Acute rheumatic fever is a serious post-immune sequela of a Group A Streptococcus (GAS) infection that can lead to chronic rheumatic heart disease (RHD). Specific therapies that can halt disease progression are lacking, in part due to gaps in understanding of disease pathogenesis. This talk will provide an overview of a programme of work aimed at updating pathogenesis models in Aotearoa New Zealand, where ARF continues to occur at unacceptably high rates in Māori and Pacific children. By combining immunology investigations with public health approaches and microbiological surveillance across a series of community and hospital-based studies a pattern of exaggerated responses has emerged. Children with ARF are observed to have increased magnitude and breadth of antibodies to GAS antigens using a number of technology platforms. Striking increases in IgG3, the most potent antibody subclass, can be attributed to both GAS- and auto-antigen responses, with the autoantibody profile providing evidence of epitope spreading as a contributor to immune mediated tissue damage. A central role for inflammation is supported by the ARF cytokine profile, while deep analysis of circulating immune cells points to a perturbed T-cell compartment as an underlying disease feature. Migration of specific immune cell populations into valvular tissue has been confirmed by multicolour immunohistochemistry of surgical tissue, with the degree of immune cell infiltrate correlating with inflammation. This updated view of ARF pathogenesis links triggering GAS infections with immune dysregulation and emphasises potential pathways for immunomodulatory intervention.