Research My Ha

Abstract

T cells are white blood cells that are elicited after exposure to pathogens, either via natural infection or vaccination. Different phenotypes of T cells exist and these are assumed to behave functionally differently. T cells recognize specific epitopes from pathogens via so-called T cell Receptors (TCR) that reside on the T cell membrane. It remains currently not known how T cells differentiate on a TCR level. In this ACTR project, we will develop highly innovative computational and mathematical models to simulate how unique T cells, represented by their TCRs, against pathogens evolve as a function of different relevant variables. T cell phenotyping will be achieved via advanced single cell sequencing technology. We will study CD8+ T cells longitudinally obtained from two different human vaccination cohorts (de novo Yellow Fever vaccination and booster measles vaccination). The insights of ACTR will be pivotal for a better fundamental understanding of CD8+ T cell immunology. We will learn, from our human studies, how T cells differentiate and how further T cell dynamics after natural (re-)exposure can be modeled. In addition, we will have more tools to understand how longitudinal T cell dynamics should be modeled after vaccination. We are convinced ACTR can revolutionize our fundamental understanding of T cell immunology.

Researcher(s)

• Promoter: Ogunjimi Benson
• Co-promoter: Ha My
• Co-promoter: Meysman Pieter

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project

Abstract

Juvenile 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.

Researcher(s)

• Promoter: Ha My

Research team(s)

• Centre for Health Economics Research and Modelling of Infectious Diseases (CHERMID)

Project type(s)

• Research Project