Oral Presentation Lancefield International Symposium for Streptococci and Streptococcal Diseases 2025

Identification of a perturbed T cell compartment that underlies rheumatic fever pathogenesis in a trans-Tasman study (118448)

Francis M Middleton 1 2 , Reuben McGregor 1 2 , Natalie Lorenz 1 2 , Anna Brooks 2 3 , Ciara Ramiah 1 , Timothy Barnett 4 5 , Michael Serralha 4 , William J Martin 6 , Florina Chan Mow 7 , Glenn Pearson 4 , Mark Mayo 8 , Julie Bennett 1 9 , Nigel J Wilson 10 , ANNA P RALPH 8 11 , Rachel H Webb 7 10 12 , Rod P Dunbar 2 13 , Jonathan Carapetis 4 14 , Nikki J Moreland 1 2
  1. Molecular Medicine and Pathology, Faculty of Medical and Healthy Sciences, The University of Auckland, Auckland, New Zealand
  2. Maurice Wilkins Centre, The University of Auckland, Auckland, New Zealand
  3. The Liggins Institute, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
  4. The Kids Research Institute Australia, University of Western Australia, Perth, Western Australia, Australia
  5. The Marshall Centre for Infectious Diseases Research and Training, School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia
  6. Independent Advisor, Wellington, New Zealand
  7. KidzFirst Children’s Hospital, Health New Zealand – Te Whatu Ora, Auckland, New Zealand
  8. Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
  9. Department of Public Health, University of Otago, Wellington, New Zealand
  10. Starship Children’s Hospital, Health New Zealand – Te Whatu Ora, Auckland, New Zealand
  11. Royal Darwin Hospital, Darwin, Northern Territory, Australia
  12. Department of Paediatrics, Child and Youth Health, The University of Auckland, Auckland, New Zealand
  13. School of Biological Sciences, The University of Auckland, Auckland, New Zealand
  14. Perth Children’s Hospital, Perth, Western Australia, Australia

Background: The pathogenesis of Acute Rheumatic Fever (ARF) is poorly understood, limiting development of immune-modulating therapies to treat ARF and prevent progression to Rheumatic Heart Disease (RHD). This prospective cohort study, which recruited participants with definite ARF in Australia and Aotearoa New Zealand, profiled circulating immune molecules and cells to inform disease mechanisms and future druggable pathways.

Methods: ARF was compared to four matched control groups (serious streptococcal infections, other inflammatory conditions, RHD, and healthy) as part of the START (Searching for a Technology driven Acute Rheumatic Fever Test) Study. Concentrations of 20 cytokines, chemokines, immunoglobulin subclass IgG3, and C-reactive protein were measured. The frequency of all major immune cell populations and expression of activation markers and chemokine receptors were evaluated by spectral flow cytometry.

Results: While ARF shared some immunological similarities with other inflammatory conditions, including elevated IL-6 and increased CD4+ T cells, disease specific features provided new insight. Elevation of the chemokine CCL5 and IgG3 and a dramatic reduction of CXCR3 chemokine receptor expression across multiple T cell populations distinguished ARF from all other groups. The CXCR3+ T cells in ARF were uncoupled from a cognate chemokine which, together with reduced T regulatory cells, underscore a perturbed T cell compartment in pathogenesis.

Conclusion: Altered T cell migration mediated by CXCR3 within a circulatory environment characterised by elevated CCL5 and IgG3 contribute to ARF immunopathology. This, in conjunction with the broadly inflammatory nature of ARF, provides a rationale for exploring currently available immune-modulating therapies to treat ARF.