Whole blood transcriptomic analysis in ANCA-associated vasculitis

Postgraduate Thesis uoadl:2879261 412 Read counter

Unit:
Specialty Molecular Biomedicine Mechanisms of Disease, Molecular and Cellular Therapies, and Bioinnovation
Library of the School of Health Sciences
Deposit date:
2019-08-26
Year:
2019
Author:
Garantziotis Panagiotis
Supervisors info:
Δημήτριος Μπούμπας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ, Επιβλέπων
Δημήτριος Βασιλόπουλος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Παναγιώτης Βεργίνης, Ερευνητής Γ', ΙΙΒΕΑΑ
Original Title:
Whole blood transcriptomic analysis in ANCA-associated vasculitis
Languages:
English
Translated title:
Whole blood transcriptomic analysis in ANCA-associated vasculitis
Summary:
AAV is a group of rare autoimmune, potentially life-threatening diseases, which can affect several organs. These are characterized by necrotizing inflammation and destruction of predominantly small vessels. AAV are commonly associated with ANCA specific for myeloperoxidase (MPO) or proteinase 3 (PR3) and there are racial/ethnic and geographic influences on the prevalence, serotype frequencies, and clinicopathologic phenotypes. The pathogenesis of these diseases is still not fully understood and a lack of efficient molecular biomarkers often prevents precise prognosis and successful patients’ stratification.
To improve classification criteria and bring new insights into underlying molecular mechanisms, whole blood transcriptome profiling of 42 AAV and 11 healthy individuals was performed using mRNA sequencing. Herein, was demonstrated that AAV is characterized by extensive deregulation of IFN signaling and neutrophil degranulation pathways. It was further shown that ANCA positivity is accompanied by transcriptional aberrations related to pink/parkin mediated mitophagy, humoral immunity pathways and Beta catenin dependent Wnt-signaling events. Type 1 IFN signaling and neutrophil degranulation pathways represent two robust signals that characterize active disease status. A remission signature is linked to genes that regulate type 1 IFN and IFNγ responses and Wnt-mediated beta catenin signaling. Comparison of whole blood transcriptional profiles of AAV patients in active versus remission status revealed alterations in IL-10 signaling pathways, although statistical significance lacked. Furthermore, it was shown whether specific gene signatures could efficiently discriminate AAV subtypes from healthy individuals. Downregulation of genes related to type 1 IFN and IFNγ signaling, neutrophil degranulation and RIK1-mediated cell death differentiated GPA patients from healthy controls. MPA subtype was associated with neutrophil degranulation disturbancies and deregulation of cell cycle checkpoints and DNA damage response mechanisms. The gene set defing EGPA was mainly enriched in pathways related to type 1 IFN responses, NCAM signaling and B cell regulation mechanisms. Finally, PCA of AAV active renal disease and active LN implied that distinct pathophysiological mechanisms distinguish the two clinical entities.
Collectively, this study brings into focus the extensive transcriptional perturbations characterizing AAV and generated a useful resource available for further hypothesis generation and experimentation. More-strict patient inclusion criteria, deconvolution analysis and cell type specific transcriptional profiling might enhance the specificity of these observations. Finally, these results may contribute to novel molecular biomarkers development or improve the effectiveness of already existing ones in diagnosis characterization and therapy guidance.
Main subject category:
Health Sciences
Keywords:
Transcriptomic analysis, Whole blood, ANCA vasculitis
Index:
No
Number of index pages:
0
Contains images:
Yes
Number of references:
174
Number of pages:
63
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