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The role of CD73 in the pathogenesis of Juvenile Idiopathic Arthritis

Botta Gordon-Smith, SL; (2015) The role of CD73 in the pathogenesis of Juvenile Idiopathic Arthritis. Doctoral thesis , UCL (University College London). Green open access

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Juvenile idiopathic arthritis (JIA) manifests as a persistent arthropathy, thought to be immune-driven, that when untreated leads to progressive joint destruction. This group of diseases represents an excellent model to investigate immunoregulation because of the possibility to sample cells aspirated from the site of inflammation. This PhD investigated the contribution of defects in purinergic pathways to the pathogenesis of JIA by examining the distribution and enzymatic activity of the ecto-nucleotidase CD73, together with some investigation of expression of CD39 and CD26. The data presented here demonstrate the significantly decreased proportion of CD73+ T and B synovial lymphocytes from JIA patients compared to peripheral blood lymphocytes of both patients and healthy subjects. This reduction increased with higher disease severity (worse in extended compared to persistent oligoarticular JIA patients) and correlated with patient’s cumulative joint count, but not with disease duration. No genetic association for NT5E (encoding CD73) was found that could explain the different levels of CD73 observed within different subtypes of JIA. Treatment with methotrexate, the first line DMARD to control arthritis, did not affect the proportion of CD73+ peripheral blood lymphocytes, nor did this proportion predict response to methotrexate. The reduction of CD73+ synovial lymphocytes and of CD73 protein expression per CD73+ cell was associated with a reduced ability to generate immunoregulatory adenosine in vitro, suggesting low levels of adenosine in the synovium. An incapacity of CD39+ and CD73+ cells to act cooperatively to metabolize ATP to adenosine, further contributes to the impression of low adenosine generation in the JIA joint, and of defective attenuation of inflammation. In vitro, downregulation of CD73+ PBMC and purified CD8+CD73+ T cells was demonstrated upon cell activation. The loss of CD73+ PBMC was associated with a diminished potential to generate adenosine. The loss of CD73+ PBMC appeared to be restricted to proliferating cells. I propose that the CD73 downregulation is associated with defective adenosine levels within the joint, which could contribute to the locally destructive inflammation seen in JIA.

Type: Thesis (Doctoral)
Title: The role of CD73 in the pathogenesis of Juvenile Idiopathic Arthritis
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL
URI: https://discovery.ucl.ac.uk/id/eprint/1468658
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