Reijnders, T.D.Y. (2016) Regulatory T cell plasticity and (in)stability in ANCA-associated Vasculitis: Between regulation and inflammation. thesis, Medicine.
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Abstract
Background: ANCA-associated Vasculitis (AAV) is a group of systemic autoimmune diseases in which T cells play an essential role. Dysfunctional anti-inflammatory Tregs and overactive proinflammatory Th17 cells perpetuate tissue-destructive inflammation. These cell lineages overlap, as Tregs can display plasticity towards Th17 cells: producing the proinflammatory cytokine IL-17 while retaining a Treg phenotype. Alternatively, unstable Tregs may lose their characteristic transcription factor FoxP3, and turn into pathogenic effector cells (exTregs). It is unknown whether this occurs in AAV. Objectives: To determine whether Tregs in AAV show increased plasticity towards Th17 or decreased stability, and how this affects their suppressive capacity. Methods: Eight patients with AAV and seven healthy controls participated in this study. PBMCs were analyzed for Treg- and Th17-related transcription factors and cytokines by flow cytometry. FACS-isolated Tregs were cultured for 5 days in the presence or absence of Th17-inducing cytokines (IL-1β, IL-6 and IL-23). Cultured Tregs were analyzed by flow cytometry, or used in coculture suppression assays with autologous CFSE-labeled CD25neg T effector cells. Results: Tregs produced more IL-17 (plasticity) and lost more FoxP3 expression (instability) when cultured in the presence of Th17-inducing cytokines. No significant differences occurred between patients and healthy controls. However, in the absence of Th17-inducing cytokines, Tregs from patients produced almost three times more IL-17 than healthy controls (p<0.01). Tregs from patients showed reduced suppressive capacity, with preliminary data indicating that they may be disproportionately negatively affected by proinflammatory cytokines. Conclusion: The data thus far are inconclusive. More patients, particularly with active disease, need to be included concurrently with healthy controls. Understanding the role of Treg plasticity and (in)stability in the pathogenesis of AAV will provide clues for novel therapeutic targets and enable the application of Treg-based therapies.
| Item Type: | Thesis (Thesis) |
|---|---|
| Supervisor name: | Faculty supervisors: and Heeringa, prof. dr. P. and Abdulahad, dr. W.H. and GIPS-M supervisor: and Kallenberg, prof. dr. C.G.M. and Home institute: University of Groningen and University Medical Center Groningen |
| Supervisor name: | Local supervisors: and Bunch, dr. D.O. and Falk, R.J. MD and University of North Carolina at Chapel Hill and Department: UNC Kidney Center |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Jun 2020 11:00 |
| Last Modified: | 25 Jun 2020 11:00 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/1998 |
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