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}
}
2009
Flacher Vincent, Sparber Florian, Tripp Christoph H, Romani Nikolaus, Stoitzner Patrizia
Targeting of epidermal Langerhans cells with antigenic proteins: attempts to harness their properties for immunotherapy Journal Article
In: Cancer immunology, immunotherapy: CII, vol. 58, no. 7, pp. 1137–1147, 2009, ISSN: 1432-0851.
Abstract | Links | BibTeX | Tags: Active, Animals, Antibodies, antibody, Antigen, Antigens, BLOOD, C-Type, cancer, CD, CD4-Positive T-Lymphocytes, CD4+ T cells, CD8-Positive T-Lymphocytes, CD8+ T cells, Dendritic Cells, DERMATOLOGY, DERMIS, Epidermis, Growth, Human, Humans, immune response, IMMUNE-RESPONSES, Immunization, Immunology, Immunotherapy, in situ, In vivo, Inbred BALB C, Inbred C57BL, INDUCTION, Langerhans Cells, LECTIN, Lectins, LYMPH, LYMPH NODE, Lymph Nodes, Major Histocompatibility Complex, Mannose-Binding Lectins, metabolism, methods, MHC class I, MHC class I molecules, Mice, Neoplasm, Neoplasms, OVALBUMIN, Patients, PROGENITORS, Protein, Proteins, RESPONSES, review, Skin, T CELLS, T-CELLS, Team-Mueller, therapy, tumor
@article{flacher_targeting_2009,
title = {Targeting of epidermal Langerhans cells with antigenic proteins: attempts to harness their properties for immunotherapy},
author = {Vincent Flacher and Florian Sparber and Christoph H Tripp and Nikolaus Romani and Patrizia Stoitzner},
doi = {10.1007/s00262-008-0563-9},
issn = {1432-0851},
year = {2009},
date = {2009-07-01},
journal = {Cancer immunology, immunotherapy: CII},
volume = {58},
number = {7},
pages = {1137--1147},
abstract = {Langerhans cells, a subset of skin dendritic cells in the epidermis, survey peripheral tissue for invading pathogens. In recent functional studies it was proven that Langerhans cells can present exogenous antigen not merely on major histocompatibility complexes (MHC)-class II molecules to CD4+ T cells, but also on MHC-class I molecules to CD8+ T cells. Immune responses against topically applied antigen could be measured in skin-draining lymph nodes. Skin barrier disruption or co-application of adjuvants was required for maximal induction of T cell responses. Cytotoxic T cells induced by topically applied antigen inhibited tumor growth in vivo, thus underlining the potential of Langerhans cells for immunotherapy. Here we review recent work and report novel observations relating to the potential use of Langerhans cells for immunotherapy. We investigated the potential of epicutaneous immunization strategies in which resident skin dendritic cells are loaded with tumor antigen in situ. This contrasts with current clinical approaches, where dendritic cells generated from progenitors in blood are loaded with tumor antigen ex vivo before injection into cancer patients. In the current study, we applied either fluorescently labeled protein antigen or targeting antibodies against DEC-205/CD205 and langerin/CD207 topically onto barrier-disrupted skin and examined antigen capture and transport by Langerhans cells. Protein antigen could be detected in Langerhans cells in situ, and they were the main skin dendritic cell subset transporting antigen during emigration from skin explants. Potent in vivo proliferative responses of CD4+ and CD8+ T cells were measured after epicutaneous immunization with low amounts of protein antigen. Targeting antibodies were mainly transported by langerin+ migratory dendritic cells of which the majority represented migratory Langerhans cells and a smaller subset the new langerin+ dermal dendritic cell population located in the upper dermis. The preferential capture of topically applied antigen by Langerhans cells and their ability to induce potent CD4+ and CD8+ T cell responses emphasizes their potential for epicutaneous immunization strategies.},
keywords = {Active, Animals, Antibodies, antibody, Antigen, Antigens, BLOOD, C-Type, cancer, CD, CD4-Positive T-Lymphocytes, CD4+ T cells, CD8-Positive T-Lymphocytes, CD8+ T cells, Dendritic Cells, DERMATOLOGY, DERMIS, Epidermis, Growth, Human, Humans, immune response, IMMUNE-RESPONSES, Immunization, Immunology, Immunotherapy, in situ, In vivo, Inbred BALB C, Inbred C57BL, INDUCTION, Langerhans Cells, LECTIN, Lectins, LYMPH, LYMPH NODE, Lymph Nodes, Major Histocompatibility Complex, Mannose-Binding Lectins, metabolism, methods, MHC class I, MHC class I molecules, Mice, Neoplasm, Neoplasms, OVALBUMIN, Patients, PROGENITORS, Protein, Proteins, RESPONSES, review, Skin, T CELLS, T-CELLS, Team-Mueller, therapy, tumor},
pubstate = {published},
tppubtype = {article}
}
2007
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).
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}
}
2000
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}
}
1999
Nisole S, Krust B, Callebaut C, Guichard G, Muller S, Briand J P, Hovanessian A G
The anti-HIV pseudopeptide HB-19 forms a complex with the cell-surface-expressed nucleolin independent of heparan sulfate proteoglycans Journal Article
In: The Journal of Biological Chemistry, vol. 274, no. 39, pp. 27875–27884, 1999, ISSN: 0021-9258.
Abstract | Links | BibTeX | Tags: Anti-HIV Agents, Binding Sites, CD4-Positive T-Lymphocytes, Cell Line, Cell Membrane, Confocal, Fibroblast Growth Factor 2, Flow Cytometry, Heparan Sulfate Proteoglycans, HIV-1, Humans, Microscopy, Oligopeptides, Peptides, Phospholipid Ethers, Phosphoproteins, Proteins, RNA-Binding Proteins
@article{nisole_anti-hiv_1999,
title = {The anti-HIV pseudopeptide HB-19 forms a complex with the cell-surface-expressed nucleolin independent of heparan sulfate proteoglycans},
author = {S Nisole and B Krust and C Callebaut and G Guichard and S Muller and J P Briand and A G Hovanessian},
doi = {10.1074/jbc.274.39.27875},
issn = {0021-9258},
year = {1999},
date = {1999-09-01},
journal = {The Journal of Biological Chemistry},
volume = {274},
number = {39},
pages = {27875--27884},
abstract = {The HB-19 pseudopeptide 5[Kpsi(CH(2)N)PR]-TASP, psi(CH(2)N) for reduced peptide bond, is a specific inhibitor of human immunodeficiency virus (HIV) infection in different CD4(+) cell lines and in primary T-lymphocytes and macrophages. Here, by using an experimental CD4(+) cell model to monitor HIV entry and infection, we demonstrate that HB-19 binds the cell surface and inhibits attachment of HIV particles to permissive cells. At concentrations that inhibit HIV attachment, HB-19 binds cells irreversibly, becomes complexed with the cell-surface-expressed nucleolin, and eventually results in its degradation. Accordingly, by confocal immunofluorescence microscopy, we demonstrate the drastic reduction of the cell-surface-expressed nucleolin following treatment of cells with HB-19. HIV particles can prevent the binding of HB-19 to cells and inhibit complex formation with nucleolin. Such a competition between viral particles and HB-19 is consistent with the implication of nucleolin in the process of HIV attachment to target cells. We show that another inhibitor of HIV infection, the fibroblast growth factor-2 (FGF-2) that uses cell-surface-expressed heparan sulfate proteoglycans as low affinity receptors, binds cells and blocks attachment of HIV to permissive cells. FGF-2 does not prevent the binding of HB-19 to cells and to nucleolin, and similarly HB-19 has no apparent effect on the binding of FGF-2 to the cell surface. The lack of competition between these two anti-HIV agents rules out the potential involvement of heparan sulfate proteoglycans in the mechanism of anti-HIV effect of HB-19, thus pointing out that nucleolin is its main target.},
keywords = {Anti-HIV Agents, Binding Sites, CD4-Positive T-Lymphocytes, Cell Line, Cell Membrane, Confocal, Fibroblast Growth Factor 2, Flow Cytometry, Heparan Sulfate Proteoglycans, HIV-1, Humans, Microscopy, Oligopeptides, Peptides, Phospholipid Ethers, Phosphoproteins, Proteins, RNA-Binding Proteins},
pubstate = {published},
tppubtype = {article}
}