par Mostmans, Yora 
Président du jury Remmelink, Myriam
Promoteur Richert, Bertrand
Co-Promoteur Michel, Olivier
Publication Non publié, 2024-07-01
Président du jury Remmelink, Myriam
Promoteur Richert, Bertrand
Co-Promoteur Michel, Olivier
Publication Non publié, 2024-07-01
Thèse de doctorat
| Résumé : | SUMMARYInflammatory Skin Diseases (ISD) represent the largest class of chronic skin diseases, but their underlying molecular dysregulation pathways often remain unclear. This thesis investigates and contributes to several caveats on what is known of the microcirculatory system and its main component/effector cells, the endothelial cells (ECs), in the pathogenesis of three different ISD with autoimmune characteristics: a) Systemic Sclerosis (SSc), a well-known autoimmune inflammatory disease affecting the skin; b) Chronic Spontaneous Urticaria (CSU), a chronic ISD with a renewed autoimmune pathogenic classification; and c) Coronavirus Disease 19 (COVID-19) induced chilblains, a completely new emerging clinical presentation of COVID-19 infection of ECs with an autoimmune signature.The first part of this thesis addressed several gaps in SSc microvasculopathy research particularly from a dermatological point of view. There have been numerous studies on the role of ECs in SSc pathogenesis but the etiology of SSc vasculopathy remains partly unclear. There is a need to better understand EC functions and intercellular communications and their clinical impact in SSc vasculopathy. We firstly discussed the role of ECs in SSc vasculopathy and the impact on clinical manifestations and serology findings; thereafter we demonstrated the diagnostic complexities of SSc through two case reports: how a contemporary microcirculatory tool like Nailfold Videocapillaroscopy (NVC) can help the diagnosis of SSc when clinical manifestations are misleading and how less frequent vascular manifestations in SSc can be diagnostically challenging. In the second part of this thesis, we wanted to better understand the role of ECs in CSU pathogenesis by performing a systematic review that summarized the EC implementation in CSU pathogenesis and its dysfunctional characteristics in different aspects of cell survival (activation and injury), maintenance of vascular structure and coagulation/fibrinolysis balance. This study was then completed by a review on autoimmune CSU endotype definitions. We set up a study to report on clinical features of patients suffering from CSU in Belgium. This was the first prospective study describing adult CSU outpatients presenting at a Belgian Immunology-Allergology Department. Results of treatment analysis in this study emphasized the need for better education in CSU treatment guidelines of general practitioners and emergency doctors, as well as dermatologists working in private practices. To contribute to the pharmaceutical development of more therapeutical options for our CSU patients, a better understanding is needed of all its underlying pathological mechanisms. We looked for evidence of vascular involvement in CSU, systemically in blood through Enzyme-Linked Immunosorbent Assay (ELISA) and NVC and locally in skin through histology and immunohistochemistry. In this study, we identified specific nailfold capillary abnormalities that could imply systemic vascular involvement in the pathogenesis of CSU. Lastly, by showing through histopathological analysis of CSU skin that non-lesional CSU(-NL) skin also shows some histological features of lesional CSU(-L) skin, we suggest that CSU pathogenesis goes beyond the (lesional) skin and that NL-CSU is somehow primed for further whealing. This could contribute to the hypothesis that CSU comes with systemic microvascular changes, in the skin and beyond. Furthermore, we showed upregulation of Stem Cell Factor (SCF) tissue expression in CSU skin, providing backbone as to why anti-KIT antibodies could potentially be very promising in future CSU therapy algorithms. The last part of this thesis focussed on finding evidence of microcirculatory involvement in coronavirus disease 2019 (COVID-19-) induced chilblains, a newly emerging clinical presentation of COVID-19 infection of ECs with an autoimmune signature. We found microcirculatory changes on NVC, confirming that reliable NVC signs of microvasculopathy in probable COVID-19-induced chilblains can be identified. Our findings also suggested that age could be a protective factor for loss of capillaries through higher VEGF concentrations. This information could be very useful in deciphering the enigma around increased prevalence of COVID-19-induced chilblains in younger patients. To conclude, our work on microcirculatory involvement in three chronic ISD with autoimmune characteristics offers several future prospectives and provide ample scope for further research. All three have been differently investigated over time, inspiring young scientists as myself to tackle pathological features over different angles in different diseases with common inflammatory autoimmune pathways, with the idea that knowing one disease can help us discover another. In the end, our results are proof that even the smallest scientific accomplishments can have great therapeutic outcomes: finding elevated SCF expression in CSU resulting in successful treatment of chronic urticaria by anti-KIT antibodies (Terhorst-Molawi and Maurer, Allergy, 2023) …Multis ictibus deicitur quercus… |
