Distinct pathogenic mechanisms in Downs Arthritis and Juvenile Idiopathic Arthritis

Down’s syndrome (DS) is a chromosomal disorder caused by an extra chromosome 21.  Immune dysregulation predisposes children with DS to high incidences of autoimmune diseases. DA is an inflammatory joint condition affecting children with DS, which is under-recognised, has a delayed diagnosis, resulting in chronic disability. Our clinical research showed an increased risk of arthritis in children with DS, with the prevalence in Ireland for DA 18-21 times greater than JIA. We demonstrated that the disease pattern is distinct in DA compared to JIA, with a marked increase in erosive joint damage in DA observed, suggesting a significant need for earlier diagnosis and better therapeutic strategies. However, little is known about the underlying mechanisms that drive disease pathogenesis in DA. Our preliminary data demonstrates significant differences in T-cell and B-cell profiles in DA compared to JIA, trisomy-21 and healthy-controls,  with a marked increase in polyfunctional T-cells observed in DA. Histological analysis of synovial-tissue demonstrated an increase in lining-layer invasiveness in DA compared to JIA, with an increase in synovial T-cells and macrophages also observed. Furthermore, increased invasiveness and metabolic-activity was demonstrated in primary synovial fibroblasts isolated from DA compared to JIA. Therefore, in this project we will further focus on identifying the cellular and metabolic mechanisms that drive inflammation in DA. Specifically we will examine, (i) the phenotype and function of pathogenic T-cells and primary synovial-fibroblasts and their reciprocal interactions, (ii) determine the effect of a metabolic shift on cell function, and (iii) examine the potential of targeting these pathways.

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