cell-nanoparticle interaction, nanotoxicity, immunology, infectious diseases, paediatric rheumatology
Immuno-sequencing of T-cells receptors in paediatric patients' synovial fluid to understand the role of HLA-B27 and T-cells in the pathogenesis of enthesitis-related juvenile idiopathic arthritis
AbstractJuvenile idiopathic arthritis (JIA) is a heterogeneous group of autoimmune diseases that mainly affect the joints in children under the age of 16-18 years. It is the most common chronic arthritis in childhood with a prevalence of 16-150 in 100,000 children, in which enthesitis-related JIA (JIA-ERA) represents up to 20% of JIA cases. JIA-ERA has long been characterised by a strong association with HLA-B27, which is a major histocompatibility complex class I on the cell surface that is responsible for presenting antigenic peptides (derived from self and nonself antigens) to T-cells. However, it remains unclear how HLA-B27 contributes to the onset and pathogenesis of JIA-ERA. In cell-mediated autoimmunity, T-cells (including CD4+ and CD8+ T-cells) have been implicated in mediating many aspects of autoimmune inflammation. Among CD4+ T-cells, CD4+CD25+FOXP3+ regulatory T-cells (Tregs), which are crucial in preserving immune homeostasis, are believed to be dysfunctional in autoimmunity. Although Tregs were identified and analysed in different rheumatic diseases, their role is incompletely understood. There are also very few publications available that investigate the heterogeneous phenotypes and functions of T-cells at the inflamed site across different paediatric rheumatic diseases. Stemming from this dilemma, there are two research questions that I want to answer in this proposed study: (1) by which mechanism HLA-B27 confers its effects in JIA-ERA (i.e., molecular mimicry/arthritogenic peptide theory, free heavy chain theory, or protein misfolding theory) and how does HLA-B27 participate distinctly in JIA-ERA compared to other adult or juvenile arthritis; (2) what are the roles of different subsets of synovial T-cells in JIA-ERA pathogenesis and how does the T-cell receptor (TCR) profile of Tregs differ from those of conventional CD4+ and CD8+ T-cells in HLA-B27+ JIA-ERA patients' synovial fluid. To my knowledge, this will be the first (pilot) study that analyses the roles of HLA-B27 and T-cells in different types of JIA and compares JIA with other adult and juvenile arthritis. Modern (paediatric) rheumatology is increasingly evolving in a direction of pathology-specific and patient-specific diagnostics and therapy (i.e., personalised medicine). Better molecular stratification is thus an absolute necessity to improve patient care. A key transforming factor in (paediatric) rheumatology has been the application of sequencing techniques (e.g., microarray, Sanger sequencing, and next-generation sequencing) in assessing the TCR repertoire in blood cells or synovial fluid cells. Characterisation of TCR profiles is rapidly becoming an important complement to conventional immunophenotyping in understanding disease pathogenesis, prognosis, and response to treatment. Considering the research questions and state-of-the-art mentioned above, I believe that studying the TCR repertoire of synovial T-cells in HLA-B27+ patients will provide important knowledge of JIA-ERA.
- Promoter: Ha My
- Research Project