THE DISTINCT AND AGGRESSIVE PATHOGENESIS OF ARTHRITIS IN CHILDREN WITH DOWN SYNDROME
Citation:
Foo, Serena Shuk Yeng, THE DISTINCT AND AGGRESSIVE PATHOGENESIS OF ARTHRITIS IN CHILDREN WITH DOWN SYNDROME, Trinity College Dublin, School of Medicine, Clinical Medicine, 2023Download Item:
Abstract:
Juvenile idiopathic arthritis (JIA) is the most common form of inflammatory arthritis (IA)
in children. However, recently we described a more aggressive form of IA in children with
Down syndrome (DS), termed Down syndrome associated Arthritis (DA). DA is 20 times
more common than JIA, occurring at a rate of 1/50 in children with DS. The early diagnosis
and treatment of IA in children is critical for long-term joint health and normal growth.
However, the diagnosis of IA in children with DS is extremely challenging. As a result, it is
rarely recognised at onset, and is under-diagnosed. Therefore, by the time these children
attend a Rheumatology Clinic, they may already have significant joint damage. While
many children with DA respond to current treatments, a significant proportion do not
respond or have adverse side effect. Therefore, new treatment strategies along with
better approaches for early diagnosis are required so that these children can be treated
early with the right treatment from the onset, which ultimately will lead to improved
quality of life. However, little is known about the proteins, genes and cells that are
involved in driving inflammation in the inflamed joint from children with DA. Therefore,
this thesis examined immune cells in the blood from children with DA, in addition to
specific cells in the joint tissue called synovial fibroblasts (which are the cell type that
invade the cartilage and bone) and endothelial cells which allow bad immune cells to enter
the joint from the circulation.
Initially we demonstrated that three key proinflammatory proteins induce the synovial
fibroblasts to become more invasive, which facilitates their ability to breakdown cartilage
and bone within the joint. Furthermore, these proteins activate endothelial cells which
allows the immune cells to enter the joint. These immune cells do not function properly
and produce more proinflammatory proteins that further enhance the inflammatory
response in the joint. This causes the joint tissue to swell resulting in more pain and
subsequent disability if not treated early. Interestingly, two of these proteins acted
together in their ability to induce inflammation, and this has implications for treatment
strategies as targeting both may produce better outcomes. We next identified that
synovial fibroblasts and endothelial cells altered the way they use energy within the cell,
a process that allows them to maintain their pathogenic inflammatory state. We showed
that blockade of these energy pathways, led to resolution of inflammation, therefore
there is potential to develop medicines that target both these specific dysfunctional
pathways. Finally, we examined immune cells in the circulation of children with DA. We
demonstrated that a specific immune cell called a T cell is more activated in children with
DA compared to JIA or healthy controls. Indeed, these particular T cells produce more
proinflammatory proteins simultaneously, and are known therefore to be more potent in
driving the inflammatory response but are also more resistant to treatment. Interestingly,
the two most dominant proinflammatory proteins being produced by these T cells are the
same two proteins that together drive synovial fibroblast and endothelial cells’ function.
Thus, the research in this thesis represents a significant advancement in our
understanding of the disease and identifies distinct immune-synovial cell dysregulation in
the pathogenesis of DA. In particular, these data have potential implications for
combination therapy or manipulation of metabolic pathways for the treatment of DA.
Further studies and support for this condition, will lead to improved diagnostic and
prognostic outcomes for these vulnerable children. It also demonstrates the importance
of translational research, and the involvement of patients with research, thus we would like to thank the children and their parents as this research could not have been
performed without them.
Sponsor
Grant Number
Arthritis Ireland
National Children's Research Centre
Description:
APPROVED
Author: Foo, Serena Shuk Yeng
Advisor:
Fearon, UrsulaPublisher:
Trinity College Dublin. School of Medicine. Discipline of Clinical MedicineType of material:
ThesisCollections
Availability:
Full text availableKeywords:
arthritis, down syndrome, cytokines, immunology, fibroblasts, adaptive immune systemMetadata
Show full item recordLicences: