Wei, Lanxuan; (2021) The role of IL-17 in the pathogenesis of systemic sclerosis. Masters thesis (M.Phil), UCL (University College London).

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Abstract

IL-17A is a pro-inflammatory cytokine secreted mainly by Th17 cells. It plays a critical role in the host defense system and is linked to various autoimmune diseases. The dual role of IL-17A in systemic sclerosis (SSc) pathogenesis is quite intriguing: on one hand IL-17A promotes pro-inflammatory cytokine synthesis and enhances immune reactions and on the other it decreases fibrotic responses and abrogates fibrosis. IL-17D belongs to the IL-17 family and could possibly regulate inflammation and autoimmune diseases including SSc. Potential mechanisms behind IL-17 family members in SSc pathogenesis is therefore worthy of investigation. Functional fibroblast assays were conducted and showed in the presence of IL-17A there was no change in cell morphology, viability or migration in dermal fibroblasts. RT-PCR was used to assess mRNA levels of key fibroblast molecules in response to IL-17A. Although most remained unaltered, IL17A was shown to inhibit expression of fibrboblast activation protein (FAP) in SSc at 50ng/mL (p=0.0144). Protein analysis using Western Blotting to examine fibroblast cell signalling pathways was employed to examine the impact of IL- 17A on the p38 MAPK pathway, Erk1/2 MAPK pathway and STAT3/gp130 pathways in fibroblasts. Measuring the culture medium by ELISA revealed that IL-17A did not induce IL-6 secretion in SSc fibroblasts. Exploring a well-defined clinical cohort of SSc patients, correlations between IL-17 family members IL- 17A and IL-17D and other cytokines and clinical parametres were examined. Although no differences were noted in circulating IL-17A and IL-17D between SSc and healthy controls, important clinical correlations between IL-17 subtypes and clinical parametres were observed. Interestingly IL-17A was shown to be associated with digital ulcers (IL-17A in patients with digital ulcers was significantly higher than patients without digital ulcers, p=0.0349). IL-17A was positively correlated with the level of erythrocyte sedimentation rate ( r=0.7188, p<0.0001, in the SSc-Pulmonary Arterial Hypertension group) and type-B natriuretic peptide (r=0.5013, p=0.0091, in the SSc-only group), which is consistent with the inflammatory aspect of IL17A. IL-10 was correlated with IL-17A in SSc-PAH patients (r=0.4506, p=0.0238). IL-17D was age-related in SSc (IL-17D in patients aged 40-60 was significantly lower than in patients aged over 60, p=0.018). IL-17D was related to the presence of lung fibrosis in CT scans of SSc patients (IL-17D in patients with no fibrosis in CT scans was significantly higher than in patients with mild fibrosis, p=0.0175). The level of IL-17A and IL-17D between healthy donors and SSc patients was compared and no significant change was detected. Haemoglobin (r=-0.4281, p=0.0259, in the SSc-only group) and mean corpuscular volume (r=-0.4599, p=0.0313, in the SSc-PAH group) were inversely correlated with IL-17D while MRSS was positively correlated with IL-17D in SSc (r=0.6934, p=0.001, in the SSc-only group). In LcSSc patients, Hb (r=0.-0.485, p=0.0001) was inversely correlated with IL-17D, while BNP (r=0.347, p=0.013) and MRSS (r=0.48, p=0.001) were positively correlated with IL-17D. This study shows that fibroblasts are able to respond to IL-17A by altering the expression of fibrogenic markers and that two IL-17 family members (IL-17A and IL-17D) exhibit important associations within defined SSc disease subsets. The precise role of the IL-17 family in SSc pathogenesis is of significant interest and studies reported here present opportunities for further explorations as potential therapy strategies for SSc.

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