Titel: | The Diagnostic Value of Circulating DNA and DNase1 for Hemolytic Uremic Syndrome | Sonstige Titel: | Der diagnostische Wert von zirkulierender DNA und DNase1 für das hämolytisch-urämische Syndrom | Sprache: | Englisch | Autor*in: | Janas, Elodie Christina Meral | Schlagwörter: | NETs; HUS; TMA; NETosis; DNase1; circulating DNA | GND-Schlagwörter: | DesoxyribonucleasenGND ThromboseGND Hämolytisch-urämisches SyndromGND Neutrophil Extracellular TrapGND EHECGND |
Erscheinungsdatum: | 2024 | Tag der mündlichen Prüfung: | 2025-01-08 | Zusammenfassung: | Hemolytic uremic syndrome (HUS) is a life-threatening disease characterized by acute thrombotic microangiopathy (TMA). The most common form of the disease is caused by infection with Shiga toxin-producing enterohemorrhagic Escherichia coli bacteria (STEC). TMAs are characterized by disseminated thrombi in the microvasculature and are associated with the formation of neutrophil extracellular traps (NETs). These NETs are composed of DNA fibers and are sensitive to digestion by plasma DNase1 in vitro. I hypothesize that HUS patients have large amounts of free extracellular DNA and lack efficient DNA resolution due to reduced DNase1 activity. To this end, I examined plasma DNA levels and plasma DNase1 activity in HUS patients in the acute stage of the disease and in remission compared to patients with non-STEC diarrhea symptoms, non-HUS-STEC infection and in healthy subjects. In this study, I show that HUS patients have elevated DNA plasma levels and decreased DNase1 activity at admission and in the acute disease state of HUS compared to healthy controls. Plasma DNA levels of HUS patients recover during therapy until discharge, whereas plasma DNase1 activity of HUS patients remains impaired compared to healthy controls. The plasma DNA content in the acute state is also increased in patients with non-HUS-STEC infection and non-STEC diarrhea symptoms compared to healthy controls, although the values in HUS patients are sometimes significantly higher. DNase1 activity is also reduced in patients with non-HUS-STEC infection and non-STEC diarrheal symptoms compared to healthy subjects, yet the picture emerges that HUS patients show the lowest DNase1 activities. High levels of plasma DNA appear to represent the acute disease state with excessive thrombi in the microvasculature. Impaired plasma DNase1 basal activity and thus inadequate plasma DNA or NET degradation can predestine a STEC patient for the development of HUS. More likely, DNase1 activity is depleted in the presence of large amounts of plasma DNA and requires more time to recover and be resynthesized in convalescent patients. To treat excessive thrombus formation in thrombotic diseases such as HUS, DNase1-mediated degradation of NETs may be crucial. TMAs have been shown to have impaired DNase1 activity, which may lead to impaired degradation of NETs. This lack of DNA degradation may contribute to HUS. Because NETs are known to trigger clotting through activation of platelets and clotting factors, inhibiting NET formation or eliminating it may prevent or treat the disease. It is conceivable that DNase1 could function as a drug against HUS, while DNase1 activity could serve as a retrospective parameter and plasma DNA levels could be used to monitor therapy. |
URL: | https://ediss.sub.uni-hamburg.de/handle/ediss/11508 | URN: | urn:nbn:de:gbv:18-ediss-125982 | Dokumenttyp: | Dissertation | Betreuer*in: | Renné, Thomas |
Enthalten in den Sammlungen: | Elektronische Dissertationen und Habilitationen |
Dateien zu dieser Ressource:
Datei | Prüfsumme | Größe | Format | |
---|---|---|---|---|
ElodieKoehler_dissertation.pdf.pdf | 6820592b1d4780154a4761a1c370098b | 1.82 MB | Adobe PDF | Öffnen/Anzeigen |
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