Acute rheumatic fever is a serious post-immune sequela of a Group A Streptococcus (GAS) infection that continues to occur at unacceptably high rates in low-income settings globally, and Māori and Pacific children in Aotearoa New Zealand. Pathogenesis remains poorly understood with the prevailing hypothesis based on molecular mimicry and immune cross‑reactivity between GAS and human proteins. Our research, which combines immunology with public health approaches, points towards a role for repeated GAS infections in priming the immune system for dysregulation. Serological evidence for immune priming was initially obtained by mapping prior GAS exposures using a large panel of M-type specific peptides. Rheumatic fever patients had significantly more serologically confirmed GAS exposures than closely matched controls, recruited as part of a nationwide case‑control study. In addition, using our novel multi-plex assay comprised of eight conserved GAS virulence factors, rheumatic fever patients displayed a unique serological profile compared with precursor GAS pharyngitis and skin infections. This includes a marked increase in antibody breadth and magnitude, likely due to repeated GAS infections that progressively boost antibody responses. The resulting immune dysregulation is associated with a broad and heterogeneous autoantibody repertoire. This is illustrated by a global increase in reactivity in rheumatic fever sera to autoantigens observed across a number of technology platforms including high-content protein and glycan arrays, as well as single antigen analyses that show patients react with different autoantigen combinations. While the molecular trigger(s) for acute rheumatic fever remain elusive, these recently identified immune features point to immune priming and epitope spreading as key mechanisms associated with disease. This updated pathogenesis model, which shares similarity with other post-infectious sequelae, will be presented.