title: Crucial role of the CB3-region of collagen IV in PARF-induced acute rheumatic fever.
abstract: Acute rheumatic fever (ARF) and rheumatic heart disease are serious autoimmune sequelae to infections with Streptococcus pyogenes. Streptococcal M-proteins have been implicated in ARF pathogenesis. Their interaction with collagen type IV (CIV) is a triggering step that induces generation of collagen-specific auto-antibodies. Electron microscopy of the protein complex between M-protein type 3 (M3-protein) and CIV identified two prominent binding sites of which one is situated in the CB3-region of CIV. In a radioactive binding assay, M3-protein expressing S. pyogenes and S. gordonii bound the CB3-fragment. Detailed analysis of the interactions by surface plasmon resonance measurements and site directed mutagenesis revealed high affinity interactions with dissociation constants in the nanomolar range that depend on the recently described collagen binding motif of streptococcal M-proteins. Because of its role in the induction of disease-related collagen autoimmunity the motif is referred to as "peptide associated with rheumatic fever" (PARF). Both, sera of mice immunized with M3-protein as well as sera from patients with ARF contained anti-CB3 auto-antibodies, indicating their contribution to ARF pathogenesis. The identification of the CB3-region as a binding partner for PARF directs the further approaches to understand the unusual autoimmune pathogenesis of PARF-dependent ARF and forms a molecular basis for a diagnostic test that detects rheumatogenic streptococci.
authors.affiliation: Department of Microbial Pathogenesis, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Dinkla
authors.forename: Susanne R
authors.initials: SR
authors.lastname: Talay
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Rikki M A
authors.initials: RM
authors.lastname: Graham
authors.forename: Manfred
authors.initials: M
authors.lastname: Rohde
authors.forename: D Patric
authors.initials: DP
authors.lastname: Nitsche-Schmitz
authors.forename: Gursharan S
authors.initials: GS
authors.lastname: Chhatwal
mesh_terms: D000208:Acute Disease; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D024141:Collagen Type IV / Q000737:chemistry / Q000502:physiology* / Q000648:ultrastructure; D017931:DNA Primers; D005260:Female; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D046529:Microscopy, Electron, Transmission; D012213:Rheumatic Fever / Q000209:etiology* / Q000382:microbiology / Q000503:physiopathology; D013297:Streptococcus pyogenes / Q000472:pathogenicity; D020349:Surface Plasmon Resonance
chemical_list: D024141:Collagen Type IV; D017931:DNA Primers