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Title: Type 1 interferons in early rheumatoid arthritis
Authors: Cooles, Faye Anisa Hogarth
Issue Date: 2017
Publisher: Newcastle University
Abstract: Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease predominantly causing synovial inflammation. Early and established RA exhibit both overlapping and distinct pathological processes. Early treatment improves clinical outcomes and delineating early disease pathology can inform novel therapeutic pathways. Type 1 interferons have diverse effects on immune function and relative exposure can be recorded using an interferon gene signature (IGS). The IGS is positive in 20-30% of established RA patients where it does not associate with disease activity but can predict response to some biological therapies. However, glucocorticoids and potentially other immunomodulatory therapies can modify the IGS. I therefore examined the IGS in early, drug naïve RA focusing on prevalence, association with clinical phenotype, and impact on disease progression. I additionally attempted to identify the source of type 1 interferons and triggers for their production. I demonstrated the IGS is increased in early RA, falls with treatment/time and appears to predict clinical response to initial therapies. In this latter capacity it out-performed baseline CRP, ESR and DAS-28. The IGS also positively associated with disease activity and IgM rheumatoid factor titres. The latter association was supported by an analysis of the B cell transcriptome of IGS+ early RA patients, where there was increased gene expression in pathways related to B cell activation; increased plasma cell differentiation; and propensity to produce IgM. Genes were also upregulated that are usually expressed in B cell malignancies, further emphasising a potentially pathologically activated state. Retroelements (SINE, LINE-1 and ERV), are putative triggers of type 1 interferons in autoimmunity. However early RA whole blood LINE-1 activity was comparable to healthy controls and was actually reduced in IGS+ patients. Furthermore pDCs showed uniformly reduced retroelement activity in early RA compared with healthy controls. Indeed there was differential retroelement expression across lymphocyte subsets in early RA; expression was highest in B and T cells and comparatively lower in DCs and monocytes. Finally despite being a major source of type 1 interferons, pDCs in IGS+ early RA patients had comparable interferon-α expression to other lymphocytes. In conclusion I demonstrate that type 1 interferons may play a pathogenic role in early RA and disease progression - although their source and triggers remain unclear. Nonetheless I hypothesise that therapies that target type 1 interferons could have clinical benefit in early RA.
Description: PhD Thesis
Appears in Collections:Institute of Cellular Medicine

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