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1. The Immunopathology of Complement Proteins and Innate Immunity in Autoimmune Disease

Author

Chantal Dumestre-Pérard, F. Defendi, Jean-Yves Cesbron, Nicole M. Thielens, Giovanna Clavarino, Centre Hospitalier Universitaire [Grenoble] (CHU), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Barrière Naturelle et Infectiosité (TIMC-IMAG-BNI), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), and Université Grenoble Alpes (UGA)

Subjects
0301 basic medicine, Complement, Autoimmunity, Autoantigens, Autoimmune Diseases, C1-inhibitor, Epitopes, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Humans, Immunology and Allergy, C3 nephritic factor, Complement Activation, Tissue homeostasis, C1q, Autoantibodies, 030203 arthritis & rheumatology, Innate immune system, C1 inhibitor, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Complement C1q, Factor H, Autoantibody, Pattern recognition receptor, Complement System Proteins, General Medicine, Complement deficiency, medicine.disease, Immunity, Innate, 3. Good health, Complement (complexity), Complement system, 030104 developmental biology, Immunology, biology.protein, Disease Susceptibility
Abstract

International audience; The complement is a powerful cascade of the innate immunity and also acts as a bridge between innate and acquired immune defence. Complement activation can occur via three distinct pathways, the classical, alternative and lectin pathways, each resulting in the common terminal pathway. Complement activation results in the release of a range of biologically active molecules that significantly contribute to immune surveillance and tissue homeostasis. Several soluble and membrane-bound regulatory proteins restrict complement activation in order to prevent complement-mediated autologous damage, consumption and exacerbated inflammation. The crucial role of complement in the host homeostasis is illustrated by association of both complement deficiency and overactivation with severe and life-threatening diseases. Autoantibodies targeting complement components have been described to alter expression and/or function of target protein resulting in a dysregulation of the delicate equilibrium between activation and inhibition of complement. The spectrum of diseases associated with complement autoantibodies depends on which complement protein and activation pathway are targeted, ranging from autoimmune disorders to kidney and vascular diseases. Nevertheless, these autoantibodies have been identified as differential biomarkers for diagnosis or follow-up of disease only in a small number of clinical conditions. For some autoantibodies, a clear relationship with clinical manifestations has been identified, such as anti-C1q, anti-Factor H, anti-C1 Inhibitor antibodies and C3 nephritic factor. For other autoantibodies, the origin and the functional consequences still remain to be elucidated, questioning about the pathophysiological significance of these autoantibodies, such as anti-mannose binding lectin, anti-Factor I, anti-Factor B and anti-C3b antibodies. The detection of autoantibodies targeting complement components is performed in specialized laboratories; however, there is no consensus on detection methods and standardization of the assays is a real challenge. This review summarizes the current panorama of autoantibodies targeting complement recognition proteins of the classical and lectin pathways, associated proteases, convertases, regulators and terminal components, with an emphasis on autoantibodies clearly involved in clinical conditions.

Published
2020
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2. Effects of immunoadsorption combined with membrane filtration on complement markers – results of a randomized, controlled, crossover study

Author

F. Defendi, Chantal Dumestre-Pérard, Georg A. Böhmig, Lionel Rostaing, Farsad Eskandary, Paolo Malvezzi, Jean-Yves Cesbron, LABORATOIRE D'IMMUNOLOGIE, Centre Hospitalier Universitaire [Grenoble] (CHU), Service de néphrologie, dialyse, aphérèses et transplantation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, division of nephrology and dialysis, Barrière Naturelle et Infectiosité (TIMC-IMAG-BNI), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), and Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
Adult, Male, kidney transplantation, chemical and pharmacologic phenomena, membrane filtration, 030230 surgery, Pharmacology, ABO Blood-Group System, 03 medical and health sciences, 0302 clinical medicine, ABO blood group system, Medicine, Humans, complement, mannose-binding lectin, Immunoadsorption, Complement Activation, Kidney transplantation, Mannan-binding lectin, Transplantation, Kidney, Cross-Over Studies, business.industry, Membranes, Artificial, Complement System Proteins, Middle Aged, medicine.disease, 3. Good health, Complement system, properdin, medicine.anatomical_structure, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Immunoglobulin M, Blood Group Incompatibility, Blood Component Removal, Properdin, Kidney Failure, Chronic, 030211 gastroenterology & hepatology, Female, Adsorption, business, immunoadsorption
Abstract

International audience; The complement system has been implicated in several kidney diseases, such as antibody-mediated rejection after kidney transplantation. Antibody-depletion techniques allow successful ABO- and/or HLA-incompatible transplantation. Considering the IgG removal, the use of semi-selective immunoadsorption (IA) has been advocated. However, because of results on incomplete IgM depletion, the adjunctive use of membrane filtration (MF) has been proposed to enhance the removal of macromolecules and to interfere with complement activation. This secondary endpoint analysis of a recently published randomized, controlled, cross-over trial was designed to investigate the effect of combined treatment IA + MF compared to IA alone on complement depletion. Two treatment sequences, a single session of IA + MF followed by IA (and vice versa), were analyzed with regard to C5b-9, properdin, and mannose-binding lectin (MBL) levels. Neither IA alone nor IA + MF provoked complement activation as demonstrated by stable low levels of C5b-9 after the procedure as compared to the previous. The combined treatment substantially lowered properdin (77% vs. 26% reduction, P

Published
2019
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3. Letter to the Editor: Protein phosphatase 1 subunit Ppp1r15a/GADD34 is overexpressed in systemic lupus erythematosus and related to the expression of type I interferon response genes

Author

Philippe Pierre, Laurence Bouillet, Jean-Louis Quesada, Françoise Sarrot-Reynauld, Chantal Dumestre-Pérard, Giovanna Clavarino, Jean-Yves Cesbron, Caroline Plazy, Pierre Audoin, LABORATOIRE D'IMMUNOLOGIE, Centre Hospitalier Universitaire [Grenoble] (CHU), Barrière Naturelle et Infectiosité (TIMC-IMAG-BNI), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Clinique de médecine interne, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, CIC- Grenoble, CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique [Grenoble] (CIC Grenoble ), and CHU Grenoble-Hôpital Michallon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
0303 health sciences, Protein subunit, Immunology, Protein phosphatase 1, Biology, Molecular biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Interferon, Unfolded protein response, medicine, Immunology and Allergy, Gene, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, medicine.drug
Abstract

International audience

Published
2018

4. Antibodies targeting circulating protective molecules in lupus nephritis: Interest as serological biomarkers

Author

Nicole M. Thielens, Giovanna Clavarino, Sophie Colliard, Chantal Dumestre-Pérard, Jean-Yves Cesbron, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, Kidney Glomerulus, Immunology, Lupus nephritis, Circulating protective molecules, Kidney, 03 medical and health sciences, 0302 clinical medicine, Immune system, Systemic lupus erythematosus, medicine, Humans, Lupus Erythematosus, Systemic, Immunology and Allergy, skin and connective tissue diseases, Autoantibodies, 030203 arthritis & rheumatology, biology, Pentraxins, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], business.industry, Autoantibody, medicine.disease, 3. Good health, Complement system, 030104 developmental biology, biology.protein, Female, Antibody, business, Nephritis, Biomarkers
Abstract

International audience; Lupus nephritis (LN) is one of the most frequent and severe manifestations of systemic lupus erythematosus (SLE), considered as the major predictor of poor prognosis. An early diagnosis of LN is a real challenge in the management of SLE and has an important implication in guiding treatments. In clinical practice, conventional parameters still lack sensitivity and specificity for detecting ongoing disease activity in lupus kidneys and early relapse of nephritis. LN is characterized by glomerular kidney injury, essentially due to deposition of immune complexes involving autoantibodies against cellular components and circulating proteins. One of the possible mechanisms of induction of autoantibodies in SLE is a defect in apoptotic cells clearance and subsequent release of intracellular autoantigens. Autoantibodies against soluble protective molecules involved in the uptake of dying cells, including complement proteins and pentraxins, have been described. In this review, we present the main autoantibodies found in LN, with a focus on the antibodies against these protective molecules. We also discuss their pathogenic role and conclude with their potential interest as serological biomarkers in LN.

Published
2018
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5. Autoantibodies targeting ficolin-2 in systemic lupus erythematosus patients with active nephritis

Author

Evelyne Gout, Jean-Yves Cesbron, Françoise Sarrot-Reynauld, Alban Deroux, Nicole M. Thielens, Laurence Bouillet, Nathalie Bardin, Chantal Dumestre-Pérard, Sophie Colliard, Mélanie Fougere, Noémie Jourde-Chiche, Giovanna Clavarino, Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Vascular research center of Marseille (VRCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Aix Marseille Université (AMU), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Clinique de médecine interne, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Grenoble Alpes (UGA), Centre recherche en CardioVasculaire et Nutrition (C2VN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), and Thomas, Frank

Subjects
Adult, Male, 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Lupus nephritis, Enzyme-Linked Immunosorbent Assay, Sensitivity and Specificity, Severity of Illness Index, Serology, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, systemic lupus erythematosus, immune system diseases, Lectins, Biopsy, Prevalence, medicine, ficolin-2, Humans, Lupus Erythematosus, Systemic, skin and connective tissue diseases, Autoantibodies, 030203 arthritis & rheumatology, lupus nephritis, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Systemic lupus erythematosus, medicine.diagnostic_test, anti-ficolin-2 antibodies, business.industry, Biopsy, Needle, Autoantibody, biomarkers, Middle Aged, medicine.disease, Immunohistochemistry, 3. Good health, 030104 developmental biology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Antibodies, Antinuclear, Immunology, Biomarker (medicine), [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, business, Nephritis, Anti-SSA/Ro autoantibodies
Abstract

Objective Systemic lupus erythematosus (SLE) is a multi-system inflammatory disease characterized by production of various autoantibodies. The aim of this study was to investigate the presence of anti-ficolin-2 antibodies in SLE patients and to evaluate the association between the levels of these autoantibodies, clinical manifestations, and disease activity. Methods This is a comparative study using a cohort of 165 SLE patients and 48 healthy subjects. SLE patients were further divided into two groups, with “low disease activity” (SLEDAI score ≤ 4, n = 88) and with “high disease activity” (SLEDAI score > 4, n = 77). Clinical manifestations were defined according to the physician in charge. Active lupus nephritis (LN) was documented by kidney biopsy. Detection of anti-ficolin-2 antibodies was performed by ELISA. Results Levels of the anti-ficolin-2 autoantibodies were significantly higher in SLE patients as compared to healthy subjects and associated with the SLEDAI score. They were found positive in 61/165 (37%) SLE patients. Presence of anti-ficolin-2 antibodies was significantly related only to renal involvement, with a very high prevalence (86%) of anti-ficolin-2 antibodies in SLE patients with active LN. Patients with active proliferative LN had significantly more positive anti-ficolin-2 antibodies than those with non-proliferative LN. The combination of anti-ficolin-2, anti-ficolin-3 and anti-C1q demonstrated a very high specificity (98%) for the diagnosis of active LN. Conclusion Our results support the usefulness of anti-ficolin-2 as a complementary serological biomarker for the diagnosis of active lupus with renal manifestation. This article is protected by copyright. All rights reserved.

Published
2018
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6. Female Infertility and Serum Auto-antibodies: a Systematic Review

Author

Alban Deroux, Laurence Bouillet, Camille Dunand-Faure, Pascale Hoffmann, Chantal Dumestre-Pérard, Service de médecine interne [CHU Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service d'immunologie [CHU Grenoble], CHU de Grenoble, Barrière Naturelle et Infectiosité (TIMC-IMAG-BNI), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Clinique de médecine interne, and Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble

Subjects
0301 basic medicine, Anti-nuclear antibody, MESH: Trophoblasts, medicine.medical_treatment, Autoimmunity, Serum auto-antibodies, MESH: Antibodies, Antinuclear, Endometrium, 0302 clinical medicine, MESH: Pregnancy, MESH: Antibodies, Antiphospholipid, Pregnancy, Adrenal Glands, Immunology and Allergy, MESH: Autoantibodies, Auto-immunity, MESH: Adrenal Glands, Unexplained infertility, education.field_of_study, 030219 obstetrics & reproductive medicine, MESH: Infertility, Female, Obstetrics, Assisted reproduction, Female infertility, Reproductive technique, General Medicine, Anti-nuclear antibodies, Trophoblasts, 3. Good health, MESH: Reproductive Techniques, Assisted, MESH: Endometrium, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Antibodies, Antinuclear, Antibodies, Antiphospholipid, Female, Immunomodulator, Thyroid function, Infertility, Female, Infertility, MESH: Ovary, medicine.medical_specialty, Reproductive Techniques, Assisted, Anti-phospholipid antibodies, Population, Fertilization in Vitro, 03 medical and health sciences, MESH: Autoimmunity, medicine, Humans, education, Autoantibodies, Gynecology, In vitro fertilisation, MESH: Humans, business.industry, Ovary, medicine.disease, MESH: Fertilization in Vitro, 030104 developmental biology, business, MESH: Female
Abstract

International audience; On average, 10 % of infertile couples have unexplained infertility. Auto-immune disease (systemic lupus erythematosus, anti-phospholipid syndrome) accounts for a part of these cases. In the last 20 years, aspecific auto-immunity, defined as positivity of auto-antibodies in blood sample without clinical or biological criteria for defined diseases, has been evoked in a subpopulation of infertile women. A systematic review was performed (PUBMED) using the MESH search terms "infertility" and "auto-immunity" or "reproductive technique" or "assisted reproduction" or "in vitro fertilization" and "auto-immunity." We retained clinical and physiopathological studies that were applicable to the clinician in assuming joint management of both infertility associated with serum auto-antibodies in women. Thyroid auto-immunity which affects thyroid function could be a cause of infertility; even in euthyroidia, the presence of anti-thyroperoxydase antibodies and/or thyroglobulin are related to infertility. The presence of anti-phospholipid (APL) and/or anti-nuclear (ANA) antibodies seems to be more frequent in the population of infertile women; serum auto-antibodies are associated with early ovarian failure, itself responsible for fertility disorders. However, there exist few publications on this topic. The methods of dosage, as well as the clinical criteria of unexplained infertility deserve to be standardized to allow a precise response to the question of the role of serum auto-antibodies in these women. The direct pathogenesis of this auto-immunity is unknown, but therapeutic immunomodulators, prescribed on a case-by-case basis, could favor pregnancy even in cases of unexplained primary or secondary infertility.

Published
2017
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7. Unfolded protein response gene GADD34 is overexpressed in rheumatoid arthritis and related to the presence of circulating anti-citrullinated protein antibodies

Author

Laurent Grange, Maxime Chevreau, Philippe Pierre, Candice Trocme, Marine Clay, Souad Adriouach, Evelina Gatti, Jean-Louis Quesada, Jean-Yves Cesbron, Chantal Dumestre-Pérard, Philippe Gaudin, Giovanna Clavarino, Barrière Naturelle et Infectiosité (TIMC-IMAG-BNI), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire d'immunologie, CHU Grenoble, Direction de la Recherche Clinique et de l'Innovation, Pole Recherche, Clinique Universitaire de Rhumatologie, hôpital Sud, CHU de Grenoble, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire de Biochemie des enzymes et des protéines, Centre Hospitalier Universitaire [Grenoble] (CHU), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Immunology, Gene Expression, Peripheral blood mononuclear cell, Proinflammatory cytokine, Arthritis, Rheumatoid, 03 medical and health sciences, Protein Phosphatase 1, Gene expression, Odds Ratio, Immunology and Allergy, Medicine, Humans, ComputingMilieux_MISCELLANEOUS, Autoantibodies, biology, business.industry, Anti–citrullinated protein antibody, 3. Good health, 030104 developmental biology, Real-time polymerase chain reaction, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Case-Control Studies, Unfolded protein response, biology.protein, Leukocytes, Mononuclear, Biomarker (medicine), Female, Antibody, business, Biomarkers
Abstract

Growth arrest and DNA damage-inducible gene 34 (GADD34) is an inducible cofactor of protein phosphatase 1, which has an important role in the unfolded protein response. GADD34 has been shown to be necessary for type I interferon and proinflammatory cytokine production in response to viral infection in murine models. We investigate the expression of GADD34 in rheumatoid arthritis (RA), in which proinflammatory cytokines have an important pathogenic role. The objective of this study was to evaluate the potential of GADD34 expression as a biomarker in RA patients. We report a case-control study on GADD34 gene expression in peripheral blood mononuclear cells of patients (n = 75) with RA and age- and sex-matched healthy controls (n = 25). The study was approved by the relevant local ethics committees. GADD34 gene expression level in peripheral blood mononuclear cells was measured by quantitative PCR and analyzed with Mann-Whitney test. The relation between GADD34 gene overexpression and clinical or biological characteristics was analyzed with univariate and multivariate analysis. GADD34 gene expression was significantly higher in RA patients compared with healthy controls (p ≤ 0.001). Interestingly, GADD34 overexpression in PBMC of patients was related to the presence of circulating anti-citrullinated protein antibodies (p = 0.030). Data of this study strengthen the evidence of an unfolded protein response during the course of RA and provide an insight of the potential interest in GADD34 as a relevant marker for RA.

Published
2016

8. Towards a specific marker for acute bradykinin-mediated angioedema attacks: a literature review

Author

Alban Deroux, Chantal Dumestre-Pérard, Laurence Bouillet, Isabelle Vilgrain, Isabelle Boccon-Gibod, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Centre Hospitalier Universitaire [Grenoble] (CHU), Clinique de médecine interne, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, and Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Bradykinin, Dermatology, Disease, endothelial dysfunction, C1-inhibitor, Fibrin Fibrinogen Degradation Products, chemistry.chemical_compound, Von Willebrand factor, medicine, Humans, Mast Cells, Angioedema, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, vascular permeability, VE cadherin, C1 inhibitor, Endothelin-1, biology, business.industry, Interleukins, biomarkers, Angiotensin-converting enzyme, medicine.disease, Blood Coagulation Factors, hereditary angioedema, 3. Good health, C-Reactive Protein, chemistry, Hereditary angioedema, Immunology, biology.protein, Biomarker (medicine), medicine.symptom, E-Selectin, business, Complement C1 Inhibitor Protein, Histamine
Abstract

Background: Bradykinin-mediated angioedema (AE) is a rare disease characterised by recurrent angioedema linked to acquired (e.g. angiotensin converting enzyme inhibitor induced AE) or hereditary disorders (e.g. AE type I or II). As the clinical picture can be misleading, diagnosis of this disease is sometimes difficult. A bradykinin-mediated AE attack may be a therapeutic emergency which requires access to effective, but expensive, treatments. Their prescription must therefore be justified. No specific marker of acute bradykinin-mediated AE attacks has yet been identified to facilitate the therapeutic decision but it has been sought in many studies. Purpose: This article reviews the literature on this type of biomarker, comparing candidate bradykinin-mediated AE markers to candidate markers of mast cell activation. Conclusion: The most interesting biomarkers are those linked to endothelial stress (VE cadherin, E-selectin, endothelin-1, von Willebrand factor and its activity) which is significantly increased during an AE attack. All these markers must now be validated by prospective studies to determine their specificity and utility in diagnosis.

Published
2015
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9. Ataxia with Cerebellar Lesions in Mice Expressing Chimeric PrP-Dpl Protein

Author

Catherine Lemaire-Vieille, Jean-Yves Cesbron, Yannick Bailly, Paul Erlich, Anne-Marie Haeberlé, Jacques Brocard, Guy Bombarde, Corinne Loeuillet, Chantal Dumestre-Pérard, Valérie Demais, Jean Gagnon, Camille Rak, Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), UPR 2356 - Neurotransmission et Secrétion Neuroendocrine, Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Plateforme d'Imagerie In Vitro, Université Louis Pasteur - Strasbourg I-Institut Fédératif de Recherche 37 des Neurosciences, Laboratoire d'Immunologie, CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
Ataxia, Prions, Transgene, Blotting, Western, Mice, Transgenic, Peptide, Biology, GPI-Linked Proteins, Mice, 03 medical and health sciences, 0302 clinical medicine, Microscopy, Electron, Transmission, Cerebellum, medicine, Animals, 030304 developmental biology, chemistry.chemical_classification, Transplantation Chimera, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, General Neuroscience, Embryo, Articles, Immunohistochemistry, Fusion protein, Molecular biology, Phenotype, Amino acid, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, Toxicity, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, 030217 neurology & neurosurgery
Abstract

Mutations within the central region of prion protein (PrP) have been shown to be associated with severe neurotoxic activity similar to that observed with Dpl, a PrP-like protein. To further investigate this neurotoxic effect, we generated lines of transgenic (Tg) mice expressing three different chimeric PrP-Dpl proteins. Chi1 (amino acids 1–57 of Dpl replaced by amino acids 1–125 of PrP) and Chi2 (amino acids 1–66 of Dpl replaced by amino acids 1–134 of PrP) abrogated the pathogenicity of Dpl indicating that the presence of a N-terminal domain of PrP (23–134) reduced the toxicity of Dpl, as reported. However, when the amino acids 1–24 of Dpl were replaced by amino acids 1–124 of PrP, Chi3 Tg mice, which express the chimeric protein at a very low level, start developing ataxia at the age of 5–7 weeks. This phenotype was not counteracted by a single copy of full-length-PrPcbut rather by its overexpression, indicating the strong toxicity of the chimeric protein Chi3. Chi3 Tg mice exhibit severe cerebellar atrophy with a significant loss of granule cells. We concluded that aa25 to aa57 of Dpl, which are not present in Chi1 and Chi2 constructs, confer toxicity to the protein. We tested this possibility by using the 25–57 Dpl peptide in primary culture of mouse embryo cortical neurons and found a significant neurotoxic effect. This finding identifies a protein domain that plays a role in mediating Dpl-related toxicity.

Published
2013
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10. M-ficolin interacts with the long pentraxin PTX3: a novel case of cross-talk between soluble pattern-recognition molecules

Author

Gérard J. Arlaud, Christine Moriscot, Andrea Doni, Guy Schoehn, Chantal Dumestre-Pérard, Nicole M. Thielens, Monique Lacroix, Evelyne Gout, Julien Pérard, Alberto Mantovani, Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Unité de Biochimie des Cancers et Biothérapies, CHU Grenoble, Unité Mixte de Thérapie Cellulaire et Tissulaire, Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Unit for Virus Host-Cell Interactions [Grenoble] (UVHCI), Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS), Humanitas Clinical and Research Institute, Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), and Centre National de la Recherche Scientifique (CNRS)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
MESH: Signal Transduction, MESH: Serum Amyloid P-Component, Ligands, chemistry.chemical_compound, MESH: Protein Structure, Tertiary, MESH: Mutant Proteins, 0302 clinical medicine, MESH: Lectins, Lectins, MESH: Ligands, Immunology and Allergy, MESH: Immunity, Humoral, 0303 health sciences, biology, MESH: Acetylglucosamine, PTX3, Cell biology, MESH: Surface Plasmon Resonance, Serum Amyloid P-Component, C-Reactive Protein, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Biochemistry, MESH: Calcium, MESH: N-Acetylneuraminic Acid, Ficolin, Protein Binding, Signal Transduction, MESH: Immune Tolerance, Immunology, MESH: Microscopy, Electron, Acetylglucosamine, 03 medical and health sciences, Tetramer, MESH: C-Reactive Protein, Immune Tolerance, Humans, MESH: Protein Binding, 030304 developmental biology, Innate immune system, MESH: Humans, Pentraxins, Lectin, Surface Plasmon Resonance, N-Acetylneuraminic Acid, Immunity, Humoral, Protein Structure, Tertiary, Sialic acid, Complement system, Microscopy, Electron, chemistry, biology.protein, Calcium, Mutant Proteins, 030215 immunology
Abstract

Ficolins and pentraxins are soluble oligomeric pattern-recognition molecules that sense danger signals from pathogens and altered self-cells and might act synergistically in innate immune defense and maintenance of immune tolerance. The interaction of M-ficolin with the long pentraxin pentraxin 3 (PTX3) has been characterized using surface plasmon resonance spectroscopy and electron microscopy. M-ficolin was shown to bind PTX3 with high affinity in the presence of calcium ions. The interaction was abolished in the presence of EDTA and inhibited by N-acetyl-D-glucosamine, indicating involvement of the fibrinogen-like domain of M-ficolin. Removal of sialic acid from the single N-linked carbohydrate of the C-terminal domain of PTX3 abolished the interaction. Likewise, an M-ficolin mutant with impaired sialic acid-binding ability did not interact with PTX3. Interaction was also impaired when using the isolated recognition domain of M-ficolin or the monomeric C-terminal domain of PTX3, indicating requirement for oligomerization of both proteins. Electron microscopy analysis of the M-ficolin–PTX3 complexes revealed that the M-ficolin tetramer bound up to four PTX3 molecules. From a functional point of view, immobilized PTX3 was able to trigger M-ficolin–dependent activation of the lectin complement pathway. These data indicate that interaction of M-ficolin with PTX3 arises from its ability to bind sialylated ligands and thus differs from the binding to the short pentraxin C-reactive protein and from the binding of L-ficolin to PTX3. The M-ficolin–PTX3 interaction described in this study represents a novel case of cross-talk between soluble pattern-recognition molecules, lending further credit to the integrated view of humoral innate immunity that emerged recently.

Published
2011
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11. Bradykinin receptor 2 antagonist (icatibant) for hereditary angioedema type III attacks

Author

Anne Gompel, C. Massot, Christian Drouet, Joël Lunardi, Chantal Dumestre-Pérard, Isabelle Boccon-Gibod, Jean Yves Cesbron, Laurence Bouillet, Nicole Monnier, Denise Ponard, département de médecine interne, CHU Grenoble, Laboratoire d'Immunologie, GREPI, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF) - Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP) - IMAG - Centre National de la Recherche Scientifique (CNRS) - Université Grenoble Alpes (UGA) - Université Joseph Fourier - Grenoble 1 (UJF) - Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP) - IMAG - Centre National de la Recherche Scientifique (CNRS) - Université Grenoble Alpes (UGA) - Groupe de Recherche et d'Etudes du Processus Inflammatoire (GREPI), Université Joseph Fourier - Grenoble 1 (UJF) - Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Université Joseph Fourier - Grenoble 1 (UJF) - Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie et génétique moléculaire, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF) - CHU Grenoble - Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie et Génétique Moléculaire, Dept of Physiology, McGill University, Unité de Gynécologie, Assistance publique - Hôpitaux de Paris (AP-HP) - Université Paris Descartes - Paris 5 (UPD5) - Hôpital Hôtel-Dieu [Paris], Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Groupe de Recherche et d'Etudes du Processus Inflammatoire (GREPI), Université Joseph Fourier - Grenoble 1 (UJF)-Université Joseph Fourier - Grenoble 1 (UJF), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Hôpital Hôtel-Dieu [Paris], VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), McGill University = Université McGill [Montréal, Canada], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Hôpital Hôtel-Dieu [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Pulmonary and Respiratory Medicine, BRADYKININ RECEPTOR 2, MESH: Complement C1 Inhibitor Protein, Immunology, Treatment outcome, MESH : Adrenergic beta-Antagonists, MESH : Complement C1 Inhibitor Protein, Bradykinin, MESH : Treatment Outcome, MESH : Gene Deletion, Pharmacology, MESH: Hereditary Angioedema Type III, MESH : Receptors, Bradykinin, Adrenergic beta-Antagonists, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Icatibant, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Immunology and Allergy, Medicine, Hereditary Angioedema Type III, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Female, 030212 general & internal medicine, Injections subcutaneous, ComputingMilieux_MISCELLANEOUS, MESH: Treatment Outcome, MESH: Bradykinin, MESH: Humans, business.industry, MESH : Humans, Antagonist, MESH: Injections, Subcutaneous, MESH: Adrenergic beta-Antagonists, MESH: Adult, MESH : Adult, 3. Good health, MESH: Receptors, Bradykinin, chemistry, MESH : Bradykinin, MESH: Gene Deletion, MESH : Hereditary Angioedema Type III, business, MESH: Female, MESH : Injections, Subcutaneous, 030215 immunology
Abstract

International audience

Published
2009

12. Residue Lys57 in the collagen-like region of human L-ficolin and its counterpart Lys47 in H-ficolin play a key role in the interaction with the mannan-binding lectin-associated serine proteases and the collectin receptor calreticulin

Author

Monique Lacroix, Nicole M. Thielens, Gunnar Houen, Guy Schoehn, Jean-Yves Cesbron, Gérard J. Arlaud, Chantal Dumestre-Pérard, Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Unit of Virus Host Cell Interactions (UVHCI), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Department of Autoimmunology, Statens Serum Institut [Copenhagen], Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Gagnon, Jean

Subjects
Proteases, Immunology, CHO Cells, Biology, Mannose-Binding Lectin, Cell Line, Serine, Cricetulus, Cricetinae, Lectins, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, Immunology and Allergy, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Binding site, Mannan-binding lectin, Binding Sites, Membrane Glycoproteins, Sequence Homology, Amino Acid, Lysine, Genetic Variation, Lectin, Molecular biology, Recombinant Proteins, Receptors, Complement, Complement system, Biochemistry, Mannose-Binding Protein-Associated Serine Proteases, Lectin pathway, biology.protein, Collagen, Calreticulin, Ficolin
Abstract

L- and H-ficolins are serum oligomeric defense proteins consisting of a collagen-like region and a fibrinogen-like recognition domain that bind to pathogen- and apoptotic cell-associated molecular patterns. They share with mannan-binding lectin (MBL) the ability to associate with MBL-associated serine proteases (MASP)-1, -2, -3, and protein MAp19 and to trigger the lectin complement pathway through MASP-2 activation. Recent studies have revealed the essential role of Lys55 in the collagenous region of MBL in the interaction with the MASPs and calreticulin (CRT). To test the possible involvement of the homologous residues Lys57 of L-ficolin and Lys47 of H-ficolin, point mutants of both proteins were produced in which these residues were mutated to Ala, Glu, or Arg. The resulting mutants exhibited oligomerization patterns and ligand binding properties similar to those of their wild-type counterparts. In contrast, all three mutations strongly inhibited the interaction of L- and H-ficolins with MAp19 and MASP-2 and impaired the ability of each ficolin to trigger the lectin pathway. In the case of MASP-1 and MASP-3, replacement of the target Lys residues by Ala or Glu abolished interaction, whereas the Lys to Arg mutations had only slight inhibitory effects. Likewise, binding of each ficolin to CRT was inhibited by mutation of Lys to Ala or Glu, but not to Arg. In conclusion, residues Lys57 of L-ficolin and Lys47 of H-ficolin are key components of the interaction with the MASPs and CRT, providing strong indication that MBL and the ficolins share homologous binding sites for both types of proteins.

Published
2009

13. Intérêt des anticorps anti-ficoline-2 dans la néphropathie lupique

Author

Colliard, Sophie, Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Chantal Dumestre-Pérard

Subjects
Lupus érythémateux systémique, Biomarqueurs, Néphropathie lupique, Systemic lupus erythematosus, Lupus nephritis, Ficolin-2, Anticorps anti-ficoline-2, Anti-ficolin-2 antibodies, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, skin and connective tissue diseases, Biomarkers
Abstract

Mémoire de Diplôme d'Etudes Spécialisées (DES) tenant lieu de thèse d'exercice.; Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by a broad spectrum of clinical manifestations and the production of various autoantibodies. The management of the SLE patient is difficult regarding the unpredictable clinical damage and their diversity. Predicting them can be crucial, especially in lupus kidneys, since they condition the patient's functional and vital prognosis. Lupus nephritis (LN) is one of the most serious complications of SLE. The aim of this stuy is twofold : on the one hand, to demonstrate the presence of anti-ficolin-2 antibodies in SLE patients and, on the other, to evaluate their interest in LN. This is a study using 48 healthy subjects and a cohort of 165 SLE patients, including 77 SLE patients with flares. 38 SLE patients had a renal involvment. Detection of anti-ficolin-2 antibodies was performed by ELISA. The anti-ficolin-2 autoantibodies are found positive in 37 % SLE patients and are associated with the global activity of SLE using the SLEDAI score. Therefore, anti-ficolin-2 antibodies significantly related to renal involvement, with a prevalence of 86 % in SLE patients with LN. Anti-ficolin-2 antibodies were associated with proliferative LN. The combination of anti-ficolin-2, anti-ficolin-3 and anti-C1q demonstrated a specificity of 98 % for the diagnosis of LN. Detecting the presence of anti-ficolin-2 antibodies represents an interest for the diagnosis of LN.; Le Lupus Erythémateux Systémique (LES) est une maladie auto-immune caractérisée par un large spectre de manifestations cliniques et la production de nombreux auto-anticorps. La prise en charge du patient lupique est une tâche difficile au regard de l’imprévisibilité des atteintes et de leur diversité. Les anticiper peut s’avérer crucial, particulièrement en cas d’atteintes rénales, puisqu’elles conditionnent le pronostic fonctionnel et vital du patient. La néphropathie lupique (NL) est une des complications les plus sévères du LES. L’objectif de ce travail est double : d’une part, démontrer la présence d’anticorps anti-ficoline-2 chez les patients lupiques, et d’autre part, évaluer l’intérêt de ces anticorps dans la NL. Cette étude inclue 48 sujets sains et 165 patients lupiques, dont 77 patients en poussée. 38 patients avaient une atteinte rénale. Les taux des anticorps anti-ficoline-2 ont été déterminés par ELISA. Les anticorps anti-ficoline-2 sont présents chez 37 % des patients lupiques et associés à l’activité globale du LES évaluée par le SLEDAI. De plus, les anticorps anti-ficoline-2 sont spécifiquement corrélés à l’atteinte rénale lupique et leur prévalence, dans ces atteintes, s’élève à 86 %. Les anticorps anti-ficoline-2 sont associés de façon significative aux NL de forme proliférative. La combinaison des anticorps anti-ficoline-2, anti-ficoline-3 et anti-C1q permet d’atteindre une spécificité diagnostique pour la NL de 98 %. La recherche des anticorps anti-ficoline-2 présente un intérêt dans le diagnostic de la néphropathie lupique.

Published
2017

14. Les marqueurs biologiques du lupus érythémateux disséminé, intérêt des anticorps anti-ficoline H

Author

Baron Lhéritier, Élise, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Chantal Dumestre-Pérard

Subjects
Anticorps anti-ADN, Anticorps anti-ficoline H, Ficoline H, Néphrite lupique, Lupus érythémateux disséminé, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Mémoire de DES (Diplôme d’Études Spécialisées) tenant lieu de thèse d'exercice; Le lupus érythémateux disséminé est une connectivite fréquente. Les marqueurs biologiques actuels, notamment les anticorps anti-ADN et les anticorps anti-C1q, sont insuffisants pour le suivi de cette pathologie en particulier en cas d’atteinte rénale. Les anticorps anti-ADN, marqueur le plus utilisé, sont très variables selon les techniques de dosage. La ficoline H est une protéine de reconnaissance de la voie des lectines du complément ; elle a un faible rôle anti-infectieux mis en évidence et par contre un rôle puissant d’opsonisation des cellules apoptotiques. La ficoline H a été initialement identifiée comme un antigène cible d’auto-anticorps chez des patients lupiques. L’objectif principal de cette étude a donc été d’évaluer l’intérêt des anticorps anti-ficoline H, parmi les autres marqueurs biologiques, chez 136 patients lupiques. Notre étude a montré que les anticorps anti-ficoline H sont présents de façon significative chez les patients lupiques par rapport aux sujets sains. Elle a aussi montré que ces anticorps sont associés à l’activité lupique : corrélation avec le SLEDAI (« Systemic lupus erythematosus disease activity index ») (50 patients en poussée, 86 patients en rémission). Chez ces patients en poussée les anticorps anti-ficoline H sont associés à l’atteinte rénale et non aux autres types d’atteintes. Ces résultats sont confirmés dans le suivi de 11 patients. En conclusion, le dosage des anticorps anti-ficoline H semble utile au diagnostic et au suivi, en particulier rénal, des patients lupiques.

Published
2013

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