Research My Ha

Abstract

Juvenile Idiopathic Arthritis (JIA) is the most common chronic rheumatic disease of childhood and a leading cause of long-term disability. Although biologic therapies have improved clinical outcomes, the immunological mechanisms driving disease initiation and persistence remain poorly understood. A key unresolved question is whether pathogenic T-cell responses in JIA primarily target self-derived or viral antigens, or whether both contribute to the chronic inflammatory process. Addressing this question is critical for understanding disease pathogenesis and developing antigen-specific biomarkers and therapeutic strategies. This project aims to systematically map viral and autoantigen-specific T-cell responses directly within the synovial compartment of JIA patients. We will focus on synovial fluid mononuclear cells (SFMCs), which reflect the local inflammatory environment more accurately than peripheral blood. A comprehensive peptide panel will be synthesized, encompassing known autoantigens implicated in joint inflammation (including structural, stress-related, and post-translationally modified proteins) together with immunodominant viral epitopes associated with arthritis. To maximize information yield from limited patient samples, peptides will be combined into two-dimensional matrix pools, allowing efficient screening and unambiguous identification of antigen-specific responses. SFMCs will be stimulated ex vivo with these peptide pools, and fluorescence-activated cell sorting (FACS) will be employed to simultaneously identify and isolate antigen-responsive T cells. FACS analysis will quantify activation, proliferation, and phenotypic diversity of responsive populations, while the sorted subsets will be subjected to T-cell receptor (TCR) sequencing. This integrated approach allows direct linking of antigen specificity with clonotypic architecture, enabling identification of expanded or convergent TCR motifs associated with autoreactive and antiviral immunity in JIA. By combining peptide-based stimulation, FACS isolation, and TCR repertoire profiling, this project will generate the first integrative map of antigen-specific T-cell responses in JIA synovial fluid. The study will reveal whether viral or self-derived antigens dominate the synovial T-cell landscape and clarify how antigen specificity correlates with clinical heterogeneity. Identifying shared or recurrent TCR motifs across patients may uncover biomarkers predictive of disease course or therapeutic response. Beyond mechanistic insight, the findings will have direct translational relevance. Mapping the antigenic landscape of JIA at the clonal level will establish a foundation for developing precision immunodiagnostics and for exploring antigen-specific tolerance induction as a therapeutic concept in pediatric rheumatology. Ultimately, this work will bridge fundamental immunology with clinical application, advancing a personalized approach to autoimmune arthritis in children.

Researcher(s)

• Promoter: Ha My

Research team(s)

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

Project type(s)

• Research Project

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