Author Identifier (ORCID)
Abstract
The pathogenesis of acute rheumatic fever (ARF) is poorly understood, limiting the development of immune-modulating therapies to treat disease and prevent progressive heart damage. Here, participants with definite ARF were compared to other severe acute paediatric conditions and matched healthy controls by profiling circulating immune molecules and cells to inform disease mechanisms and potential druggable pathways. ARF shared immunological similarities with other inflammatory conditions, including elevated serum IL-6 and an increased frequency of circulating CD4+ T cells. However, elevation of the chemokine CCL5 and immunoglobulin IgG3, along with reduced expression of the chemokine receptor CXCR3 in the T cell compartment distinguished ARF from all other groups. Immunofluorescence imaging of rheumatic valve tissue confirmed a role for CXCR3-mediated T cell tissue homing during inflammatory disease. Together with a reduced frequency of circulating regulatory T cells, these data underscore a perturbed T cell compartment and provide a rationale for exploring currently available immune-modulating therapies to treat ARF.
Keywords
acute rheumatic fever, CXCR3, T-cells, immunology, heart damage, regulatory t cells
Document Type
Journal Article
Date of Publication
12-1-2026
Article Number
4664
Volume
17
PubMed ID
41916981
Publication Title
Nature Communications
Publisher
Nature
School
School of Science
Funding Information
This study was funded by the Australian National Health and Medical Research Council (NHMRC) grant APP1147531 (J.C., A.R., G.P., M.M., D.B. and N.J.M.), and the Health Research Council (HRC) of New Zealand grant 20-374 (R.M., N.L., W.J.M., N.J.W. and N.J.M.). F.M.M. was supported by a University of Auckland Doctoral Scholarship. A.P.R. is supported by NHMRC investigator grant 202537. T.C.B. is supported by fellowships from the Stan Perron Charitable Foundation and the Western Australian Future Health Research and Innovation Fund.
Funding received from the National Health and Medical Research Council (NHMRC)
APP1147531, 202537
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Recommended Citation
Middleton, F. M., McGregor, R., Lorenz, N., Kilian, S., Brooks, A. E. S., Park, S. M., Ramiah, C., Tresidder, J., Barnett, T. C., Serralha, M., Martin, W. J., Mow, F. C., Pearson, G., Mayo, M., Broadhurst, D. I., Bennett, J., Brink, J., Wilson, N. J., Ralph, A. P., . . . Moreland, N. J. (2026). CXCR3 is associated with T-cell-induced heart damage in acute rheumatic fever. Nature Communications, 17, Article 4664. https://doi.org/10.1038/s41467-026-71094-8