title: Antibodies from multiple sclerosis patients preferentially recognize hyperglucosylated adhesin of non-typeable Haemophilus influenzae.
abstract: In autoimmune diseases, there have been proposals that exogenous “molecular triggers”, i.e., specific ‘non-self antigens’ accompanying infectious agents, might disrupt control of the adaptive immune system resulting in serious pathologies. The etiology of multiple sclerosis (MS) remains unclear. However, epidemiologic data suggest that exposure to infectious agents may be associated with increased MS risk and progression may be linked to exogenous, bacterially-derived, antigenic molecules, mimicking mammalian cell surface glycoconjugates triggering autoimmune responses. Previously, antibodies specific to a gluco-asparagine (N-Glc) glycopeptide, CSF114(N-Glc), were identified in sera of an MS patient subpopulation. Since the human glycoproteome repertoire lacks this uniquely modified amino acid, we turned our attention to bacteria, i.e., Haemophilus influenzae, expressing cell-surface adhesins including N-Glc, to establish a connection between H. influenzae infection and MS. We exploited the biosynthetic machinery from the opportunistic pathogen H. influenzae (and the homologous enzymes from A. pleuropneumoniae) to produce a unique set of defined glucosylated adhesin proteins. Interestingly we revealed that a hyperglucosylated protein domain, based on the cell-surface adhesin HMW1A, is preferentially recognized by antibodies from sera of an MS patient subpopulation. In conclusion the hyperglucosylated adhesin is the first example of an N-glucosylated native antigen that can be considered a relevant candidate for triggering pathogenic antibodies in MS.
authors.affiliation: Departments of Biology and Chemistry Massachusetts Institute of Technology 77 Massachusetts Ave., Cambridge, MA, USA.
authors.forename: Marthe T C
authors.initials: MT
authors.lastname: Walvoort
authors.affiliation: French-Italian Interdepartmental Laboratory of Peptide and Protein Chemistry and Biology, University of Florence, 50019, Sesto Fiorentino, Italy.|Department of Neurosciences, Psychology, Drug Research and Child Health - Section of Pharmaceutical Sciences and Nutraceutics, University of Florence, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Testa
authors.affiliation: Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot, 761001, Israel.
authors.forename: Raya
authors.initials: R
authors.lastname: Eilam
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, 761001, Israel.
authors.forename: Rina
authors.initials: R
authors.lastname: Aharoni
authors.affiliation: French-Italian Interdepartmental Laboratory of Peptide and Protein Chemistry and Biology, University of Florence, 50019, Sesto Fiorentino, Italy.|Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Nuti
authors.affiliation: French-Italian Interdepartmental Laboratory of Peptide and Protein Chemistry and Biology, University of Florence, 50019, Sesto Fiorentino, Italy.|Department of Neurosciences, Psychology, Drug Research and Child Health - Section of Pharmaceutical Sciences and Nutraceutics, University of Florence, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Rossi
authors.affiliation: French-Italian Interdepartmental Laboratory of Peptide and Protein Chemistry and Biology, University of Florence, 50019, Sesto Fiorentino, Italy.|Department of Neurosciences, Psychology, Drug Research and Child Health - Section of Pharmaceutical Sciences and Nutraceutics, University of Florence, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.
authors.forename: Feliciana
authors.initials: F
authors.lastname: Real-Fernandez
authors.affiliation: Multiple Sclerosis Clinical Care and Research Centre, Department of Neurosciences, Reproductive Sciences and Odontostomatology, Federico II University, Via Sergio Pansini 5, 80131 Naples, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Lanzillo
authors.affiliation: Multiple Sclerosis Clinical Care and Research Centre, Department of Neurosciences, Reproductive Sciences and Odontostomatology, Federico II University, Via Sergio Pansini 5, 80131 Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Brescia Morra
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134 Firenze, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lolli
authors.affiliation: French-Italian Interdepartmental Laboratory of Peptide and Protein Chemistry and Biology, University of Florence, 50019, Sesto Fiorentino, Italy.|Department of Neurosciences, Psychology, Drug Research and Child Health - Section of Pharmaceutical Sciences and Nutraceutics, University of Florence, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Rovero
authors.affiliation: Departments of Biology and Chemistry Massachusetts Institute of Technology 77 Massachusetts Ave., Cambridge, MA, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Imperiali
authors.affiliation: French-Italian Interdepartmental Laboratory of Peptide and Protein Chemistry and Biology, University of Florence, 50019, Sesto Fiorentino, Italy.|Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy.|PeptLab@UCP and Laboratory of Chemical Biology EA4505, Université Paris-Seine, 5 Mail Gay-Lussac, 95031 Cergy-Pontoise, France.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Papini
mesh_terms: D018829:Adhesins, Bacterial / Q000276:immunology*; D000328:Adult; D000368:Aged; D000906:Antibodies / Q000276:immunology*; D000942:Antigens, Bacterial / Q000276:immunology; D001216:Asparagine / Q000276:immunology; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology; D005260:Female; D006001:Glycoconjugates / Q000276:immunology; D006020:Glycopeptides / Q000276:immunology; D006193:Haemophilus influenzae / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology*; D055815:Young Adult
chemical_list: D018829:Adhesins, Bacterial; D000906:Antibodies; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D006001:Glycoconjugates; D006020:Glycopeptides; D001216:Asparagine