Ab dem 31. Januar stellt buchhandel.de die Verkaufsfunktion ein!

Bitte sichern Sie alle notwendigen Daten, wie etwa Rechnungen oder Ihre Wunschliste in Ihrem Kundenprofil.
Weitere Informationen finden Sie hier: https://www.buchhandel.de/info/hilfe.
Suche ›

Distinction of vasculitis-associated ANCA subsets and their pathogenic role in a new mouse model with the humanized target antigen

29,80 € Preisreferenz Lieferbar in 2-3 Tagen


Granulomatosis with Polyangiitis (GPA) is an ANCA (anti-neutrophil cytoplasmic antibody) associated vasculitis. It typically starts in the respiratory tract and the lungs and progresses to a generalized life-threatening, relapsing-remitting disease of small blood vessels in multiple essential organs such as the lungs and kidneys. GPA is strongly associated with the presence of autoantibodies, so-called ANCA, which are mainly directed against the neutrophil serine protease proteinase 3 (PR3). Despite numerous attempts to determine the role of ANCA at the onset and during progression of GPA, the pathogenicity of ANCA remains still unclear. The aim of this thesis was to explore the mechanisms by which ANCA contribute to the development of GPA and influence disease progression and severity. The induction of small-vessel vasculitis by the action of ANCA was investigated using a newly developed humanized mouse model. Transfer of monoclonal antibodies (mAbs) against human PR3 (hPR3) into a hPR3 knock-in mouse was planned to provide new insights into the pathogenicity of ANCA. Expression and functionality of hPR3 in the neutrophils of the newly generated mouse line was observed. Active hPR3 was transported to the surface of the neutrophils and was thus accessible to antibodies. Based on the literature, antibodies, which are able to inhibit the proteolytic activity of PR3, were thought to have the highest pathogenic potential and to influence the development of relapses. Characterization of mAbs indeed revealed one mAb, MCPR3-7, as inhibiting for PR3 and this mAb even impaired the interaction of PR3 with its natural inhibitor, a1-proteinase inhibitor. This antibody, however, could not be used for transfer experiments, due to its inability to bind to membrane-bound PR3. Analysis of a large GPA patient cohort confirmed the existence of ANCA with inhibitory capacity towards PR3. Inhibitory ANCA, however, were not restricted to samples from relapsing patients, but occurred also during remission phases. No correlation of inhibitory ANCA with disease outbreak, relapses or severity could be detected. Therefore, instead of transferring inhibitory PR3 antibodies, non-inhibitory antibodies of different IgG subclasses were evaluated in hPR3 knock-in mice. One mAb was indeed able to induce a strong inflammatory response in the mice, proofing their pathogenic potential. After recruitment of immune cells, activation and degranulation of neutrophils led to vasculitis-like and pulmonary lesions. IgG2a antibodies were able to elicit a stronger inflammatory response than IgG2b, suggesting that the development of a GPA-like phenotype seems to be dependent on the IgG subclass.


Titel: Distinction of vasculitis-associated ANCA subsets and their pathogenic role in a new mouse model with the humanized target antigen
Autoren/Herausgeber: Lisa Hinkofer
Aus der Reihe: Edition Scientifique
Ausgabe: Neuausgabe

ISBN/EAN: 9783835962958

Seitenzahl: 131
Format: 21 x 14,6 cm
Produktform: Buch
Gewicht: 259 g
Sprache: Englisch

buchhandel.de - Newsletter
Möchten Sie sich für den Newsletter anmelden?

Bitte geben Sie eine gültige E-Mail-Adresse ein.
Lieber nicht