Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Trakaki, A.
High-density lipoprotein (HDL) in Allergy and Skin Diseases: Elucidating the effects on HDL composition, metabolism and function
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2021. pp. 165
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Böhm Eva
- Frank Sasa
- Marsche Gunther
- Altmetrics:
- Abstract:
- In recent decades, the prevalence of allergy and inflammatory skin diseases has increased dramatically, a fact that is associated to changes in environmental exposures and lifestyle practices. High-density lipoprotein (HDL) particles comprise the most abundant lipoproteins and the most heterogeneous in terms of their structure, composition and biological functions. Despite strong evidence on the role of HDL in modulating immune cell activity, the function of HDL in allergic and inflammatory skin diseases is yet poorly understood. In the first part of my thesis, I investigated the HDL composition, particle distribution as well as functional properties in subjects suffering from allergic rhinitis. We were able to demonstrate that allergic rhinitis is associated with marked alterations in HDL composition, specifically with increased levels of HDL-associated apolipoprotein (apo) A-II, triglycerides and lyso-phosphatidylcholine. On the other side, allergic rhinitis was associated with decreased levels of HDL-associated apoA-I and phosphatidylcholine. Analysis of HDL subfractions revealed a decrease in the HDL3 subclass in allergic rhinitis patients in comparison to controls. Moreover, when performing a thorough functional characterization of allergic rhinitis-derived HDL, we could demonstrate that HDL of allergic rhinitis patients showed an impaired anti-oxidative capacity and an impaired ability to suppress monocyte nuclear factor-κB expression. This was linked to secretion of pro-inflammatory cytokines including tumor necrosis factor alpha, interleukin (IL) 1 beta, IL-4, IL-6 and IL-8. In addition, we observed impaired cholesteryl-ester transfer protein and paraoxonase activities, but improved lipoprotein-associated phospholipase A2 activity in sera from allergic rhinitis patients in comparison to controls. To our surprise, apoB-depleted serum as well as HDL derived from allergic rhinitis patients showed an increased ability to suppress eosinophil effector responses due to eotaxin-2/CCL24 stimulation in comparison to controls. We observed multiple and complex associations of the composition/structure of allergic rhinitis-HDL with metrics of HDL function suggesting a link between HDL functionality and allergic rhinitis. In the second part of my thesis, I investigated the HDL composition, particle distribution and functionality in psoriasis subjects under biologic anti-psoriatic therapy. We demonstrated that in comparison to healthy controls, serum samples of psoriasis patients at baseline showed significantly impaired cholesterol efflux capacity, lecithin-cholesterol acyltransferase and paraoxonase activities and increased levels of the intermediate HDL subclass. Importantly, short- (3 to 6 months) and especially intermediate-term (1 to 2 years) biologic anti-psoriatic therapy markedly impaired HDL-cholesterol efflux capacity and rendered HDL pro-inflammatory; however, it increased lecithin-cholesterol acyltransferase and paraoxonase activities. In addition, intermediate-term biologic anti-psoriatic therapy impaired the adenosine triphosphate-binding cassette subfamily A member 1-mediated cholesterol efflux capacity and the anti-oxidative capacity of apoB-depleted serum and decreased the large HDL subclass. Alterations were also observed in the composition of HDL at intermediate-term therapy, specifically increased apoA-II and phosphatidylcholine but decreased free cholesterol levels were observed in comparison to baseline. We observed that all biologic agents caused similar changes in HDL composition, subclass distribution and cholesterol efflux capacity, indicating that the observed effects are not due to the effect of a particular biological active agent. Finally, as part of my thesis I reviewed and evaluated the existing literature regarding the newly identified changes in the composition, metabolism and function of HDL in allergic and inflammatory skin diseases, as well as the immune cell modulatory activities of HDL and H