mice, Monneaux, Rheumatoid Factor, Team-Dumortier, transgenic},
pubstate = {published},
tppubtype = {article}
}
Monneaux Fanny, Parietti Véronique, Briand Jean-Paul, Muller Sylviane
Importance of spliceosomal RNP1 motif for intermolecular Ŧ-B cell spreading and tolerance restoration in lupus Journal Article
In: Arthritis Research & Therapy, vol. 9, no. 5, pp. R111, 2007, ISSN: 1478-6362.
Abstract | Links | BibTeX | Tags: Amino Acid Motifs, Amino Acid Sequence, Animals, B-Lymphocytes, I2CT, Immune Tolerance, Inbred MRL lpr, Lupus Erythematosus, Mice, Molecular Sequence Data, Monneaux, Ribonucleoproteins, RNA-Binding Proteins, Saccharomyces cerevisiae Proteins, Spliceosomes, Systemic, T-Lymphocytes, Team-Dumortier
@article{monneaux_importance_2007,
title = {Importance of spliceosomal RNP1 motif for intermolecular Ŧ-B cell spreading and tolerance restoration in lupus},
author = {Fanny Monneaux and Véronique Parietti and Jean-Paul Briand and Sylviane Muller},
doi = {10.1186/ar2317},
issn = {1478-6362},
year = {2007},
date = {2007-01-01},
journal = {Arthritis Research & Therapy},
volume = {9},
number = {5},
pages = {R111},
abstract = {We previously demonstrated the importance of the RNP1 motif-bearing region 131-151 of the U1-70K spliceosomal protein in the intramolecular T-B spreading that occurs in MRL/lpr lupus mice. Here, we analyze the involvement of RNP1 motif in the development and prevention of naturally-occurring intermolecular T-B cell diversification. We found that MRL/lpr peripheral blood lymphocytes proliferated in response to peptides containing or corresponding exactly to the RNP1 motif of spliceosomal U1-70K, U1-A and hnRNP-A2 proteins. We also demonstrated that rabbit antibodies to peptide 131-151 cross-reacted with U1-70K, U1-A and hnRNP-A2 RNP1-peptides. These antibodies recognized the U1-70K and U1-A proteins, and also U1-C and SmD1 proteins, which are devoid of RNP1 motif. Repeated administration of phosphorylated peptide P140 into MRL/lpr mice abolished T-cell response to several peptides from the U1-70K, U1-A and SmD1 proteins without affecting antibody and T-cell responses to foreign (viral) antigen in treated mice challenged with infectious virus. These results emphasized the importance of the dominant RNP1 region, which seems to be central in the activation cascade of B and T cells reacting with spliceosomal RNP1+ and RNP1- spliceosomal proteins. The tolerogenic peptide P140, which is recognized by lupus patients' CD4+ T cells and known to protect MRL/lpr mice, is able to thwart emergence of intermolecular T-cell spreading in treated animals.},
keywords = {Amino Acid Motifs, Amino Acid Sequence, Animals, B-Lymphocytes, I2CT, Immune Tolerance, Inbred MRL lpr, Lupus Erythematosus, Mice, Molecular Sequence Data, Monneaux, Ribonucleoproteins, RNA-Binding Proteins, Saccharomyces cerevisiae Proteins, Spliceosomes, Systemic, T-Lymphocytes, Team-Dumortier},
pubstate = {published},
tppubtype = {article}
}
2005
Monneaux Fanny, Hoebeke Johan, Sordet Christelle, Nonn Céline, Briand Jean-Paul, Maillère Bernard, Sibilia Jean, Muller Sylviane
Selective modulation of CD4+ Ŧ cells from lupus patients by a promiscuous, protective peptide analog Journal Article
In: Journal of Immunology (Baltimore, Md.: 1950), vol. 175, no. 9, pp. 5839–5847, 2005, ISSN: 0022-1767.
Abstract | Links | BibTeX | Tags: Amino Acid Sequence, CD4-Positive T-Lymphocytes, HLA-DR Antigens, Humans, I2CT, Interleukin-10, Lupus Erythematosus, Lymphocyte Activation, Molecular Sequence Data, Monneaux, Peptide Fragments, Phosphorylation, Ribonucleoprotein, Systemic, Team-Dumortier, U1 Small Nuclear
@article{monneaux_selective_2005,
title = {Selective modulation of CD4+ Ŧ cells from lupus patients by a promiscuous, protective peptide analog},
author = {Fanny Monneaux and Johan Hoebeke and Christelle Sordet and Céline Nonn and Jean-Paul Briand and Bernard Maillère and Jean Sibilia and Sylviane Muller},
doi = {10.4049/jimmunol.175.9.5839},
issn = {0022-1767},
year = {2005},
date = {2005-11-01},
journal = {Journal of Immunology (Baltimore, Md.: 1950)},
volume = {175},
number = {9},
pages = {5839--5847},
abstract = {A peptide encompassing residues 131-151 of the spliceosomal U1-70K protein and its analog phosphorylated at Ser140 were synthesized as potential candidates for the treatment of patients with lupus. Studies in the MRL/lpr and (NZB x NZW)F1 lupus models have demonstrated that these sequences contain a CD4+ T cell epitope but administration of the phosphorylated peptide only ameliorates the clinical manifestations of treated MRL/lpr mice. Binding assays with soluble HLA class II molecules and molecular modeling experiments indicate that both peptides behave as promiscuous epitopes and bind to a large panel of human DR molecules. In contrast to normal T cells and T cells from non-lupus autoimmune patients, we found that PBMCs from 40% of lupus patients selected randomly and CFSE-labeled CD4+ T cells proliferate in response to peptide 131-151. Remarkably, however, we observed that phosphorylation of Ser140 prevents CD4+ T cells proliferation but not secretion of regulatory cytokines, suggesting a striking immunomodulatory effect of phosphorylated analog on lupus CD4+ T cells that was unique to patients. The analog might act as an activator of regulatory T cells or as a partial agonist of TCR.},
keywords = {Amino Acid Sequence, CD4-Positive T-Lymphocytes, HLA-DR Antigens, Humans, I2CT, Interleukin-10, Lupus Erythematosus, Lymphocyte Activation, Molecular Sequence Data, Monneaux, Peptide Fragments, Phosphorylation, Ribonucleoprotein, Systemic, Team-Dumortier, U1 Small Nuclear},
pubstate = {published},
tppubtype = {article}
}
2004
Monneaux Fanny, Parietti Véronique, Briand Jean-Paul, Muller Sylviane
Intramolecular Ŧ cell spreading in unprimed MRL/lpr mice: importance of the U1-70k protein sequence 131-151 Journal Article
In: Arthritis and Rheumatism, vol. 50, no. 10, pp. 3232–3238, 2004, ISSN: 0004-3591.
Abstract | Links | BibTeX | Tags: Animals, Cell Division, Female, I2CT, Immunization, Inbred BALB C, Inbred MRL lpr, Lupus Erythematosus, Lymphocytes, Mice, Monneaux, Peptides, Phosphorylation, Ribonucleoprotein, Systemic, Team-Dumortier, U1 Small Nuclear
@article{monneaux_intramolecular_2004,
title = {Intramolecular Ŧ cell spreading in unprimed MRL/lpr mice: importance of the U1-70k protein sequence 131-151},
author = {Fanny Monneaux and Véronique Parietti and Jean-Paul Briand and Sylviane Muller},
doi = {10.1002/art.20510},
issn = {0004-3591},
year = {2004},
date = {2004-10-01},
journal = {Arthritis and Rheumatism},
volume = {50},
number = {10},
pages = {3232--3238},
abstract = {OBJECTIVE: To analyze spontaneous T cell spreading against determinants of the U1-70K protein in young autoimmune MRL/lpr lupus mice, in comparison with the T cell spreading occurring in normal BALB/c mice immunized with peptide 131-151 of this protein.
METHODS: Peripheral blood lymphocytes (PBLs) from both unprimed MRL/lpr mice and immunized BALB/c mice were tested for their ability to proliferate ex vivo in response to 18 overlapping peptides of the U1-70K spliceosomal protein, using assays for lymphocyte proliferation and secretion of interleukin-2.
RESULTS: The proliferative response to peptides of the U1-70K protein evolved rapidly in MRL/lpr mice tested at different ages. At least 5 peptides were recognized by PBLs from 8-week-old autoimmune mice, whereas a different peptide was recognized by PBLs from MRL/lpr mice at 12 weeks of age. At 15 weeks, the proliferative response was weak or negative when assessed with any of the test peptides. At least 2 major peptides recognized by MRL/lpr PBLs were also recognized by PBLs generated in the BALB/c mice primed with peptide 131-151. We further demonstrated that, in preautoimmune MRL/lpr mice, repeated administration of phosphorylated peptide 131-151 (called P140), which was shown previously to be protective, transiently abolished T cell intramolecular spreading to other regions of the 70K protein.
CONCLUSION: This is the first study to demonstrate that intramolecular T cell spreading effectively occurs in MRL/lpr mice with lupus, and that region 131-151 is important in the cascade of events observed in the murine lupus response. This sequence might originate a mechanism of tolerance spreading that leads to the beneficial effect observed in MRL/lpr mice after treatment with the phosphorylated peptide 131-151.},
keywords = {Animals, Cell Division, Female, I2CT, Immunization, Inbred BALB C, Inbred MRL lpr, Lupus Erythematosus, Lymphocytes, Mice, Monneaux, Peptides, Phosphorylation, Ribonucleoprotein, Systemic, Team-Dumortier, U1 Small Nuclear},
pubstate = {published},
tppubtype = {article}
}
METHODS: Peripheral blood lymphocytes (PBLs) from both unprimed MRL/lpr mice and immunized BALB/c mice were tested for their ability to proliferate ex vivo in response to 18 overlapping peptides of the U1-70K spliceosomal protein, using assays for lymphocyte proliferation and secretion of interleukin-2.
RESULTS: The proliferative response to peptides of the U1-70K protein evolved rapidly in MRL/lpr mice tested at different ages. At least 5 peptides were recognized by PBLs from 8-week-old autoimmune mice, whereas a different peptide was recognized by PBLs from MRL/lpr mice at 12 weeks of age. At 15 weeks, the proliferative response was weak or negative when assessed with any of the test peptides. At least 2 major peptides recognized by MRL/lpr PBLs were also recognized by PBLs generated in the BALB/c mice primed with peptide 131-151. We further demonstrated that, in preautoimmune MRL/lpr mice, repeated administration of phosphorylated peptide 131-151 (called P140), which was shown previously to be protective, transiently abolished T cell intramolecular spreading to other regions of the 70K protein.
CONCLUSION: This is the first study to demonstrate that intramolecular T cell spreading effectively occurs in MRL/lpr mice with lupus, and that region 131-151 is important in the cascade of events observed in the murine lupus response. This sequence might originate a mechanism of tolerance spreading that leads to the beneficial effect observed in MRL/lpr mice after treatment with the phosphorylated peptide 131-151.
Monneaux Fanny, Muller Sylviane
Peptide-based immunotherapy of systemic lupus erythematosus Journal Article
In: Autoimmunity Reviews, vol. 3, no. 1, pp. 16–24, 2004, ISSN: 1568-9972.
Abstract | Links | BibTeX | Tags: Animals, Antibodies, Antinuclear, Epitopes, Humans, I2CT, Immunotherapy, Lupus Erythematosus, Mice, Monneaux, Peptides, Systemic, T-Lymphocytes, Team-Dumortier
@article{monneaux_peptide-based_2004,
title = {Peptide-based immunotherapy of systemic lupus erythematosus},
author = {Fanny Monneaux and Sylviane Muller},
doi = {10.1016/S1568-9972(03)00061-2},
issn = {1568-9972},
year = {2004},
date = {2004-01-01},
journal = {Autoimmunity Reviews},
volume = {3},
number = {1},
pages = {16--24},
abstract = {Current drug-based therapy for systemic lupus erythematosus (SLE) are non-specific and often counterbalanced by adverse effects. Current research aims at developing specific treatments that target deleterious cells only and not the whole immune system. This strategy requires the identification of sequences derived from major lupus autoantigens, responsible for the activation of autoreactive B and T cells. This review summarizes the identification and characterization of peptides, which are able to modulate T cells ex vivo, and describes the promising results obtained after administration of some of these peptides in lupus mice. Although these therapeutic trials are encouraging, the precise mode of action of peptide-based immunotherapy is still elusive. Here, we discuss the possible mechanisms leading to T-cell tolerance induction and the feasibility of extending the success of peptide-based therapy from animal models to human.},
keywords = {Animals, Antibodies, Antinuclear, Epitopes, Humans, I2CT, Immunotherapy, Lupus Erythematosus, Mice, Monneaux, Peptides, Systemic, T-Lymphocytes, Team-Dumortier},
pubstate = {published},
tppubtype = {article}
}
2003
Monneaux Fanny, Lozano José Manuel, Patarroyo Manuel E, Briand Jean-Paul, Muller Sylviane
T cell recognition and therapeutic effect of a phosphorylated synthetic peptide of the 70K snRNP protein administered in MR/lpr mice Journal Article
In: European Journal of Immunology, vol. 33, no. 2, pp. 287–296, 2003, ISSN: 0014-2980.
Abstract | Links | BibTeX | Tags: Amino Acid Sequence, Animal, Animals, Autoantibodies, Autoantigens, Autoimmune Diseases, B-Lymphocytes, Cross Reactions, Disease Models, Female, HLA-DR Antigens, HLA-DR Serological Subtypes, HLA-DR1 Antigen, HLA-DR4 Antigen, Humans, I2CT, Immunization, Immunotherapy, Inbred BALB C, Inbred MRL lpr, Lupus Erythematosus, Lupus Nephritis, Mice, Molecular Sequence Data, Monneaux, Peptide Fragments, Phosphorylation, Protein Binding, Ribonucleoprotein, Systemic, T-Lymphocytes, Team-Dumortier, U1 Small Nuclear
@article{monneaux_t_2003,
title = {T cell recognition and therapeutic effect of a phosphorylated synthetic peptide of the 70K snRNP protein administered in MR/lpr mice},
author = {Fanny Monneaux and José Manuel Lozano and Manuel E Patarroyo and Jean-Paul Briand and Sylviane Muller},
doi = {10.1002/immu.200310002},
issn = {0014-2980},
year = {2003},
date = {2003-01-01},
journal = {European Journal of Immunology},
volume = {33},
number = {2},
pages = {287--296},
abstract = {Modifications of self antigens that occur during apoptosis might be involved in the generation of neo-antigens, which can break tolerance and induce autoimmunity. We have previously identified an epitope at residues 131-151 of the U1-70K snRNP protein, recognized by IgG antibodies and CD4+ T cells from at least two strains of lupus mice. With the aim of investigating the possible role of phosphorylation on the antigenicity of peptide 131-151 and to gain a better understanding of how this peptide can drive autoimmune response, we synthesized two peptides phosphorylated on Ser137 and 140, respectively. We show here that peptide P140 phosphorylated on Ser140 is recognized by both CD4+ T cells and antibodies from MRL/lpr mice. Furthermore, intravenous administration to lupus-prone MRL/lpr mice of P140 in saline (but not of the non-phosphorylated peptide) decreased proteinuria and anti-DNA antibody production, and significantly prolonged survival of treated mice. We further demonstrated that P140 is recognized by antibodies from lupus patients and binds to various HLA DR molecules, offering new hope for manipulating T cell response in humans.},
keywords = {Amino Acid Sequence, Animal, Animals, Autoantibodies, Autoantigens, Autoimmune Diseases, B-Lymphocytes, Cross Reactions, Disease Models, Female, HLA-DR Antigens, HLA-DR Serological Subtypes, HLA-DR1 Antigen, HLA-DR4 Antigen, Humans, I2CT, Immunization, Immunotherapy, Inbred BALB C, Inbred MRL lpr, Lupus Erythematosus, Lupus Nephritis, Mice, Molecular Sequence Data, Monneaux, Peptide Fragments, Phosphorylation, Protein Binding, Ribonucleoprotein, Systemic, T-Lymphocytes, Team-Dumortier, U1 Small Nuclear},
pubstate = {published},
tppubtype = {article}
}
2002
Monneaux Fanny, Muller Sylviane
Epitope spreading in systemic lupus erythematosus: identification of triggering peptide sequences Journal Article
In: Arthritis and Rheumatism, vol. 46, no. 6, pp. 1430–1438, 2002, ISSN: 0004-3591.
Links | BibTeX | Tags: Amino Acid Sequence, Animals, B-Lymphocyte, Epitopes, Humans, I2CT, Lupus Erythematosus, Molecular Sequence Data, Monneaux, Systemic, T-Lymphocyte, Team-Dumortier
@article{monneaux_epitope_2002,
title = {Epitope spreading in systemic lupus erythematosus: identification of triggering peptide sequences},
author = {Fanny Monneaux and Sylviane Muller},
doi = {10.1002/art.10263},
issn = {0004-3591},
year = {2002},
date = {2002-06-01},
journal = {Arthritis and Rheumatism},
volume = {46},
number = {6},
pages = {1430--1438},
keywords = {Amino Acid Sequence, Animals, B-Lymphocyte, Epitopes, Humans, I2CT, Lupus Erythematosus, Molecular Sequence Data, Monneaux, Systemic, T-Lymphocyte, Team-Dumortier},
pubstate = {published},
tppubtype = {article}
}
2001
Monneaux F, Muller S
Key sequences involved in the spreading of the systemic autoimmune response to spliceosomal proteins Journal Article
In: Scandinavian Journal of Immunology, vol. 54, no. 1-2, pp. 45–54, 2001, ISSN: 0300-9475.
Abstract | Links | BibTeX | Tags: Animals, Autoantibodies, Autoimmune Diseases, Autoimmunity, B-Lymphocyte, Epitopes, Humans, I2CT, Mice, Monneaux, Ribonucleoproteins, Spliceosomes, Team-Dumortier
@article{monneaux_key_2001,
title = {Key sequences involved in the spreading of the systemic autoimmune response to spliceosomal proteins},
author = {F Monneaux and S Muller},
doi = {10.1046/j.1365-3083.2001.00942.x},
issn = {0300-9475},
year = {2001},
date = {2001-01-01},
journal = {Scandinavian Journal of Immunology},
volume = {54},
number = {1-2},
pages = {45--54},
abstract = {Immune spreading to multiple intracellular antigens is likely to be of primary importance in organ-specific and systemic autoimmune diseases. A number of mechanisms by which immune spreading may occur from only a single autoreactive epitope have been proposed. Search for an initiator or early epitope thus represents an important area of investigation. For example, many studies have focused on the identification of epitopes recognized by the antibodies from both patients with systemic lupus erythematosus (SLE) and lupus-prone mice. Recently, an autoepitope present in the 70K U1 ribonucleo protein (RNP) and recognized by CD4+ T cells from lupus mice has also been identified. Here, we analyze the results of B- and T-cell-epitope mapping studies of several RNPs present in the spliceosome and propose a model of epitope spreading. In this model, a consensus sequence (the RNP motif) conserved in many nuclear, nucleolar and cytoplasmic antigens, might play a role as 'driver' epitope. This hypothesis is based on the observation that this sequence is recognized by CD4+ T cells from lupus mice and is often targeted by autoantibodies, very early during the course of the disease. Targeting this region that is repeated in different self-antigens, might represent an interesting strategy to interfere with the continuous T-cell stimulation and exposure to specific antigens.},
keywords = {Animals, Autoantibodies, Autoimmune Diseases, Autoimmunity, B-Lymphocyte, Epitopes, Humans, I2CT, Mice, Monneaux, Ribonucleoproteins, Spliceosomes, Team-Dumortier},
pubstate = {published},
tppubtype = {article}
}
Monneaux F, Dumortier H, Steiner G, Briand J P, Muller S
In: International Immunology, vol. 13, no. 9, pp. 1155–1163, 2001, ISSN: 0953-8178.
Abstract | Links | BibTeX | Tags: Animals, Antibody Specificity, B-Lymphocytes, Crosses, Dumortier, fas Receptor, Female, Genetic, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Heterogeneous-Nuclear Ribonucleoproteins, Histocompatibility Antigens Class II, I2CT, Immunoglobulin G, Inbred MRL lpr, Inbred NZB, Lupus Erythematosus, Mice, Monneaux, Peptide Fragments, Ribonucleoprotein, Ribonucleoproteins, Small Nuclear, Species Specificity, Spliceosomes, Systemic, T-Lymphocytes, Team-Dumortier, U1 Small Nuclear
@article{monneaux_murine_2001,
title = {Murine models of systemic lupus erythematosus: B and Ŧ cell responses to spliceosomal ribonucleoproteins in MRL/Fas(lpr) and (NZB x NZW)F(1) lupus mice},
author = {F Monneaux and H Dumortier and G Steiner and J P Briand and S Muller},
doi = {10.1093/intimm/13.9.1155},
issn = {0953-8178},
year = {2001},
date = {2001-01-01},
journal = {International Immunology},
volume = {13},
number = {9},
pages = {1155--1163},
abstract = {(NZB x NZW)F(1) and MRL/Fas(lpr) lupus mice present a similar phenotype with a spectrum of autoantibodies associated with very severe nephritis. It is thought, however, that in contrast to other lupus-prone mice such as MRL/Fas(lpr) mice, (NZB x NZW)F(1) mice do not generate autoantibodies to ribonucleoproteins (RNP) Sm/RNP. In this study, we demonstrate that contrary to previous reports, the autoimmune response directed against Sm/RNP antigens also occurs in NZB x NZW mice. CD4(+) T cells from unprimed 10-week-old NZB x NZW mice proliferate and secrete IL-2 in response to peptide 131-151 of the U1-70K protein, which is known to contain a T(h) epitope recognized by CD4(+) T cells from MRL/Fas(lpr) mice. Peptide 131-151, which was found to bind I-A(k) and I-E(k) class II MHC molecules, also bound both I-A(d) and I-E(d) molecules. This result led us to also re-evaluate longitudinally the anti-Sm/RNP antibody response in NZB x NZW mice. We found that 25-week-old mice do produce antibodies reacting with several small nuclear and heterogeneous nuclear (hn) RNP proteins, such as SmD1, U1-70K and hnRNP A2/B1 proteins. The fine specificity of these antibodies was studied with overlapping synthetic peptides. The same antigenically positive and negative peptides were characterized in MRL/Fas(lpr) and NZB x NZW mice in the three proteins. This new finding can help to understand the mechanisms involved in the development of the anti-Sm/RNP antibody response and, particularly, the role played by non-MHC genes in this autoimmune response.},
keywords = {Animals, Antibody Specificity, B-Lymphocytes, Crosses, Dumortier, fas Receptor, Female, Genetic, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Heterogeneous-Nuclear Ribonucleoproteins, Histocompatibility Antigens Class II, I2CT, Immunoglobulin G, Inbred MRL lpr, Inbred NZB, Lupus Erythematosus, Mice, Monneaux, Peptide Fragments, Ribonucleoprotein, Ribonucleoproteins, Small Nuclear, Species Specificity, Spliceosomes, Systemic, T-Lymphocytes, Team-Dumortier, U1 Small Nuclear},
pubstate = {published},
tppubtype = {article}
}
2000
Monneaux F, Muller S
Laboratory protocols for the identification of Th cell epitopes on self-antigens in mice with systemic autoimmune diseases Journal Article
In: Journal of Immunological Methods, vol. 244, no. 1-2, pp. 195–204, 2000, ISSN: 0022-1759.
Abstract | Links | BibTeX | Tags: Animals, Antigen Presentation, Antigen-Presenting Cells, Autoantigens, B-Lymphocytes, Coculture Techniques, Epitopes, Female, Flow Cytometry, I2CT, Inbred MRL lpr, Inbred NZB, Lupus Erythematosus, Lymphocyte Activation, Mice, Monneaux, Ribonucleoproteins, Small Nuclear, Systemic, T-Lymphocyte, Team-Dumortier, Th1 Cells, Th2 Cells
@article{monneaux_laboratory_2000,
title = {Laboratory protocols for the identification of Th cell epitopes on self-antigens in mice with systemic autoimmune diseases},
author = {F Monneaux and S Muller},
doi = {10.1016/s0022-1759(00)00256-8},
issn = {0022-1759},
year = {2000},
date = {2000-10-01},
journal = {Journal of Immunological Methods},
volume = {244},
number = {1-2},
pages = {195--204},
abstract = {T cells play a critical role in both the immunological and clinical manifestations of systemic autoimmune diseases such as systemic lupus erythematosus (SLE). Although in normal mice multiple T cell epitopes have been characterized in several self-proteins, there is little information on the fine specificity of autoreactive T cells in lupus model mice and humans. In SLE-prone mice and humans, the only Th cell epitopes identified at the molecular level in self-antigens concern histones and nucleosomes, and the 70-kD U1-snRNP protein. T cell characterization in certain autoimmune mice such as MRL lpr/lpr and NZB/NZW mice has been largely impaired by their hyporesponsiveness in response to mitogen and minimal IL-2 secretion. In addition, MRL lpr/lpr mice also develop lymphadenopathy characterized by the progressive accumulation of functionally immature CD4(-) CD8(-) T cells. It is therefore important to optimize the methods used to measure T cell proliferation and cytokine production ex vivo in order to identify minimal activation in the presence of appropriate antigen. The protocol described in this article has been used for identifying in young MRL lpr/lpr and NZB/NZW mice a CD4(+) T cell epitope in the murine 70-kD U1-RNP protein.},
keywords = {Animals, Antigen Presentation, Antigen-Presenting Cells, Autoantigens, B-Lymphocytes, Coculture Techniques, Epitopes, Female, Flow Cytometry, I2CT, Inbred MRL lpr, Inbred NZB, Lupus Erythematosus, Lymphocyte Activation, Mice, Monneaux, Ribonucleoproteins, Small Nuclear, Systemic, T-Lymphocyte, Team-Dumortier, Th1 Cells, Th2 Cells},
pubstate = {published},
tppubtype = {article}
}
Dumortier H, Monneaux F, Jahn-Schmid B, Briand J P, Skriner K, Cohen P L, Smolen J S, Steiner G, Muller S
B and Ŧ cell responses to the spliceosomal heterogeneous nuclear ribonucleoproteins A2 and B1 in normal and lupus mice Journal Article
In: Journal of Immunology (Baltimore, Md.: 1950), vol. 165, no. 4, pp. 2297–2305, 2000, ISSN: 0022-1767.
Abstract | Links | BibTeX | Tags: Amino Acid Sequence, Animals, Autoantibodies, B-Lymphocytes, Dumortier, Epitope Mapping, Female, Heterogeneous Nuclear, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Heterogeneous-Nuclear Ribonucleoproteins, Humans, I2CT, Immunoglobulin G, Inbred BALB C, Inbred C57BL, Inbred CBA, Inbred MRL lpr, Injections, Lupus Nephritis, Lymphocyte Activation, Male, Mice, Molecular Sequence Data, Monneaux, Peptide Fragments, Recombinant Proteins, Ribonucleoproteins, RNA, Spliceosomes, Subcutaneous, T-Lymphocytes, Team-Dumortier, transgenic
@article{dumortier_b_2000,
title = {B and Ŧ cell responses to the spliceosomal heterogeneous nuclear ribonucleoproteins A2 and B1 in normal and lupus mice},
author = {H Dumortier and F Monneaux and B Jahn-Schmid and J P Briand and K Skriner and P L Cohen and J S Smolen and G Steiner and S Muller},
doi = {10.4049/jimmunol.165.4.2297},
issn = {0022-1767},
year = {2000},
date = {2000-08-01},
journal = {Journal of Immunology (Baltimore, Md.: 1950)},
volume = {165},
number = {4},
pages = {2297--2305},
abstract = {Autoantibodies directed against spliceosomal heterogeneous nuclear ribonucleoproteins (hnRNPs) are a typical feature of rheumatoid arthritis, systemic lupus erythematosus, and mixed-connective tissue disease. With the aim of investigating a potential pathogenic role of these Abs, we have studied the Ab response to A2/B1 hnRNPs in different murine models of lupus. The specificity of anti-A2/B1 Abs was tested with a series of 14 overlapping synthetic peptides covering the region 1-206 of A2 that contains most of the epitopes recognized by patients' Abs. A major epitope recognized very early during the course of the disease by Abs from most of MRL lpr/lpr mice but not from other lupus mice and from mice of different MHC haplotypes immunized against B1 was identified in residues 50-70. This peptide contains a highly conserved sequence RGFGFVTF also present in other hnRNPs and small nuclear ribonucleoproteins. Abs reacting with a second A2 epitope identified in residues 35-55 were detectable several weeks later, suggesting an intramolecular B cell epitope spreading during the course of the disease. We identified several T cell epitopes within the region 35-175 that generated an effective Th cell response with IL-2 and IFN-gamma secretion in nonautoimmune CBA/J mice sharing the same MHC haplotype H-2k as MRL/lpr mice. None of the peptides stimulated T cells primed in vivo with B1. Because Abs to peptide 50-70 were detected significantly earlier than Abs reacting with other A2 peptides and the protein itself, it is possible that within the protein, this segment contains residues playing an initiator role in the induction of the anti-A2/B1 and antispliceosome Ab response.},
keywords = {Amino Acid Sequence, Animals, Autoantibodies, B-Lymphocytes, Dumortier, Epitope Mapping, Female, Heterogeneous Nuclear, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Heterogeneous-Nuclear Ribonucleoproteins, Humans, I2CT, Immunoglobulin G, Inbred BALB C, Inbred C57BL, Inbred CBA, Inbred MRL lpr, Injections, Lupus Nephritis, Lymphocyte Activation, Male, Mice, Molecular Sequence Data, Monneaux, Peptide Fragments, Recombinant Proteins, Ribonucleoproteins, RNA, Spliceosomes, Subcutaneous, T-Lymphocytes, Team-Dumortier, transgenic},
pubstate = {published},
tppubtype = {article}
}
Monneaux F, Briand J P, Muller S
In: European Journal of Immunology, vol. 30, no. 8, pp. 2191–2200, 2000, ISSN: 0014-2980.
Abstract | Links | BibTeX | Tags: Amino Acid Motifs, Animals, Antigen-Presenting Cells, Autoimmunity, B-Lymphocytes, CD4-Positive T-Lymphocytes, Epitopes, Female, I2CT, Inbred BALB C, Inbred CBA, Inbred MRL lpr, Lupus Vulgaris, Lymphocyte Activation, Mice, Monneaux, Peptide Fragments, Ribonucleoprotein, T-Lymphocyte, Team-Dumortier, U1 Small Nuclear
@article{monneaux_b_2000,
title = {B and Ŧ cell immune response to small nuclear ribonucleoprotein particles in lupus mice: autoreactive CD4(+) Ŧ cells recognize a Ŧ cell epitope located within the RNP80 motif of the 70K protein},
author = {F Monneaux and J P Briand and S Muller},
doi = {10.1002/1521-4141(2000)30:8<2191::AID-IMMU2191>3.0.CO;2-R},
issn = {0014-2980},
year = {2000},
date = {2000-08-01},
journal = {European Journal of Immunology},
volume = {30},
number = {8},
pages = {2191--2200},
abstract = {Systemic lupus erythematosus is characterized by the presence of high titers of autoantibodies reacting with various components of the U1 small nuclear ribonucleoprotein particle (snRNP). It has been suggested that these antibodies are produced by an antigen-driven mechanism under the dependence of antigen-specific T cells. To investigate the role of T cell help in this process, we sought, with 20 overlapping peptides, the Th epitopes on the U1-70K snRNP in unprimed H-2(k) MRL / lpr lupus mice and immunized CBA normal mice. The peptide 131 - 151 was recognized by both IgG autoantibodies and CD4(+) T cells from 7 - 9-week-old MRL / lpr mice. In this test, antigen-presenting cells (APC) from MRL / lpr mice were required; APC from naive CBA mice failed to stimulate CD4(+) cells from MRL / lpr mice. The potential role of MRL / lpr B cells as APC, the expression of MHC class II molecules at their surface and their activation state (expression of CD69, CD80 / B7-1 and CD86 / B7-2 molecules) were studied. Peptide 131 - 151 bound both I-A(k) and I-E(k) class II molecules and favored an IL-2-positive T cell response but not IFN-gamma, IL-6 and IL-10 secretion. Segment 131 - 151 is localized within the RNP80 motif and contains residues that are highly conserved in many nuclear, nucleolar and cytoplasmic RNA binding proteins.},
keywords = {Amino Acid Motifs, Animals, Antigen-Presenting Cells, Autoimmunity, B-Lymphocytes, CD4-Positive T-Lymphocytes, Epitopes, Female, I2CT, Inbred BALB C, Inbred CBA, Inbred MRL lpr, Lupus Vulgaris, Lymphocyte Activation, Mice, Monneaux, Peptide Fragments, Ribonucleoprotein, T-Lymphocyte, Team-Dumortier, U1 Small Nuclear},
pubstate = {published},
tppubtype = {article}
}