Abstract
The overarching hypothesis of this MD thesis was that IL-17A+ CD8+ T cells (Tc17) cells are present within the joints of patients with Spondyloarthritis (SpA), both at the early and established stage of disease, and that their presence correlates with Tissue Resident Memory (TRM) T cells. SpA is a group of seronegative inflammatory arthritides that overlap in terms of clinical, histological and genetic features. SpA has known associations with peripheral and axial arthritis, inflammatory bowel disease, anterior uveitis and psoriasis. Previous work from the Taams’ lab showed the presence of IL-17A producing CD8+ T cells within the SF of patients with PsA, but not RA. The aim of this project was to extend these data to SpA as well as to early inflammatory arthritis (EIA), when a definitive diagnosis is not yet available. The hypothesis was that Tc17 cells will be enriched in the joints of patients with EIA who go on to develop PsA/SpA.To address these hypotheses, I investigated the presence of cytokine expressing T cells including IL-17 producing CD8+ and CD4+ T cells and CD69+CD103+ TRM cells in the synovial fluid (SF) of patients with early and established SpA, or RA as a control. I completed similar preliminary investigations on peripheral blood (PB) samples from patients who have developed drug induced de novo SpA. I also investigated if there was a correlation between various clinical features or ultrasound findings and Tc17 or TRM cell frequencies.
In chapter 3 I confirmed that synovial Tc17 cells were present at greater frequencies in patients with PsA, which is known to be a subset of SpA. The frequency of Tc17 cells correlated with the TRM cell frequencies in PsA synovial fluid. A trend towards correlation was observed between synovial Tc17 cells and CRP in established arthritis.
TRM cells were detected in the SF of all established disease groups. I also performed preliminary investigation of the expression of tissue homing markers on synovial Tc17 cells. These results corroborate previous research performed in the Taams’ lab but expand this further with increased numbers of patients and also that TRM cells are enriched in IL-17A producing cells.
In chapter 4 I included patients with EIA of less than one year duration. I showed that Tc17 cells were present at greater frequencies in EIA samples of patients later diagnosed as having PsA/SpA. Additionally, I found that TRM cells were found at greater frequencies in the SF of patients with early PsA. I showed a correlation between Tc17 cells and ESR/CRP in patients with EIA. Additionally, I showed a correlation between CRP and PDUS activity in these EIA patients. My results show that the type 17 pathway is functional early in the disease process. Additionally, if this work is confirmed with larger patient numbers, it may be possible to use Tc17 cells for earlier identification of patients suitable for biologic treatment with IL-17 inhibitors.
The work from chapters 3 and 4 should be progressed to investigate the presence of these cells in synovial tissue from patients with inflammatory arthritis.
In chapter 5 I described the clinical phenotype of 26 patients who developed de novo arthritis whilst receiving dupilumab. We hypothesised that the blockade of IL-4 and/or IL-13 alters the cytokine balance in the joints and entheses, resulting in unopposed IL-17/23 expression leading to symptoms with many similarities to PsA (SpA). The presence of cytokine expressing T cells was found within PB of four cases, and two controls, however due to the small case numbers meaningful conclusions could not be drawn. Progression of this exciting work may lead to a better understanding of the initiation and establishment of peripheral SpA.
Taken together, this thesis clearly shows the presence of IL-17A producing CD8+ T cells within the joints or the peripheral blood of three different stages of PsA/SpA. This work will set the stage for further research and perhaps a better understanding of the origin of SpA itself.
| Date of Award | 1 Jun 2024 |
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| Original language | English |
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| Supervisor | Leonie Taams (Supervisor) |