Zweigstelle	Standorte	Status	Vorbestellungen	Frist	Barcode	Lageplan	Ausleihhinweis
Zweigstelle: Hauptstelle	Standorte: Diss. Gulo	Status: Verfügbar	Vorbestellungen: 0	Frist:	Barcode: 00317969	Lagepläne: Lageplan	Ausleihhinweis:

Streptococcus pyogenes infects more than 600 million humans every year. Moreover, this bacterium causes acute rheumatic fever (ARF), an autoimmune sequela that frequently develops into rheumatic heart disease (RHD),a leading health problem in several low-resource regions in the world. Streptococcal M protein has been implicated in the pathogenesis of ARF. This protein triggers autoimmunity by molecular mimicry of host proteins with coiled-coil structure such as myosin or laminin. In addition, a collagen-binding A/T/E)xYLxx(L/F)N motif that occurs in the N-terminal part of some M proteins evoked collagen IV autoimmunity in vivo. This collagen IV autoimmunity is observed in ARF patients, but is not caused by molecular mimicry. Because patient and experimental data suggested a link between the collagen binding motif and the autoimmune responses in ARF, the motif was named “peptide associated with rheumatic fever” (PARF). However, the role of collagen-binding by M proteins in triggering anti-collagen IV and other autoimmune responses remained elusive. Therefore, different M proteins were tested in this work for their ability to bind collagens I or IV and to evoke autoimmune responses against these collagens and the coiled-coil proteins myosin and laminin in a mouse model. The work proved for the first time that induction of collagen IV autoimmunity is PARF-specific, thus not caused by other parts or properties of the M protein. Further evidence for the role of PARF as a trigger of autoimmunity came from experiments with a recombinant protein (PARF tandem) that contained all known naturally occuring PARF motifs. PARF tandem induced autoimmunity against collagen IV and myosin in mice. Notably, PARF tandem induced in rabbit the production of opsonizing antibodies that reacted with PARF-positive M proteins. As immunization with PARF tandem caused autoimmunity, a vaccine strategy that targets PARF would require further development. The discovery of Spa as a novel collagen binding protein that triggers autoimmunity against collagen, broadens the spectrum of potential rheumatogenic factors in S. pyogenes. For the first time, a trigger of autoimmunity was identified in an emm-type (emm18) that is clearly associated with outbreaks of ARF. The presented work clearly points towards a role of interactions between host and microbial proteins in triggering autoimmunity and may have uncovered a new facet in the pathogenesis of autoimmune diseases in general.