Background- Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are autoimmune consequences of group A streptococcus (GAS) infection and remain major causes of cardiovascular morbidity and mortality around the world. Improved treatment has been stymied by gaps in understanding key steps in the immunopathogenesis of ARF and RHD. This study aimed to identify 1) effector T cell cytokine(s) that might be dysregulated in the autoimmune response of ARF patients by GAS 2) an immunomodulatory agent that suppresses this response and could be clinically translatable to high-risk ARF patients.
Methods - Theimmune response to GAS was analyzed in peripheral blood mononuclear cells (PBMC) from an Australian Aboriginal ARF cohortby a combination of multiplex cytokine array, flow cytometric analysis and global gene expression analysis by RNA sequencing (RNAseq). The widely used immunomodulatory drug hydroxychloroquine (HCQ) was tested for effects on this response.
Results- We found a dysregulated IL-1b-GM-CSF cytokine axis in ARF PBMCs exposed to GAS in vitro, whereby persistent IL-1bproduction is coupled to overproduction of GM-CSF and selective expansion of CXCR3+CCR4-CCR6-CD4 T cells. CXCR3+CCR4-CCR6-CD4 T cells are the major source of GM-CSF in human CD4 T cells and CXCL10, a CXCR3 ligand and potent Th1 chemoattractant, was elevated in sera from ARF patients. GM-CSF has recently emerged as a key T cell-derived effector cytokine in numerous autoimmune diseases, including myocarditis,and production of CXCL10 may explain selective trafficking of these cells to the heart.We provide evidence that IL-1bamplifies the expansion of GM-CSF-expressing CD4 T cells, which is effectively suppressed by hydroxychloroquine (HCQ). RNAseq showed shifts in gene expression profiles and differentially expressed genes in PBMC derived from patients at different clinical stages of ARF.