title: Immunological and structural analysis of IgE-mediated cross-reactivity between manganese superoxide dismutases.
abstract: BACKGROUND
  Allergy results from inappropriate immune responses to normally innocuous proteins. More than 300 IgE-binding proteins have been cloned and shown to cover structurally and functionally heterogeneous protein families including enzymes, backbone and storage proteins as well as proteins with unknown function. Structurally related cross-reactive allergens are involved in the pathogenesis of important clinical syndromes. We found that phylogenetically highly conserved proteins, including human manganese superoxide dismutase (MnSOD), are involved in IgE-mediated autoreactivity.
  
  
  METHODS
  MnSOD cloned from different phylogenetically distant species were produced as recombinant proteins in Escherichia coli and used to study IgE-mediated cross-reactivity and proliferative responses in peripheral blood mononuclear cells (PBMC) of individuals sensitised to Aspergillus fumigatus MnSOD. Homology models of the three-dimensional structures of MnSOD from A. fumigatus, Drosophila melanogaster and Saccharomyces cerevisiae using the human MnSOD structure refined at 2.2 A as template were constructed to identify conserved amino acid residues exposed to the solvent.
  
  
  RESULTS
  Cross-reactivity between the MnSOD at B and T cell level was demonstrated by inhibition experiments showing shared B cell epitopes and by the capability of the different MnSODs to induce proliferative responses in PBMCs of sensitised individuals. Structural modelling allowed to identify conserved residues exposed to the solvent. The identified residues are scattered over the sequence of the enzyme indicating putative conformational IgE-binding epitopes.
  
  
  CONCLUSIONS
  The results obtained corroborate molecular mimicry as a plausible mechanism to explain autoreactivity to human MnSOD. Moreover, homology modelling provides a rational tool to identify conserved residues involved in defining cross-reactive B cell epitopes.
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Flückiger
authors.forename: Leonardo
authors.initials: L
authors.lastname: Scapozza
authors.forename: Christina
authors.initials: C
authors.lastname: Mayer
authors.forename: Kurt
authors.initials: K
authors.lastname: Blaser
authors.forename: Gerd
authors.initials: G
authors.lastname: Folkers
authors.forename: Reto
authors.initials: R
authors.lastname: Crameri
mesh_terms: D000328:Adult; D000485:Allergens / Q000737:chemistry / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000175:diagnosis / Q000276:immunology*; D001232:Aspergillus fumigatus / Q000201:enzymology; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology; D002478:Cells, Cultured; D017124:Conserved Sequence; D003429:Cross Reactions; D004331:Drosophila melanogaster / Q000201:enzymology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000276:immunology; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D020539:Sequence Analysis, Protein; D017386:Sequence Homology, Amino Acid; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*
chemical_list: D000485:Allergens; D001324:Autoantigens; D000939:Epitopes; D011994:Recombinant Proteins; D007073:Immunoglobulin E; D013482:Superoxide Dismutase