Flint, Julia; (2020) A human in-vivo model of acute resolving inflammation to study the pathogenesis of Rheumatoid Arthritis. Doctoral thesis (M.D(Res)), UCL (University College London).

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Abstract

Background Rheumatoid arthritis (RA) is a systemic autoimmune disease. The hypothesis of this study is that defects in the resolution of episodes of acute inflammation may contribute to the pathogenesis of this disease. The primary aim of this thesis is to establish if there is a difference in the onset and resolution of acute inflammation in patients with RA and Osteoarthritis (OA) compared to healthy controls. Methods A human model of acute, spontaneously resolving inflammation in response to intradermal ultra-violet light killed E.coli (UVkEC) has been developed. The use of suction blisters enables study of the whole coordinated immune response from onset through to resolution. This UVkEc blister model was used to assess the innate immune response in a cohort of healthy females. After demonstrating the acceptability to human volunteers, it was translated into participants with RA and OA and healthy control groups. The systemic and local response was assessed; encompassing clinical parameters as well as the response at the level of cells, proteins and lipids to identify a defect in the resolution of inflammation. Results This research identified key differences between the innate immune response of healthy human females and males, encompassing local blood flow, influx of haematopoietic cells, and production of inflammatory cytokines. Study of the innate immune response in participants with RA demonstrated no evidence of defective resolution of inflammation in the indices measured. In fact, there was a trend towards quicker or more efficient resolution. The response in participants with OA resembled that of RA participants. Conclusions This work demonstrates the practicability and challenges of using the UVkEc blister model in patients. The differences identified between males and females may be relevant to the prevalence of autoimmune disease in the different sexes and highlights the need for including both sexes in the early phases of research. Differences identified in the immune response of participants with RA and OA can be extended to further understand the pathogenesis of these diseases and may contribute to the debate surrounding the inflammatory component of OA.

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