title: Working mechanism of immunoglobulin A1 (IgA1) protease: cleavage of IgA1 antibody to Neisseria meningitidis PorA requires de novo synthesis of IgA1 Protease.
abstract: Neisseria meningitidis secretes a protease that specifically cleaves the hinge region of immunoglobulin A1 (IgA1), releasing the effector (Fc) domain of IgA1 from the antigen binding (Fab) determinants. Theoretically, the remaining Fab fragments can block pathogen receptors or toxins and still provide protection. Here, we describe binding of V-gene-matched human IgA1 and IgA2 to PorA of strain H44/76. On live meningococci, efficient cleavage of IgA1, but not cleavage of IgA2, was observed, and up to approximately 80% of the IgA1 Fc tails were lost from the meningococcal surface within 30 min. No cleavage of IgA1 was found on an isogenic H44/76 strain lacking IgA1 protease. Furthermore, our data indicate that PorA-bound IgA1 is masked by the serogroup B polysaccharide capsule, rendering the IgA1 less accessible to degradation by secreted IgA1 protease present in the bacterial surroundings. Experiments with protein synthesis inhibitors showed that de novo production of IgA1 protease was responsible for cleavage of PorA-bound IgA1 on encapsulated bacteria. Finally, our data suggest that cleavage of IgA1 by IgA1 protease releases a significant proportion of Fab fragments from the bacterium, probably as a result of their reduced avidity compared to that of whole antibodies.
authors.affiliation: Immunotherapy Laboratory, Department of Immunology, University Medical Center Utrecht (UMCU), The Netherlands. G.Vidarsson@lab.azu.nl
authors.forename: Gestur
authors.initials: G
authors.lastname: Vidarsson
authors.forename: Natasja
authors.initials: N
authors.lastname: Overbeeke
authors.forename: Annette M
authors.initials: AM
authors.lastname: Stemerding
authors.forename: Germie
authors.initials: G
authors.lastname: van den Dobbelsteen
authors.forename: Peter
authors.initials: P
authors.lastname: van Ulsen
authors.forename: Peter
authors.initials: P
authors.lastname: van der Ley
authors.forename: Mogens
authors.initials: M
authors.lastname: Kilian
authors.forename: Jan G J
authors.initials: JG
authors.lastname: van de Winkel
mesh_terms: D016667:Bacterial Capsules / Q000276:immunology; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D009345:Neisseria meningitidis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D009895:Opsonin Proteins / Q000276:immunology / Q000378:metabolism; D018272:Porins / Q000276:immunology*; D014176:Protein Biosynthesis / Q000187:drug effects; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D007070:Immunoglobulin A; D007140:Immunoglobulin Fab Fragments; D007141:Immunoglobulin Fc Fragments; D009895:Opsonin Proteins; D018272:Porins; C057699:porin protein, Neisseria; D012697:Serine Endopeptidases; C021433:IgA-specific serine endopeptidase