|
|
| Identifier |
000404207 |
| Title |
Delineating novel innate inflammatory pathways involved in chronic autoinflammatory and autoimmune diseases such as Rheumatoid arthritis and its subtypes like Still’s disease. |
| Alternative Title |
Διερεύνηση νέων φλεγμονωδών μηχανισμών της έμφυτης ανοσίας σε χρόνια αυτοφλεγμονώδη και αυτοάνοσα νοσήματα όπως η Ρευματοειδής αρθρίτιδα και οι υπότυποι της όπως η νόσος του Still. |
|
Author
|
Παπαδάκη, Γαρυφαλιά
|
|
Thesis advisor
|
Βεργίνης, Παναγιώτης
Σιδηρόπουλος, Πρόδρομος
|
|
Reviewer
|
Μπούμπας, Δ.
Γουλιέλμος, Γ.
Μπερτσιάς, Γ.
Χαμηλός, Γ.
Παπαδάκη, Ε.
Καρδάσης, Δ.
|
| Abstract |
Rheumatoid arthritis (RA) is a chronic immune inflammatory disease characterized by synovial hyperplasia, joint destruction and extra-articular manifestations with a significant impact on both morbidity and mortality. Disease severity correlates with the presence of citrullinated proteins and immune complexes containing various citrullinated antigens which exhibit increased immunogenicity and arthritogenicity. The source of these proteins and immune complexes remains unknown.
RA presents local inflammation in the joints, which subsequently develops into a systemic disorder as a result of the loss of immune tolerance. Pathogenic T cells not only help B cells produce auto-Abs (rheumatoid factor (RF) and anti-citrullinated protein, anti-CCPs), but also actively mediate tissue destruction by secreting proinflammatory cytokines (IL-17, IL-6, and TNF-a) thus creating an inflammatory microenvironment that favors macrophage and neutrophil recruitment and osteoclast activation.
Dendritic cells (DCs) as professional antigen presenting cells (APCs), migrate to the lymph nodes where they process and present acquired antigens to naïve T cells and secrete cytokines resulting in skewing of naïve T cells toward T helper (Th1, Th17). Emerging data have revealed that the Th1 and Th17 are of the major T cell subsets during the course of RA but what drives their polarization and expansion is unknown.
In the clinical setting, neutrophils are present in high numbers in the synovial tissue during the initial stages of RA and persist in the synovial fluid during the perpetuation of the disease. A novel feature of neutrophils, recently described, is their ability to form neutrophil extracellular traps (NETs), a cell death mechanism that is referred as NETosis. NETs are composed of chromatin decorated with a variety of granular proteins. NETs may promote differential cell activation and cytokine release.
PhD Thesis
9
Aberrant formation of neutrophil extracellular traps (NETs) is a key feature in Rheumatoid arthritis (RA) and has been demonstrated to play a pivotal role in disease pathogenesis. However, the mechanism through which NETs shape the autoimmune response in RA remains elusive. Our aims were: (a) to delineate the role of NETs in shaping the RA autoimmune response, (b) to explore the mechanism involved in the NETs-mediated regulation of the autoimmune response.
In this study, we demonstrate that inhibition of peptidylarginine deiminases (PADs) activity in collagen-induced arthritis (CIA) mouse model significantly reduced NET formation, attenuated clinical disease activity and inhibited joint destruction. Importantly, blocking of PADs markedly reduced the frequency of collagen-specific IFN-γ producing Th1 cells in the draining lymph nodes (dLNs) of immunized animals whereas the levels of Th17 cells remained unaffected. Mechanistically, we showed that exposure of DCs to CIA-derived NETs induced DC maturation characterized by significant up-regulation of CD80 and CD86 costimulatory molecules as well as elevated secretion of the inflammatory cytokine IL-6. In support, CIA-NET-treated DCs promoted the induction of antigen-specific Th1 cells in vitro. Finally, RA-derived NETs showed an increased potential to induce the maturation of DCs from healthy individuals corroborating the findings obtained in CIA mouse model.
Collectively, our findings delineate an important role of NETs in the induction and expansion of Th1 pathogenic cell subsets in CIA through maturation of DCs. These findings reveal a novel role of NETs in shaping the RA autoimmune response that could be exploited therapeutically.
|
| Language |
English |
| Subject |
Collagen-induced arthritis |
|
Neutrophil extracellular traps |
|
Δενδριτικά κύτταρα |
|
Εξωκυττάριες παγίδες ουδετερόφιλων |
|
Πολυμορφοπύρηνα-ουδετερόφιλα |
| Issue date |
2016-12-13 |
| Collection
|
School/Department--School of Medicine--Department of Medicine--Doctoral theses
|
|
|
Type of Work--Doctoral theses
|
| Views |
526 |
Delineating novel innate inflammatory pathways involved in chronic autoinflammatory and autoimmune diseases such as Rheumatoid arthritis and its subtypes like Still’s disease.
