Background:
Acute rheumatic fever (ARF) and associated rheumatic heart disease (RHD) are serious sequelae of Streptococcus A (Strep A) infection. Pathogenesis remains poorly understood, with current hypotheses based on molecular mimicry generating antibodies in response to StrepA infection, which cross-react with cardiac proteins such as myosin. Contemporary investigations to profile the autoantibody response in ARF are needed to inform pathogenesis and identify new biomarkers for the disease.
Methods:
High content protein arrays (Protoarray, 9000 proteins and HuProt Array, 16,000 proteins) and phage immunoprecipitation sequencing (PhIP-seq, 259,345 overlapping 90-mer peptide sequences covering the human proteome) were utilised to analyse ARF autoreactivity. Sera was obtained from ARF patients and matched healthy controls recruited as part of a nationwide case-control study of ARF conducted in New Zealand (RF RISK Study), as well as and patients with uncomplicated StrepA pharyngitis from a recently completed study of paediatric Strep A infections.
Results:
Analysis of data from both the high content protein array and the PhiP-Seq platforms showed a global increase in autoantigen reactivity in ARF patients compared with controls, as well as marked heterogeneity in the autoantibody fingerprint between ARF patients. Autoantibody profiling using the different platforms identified known disease-associated autoantigens (such as myosin and collagen) as well as novel autoantigens, several of which have roles in heart structure and function.
Conclusion:
The broad yet heterogenous elevation of autoantibodies observed suggests epitope spreading, and an expansion of the autoantibody repertoire, likely plays a key role in ARF pathogenesis and disease progression. Multiple autoantigens may be needed as diagnostic biomarkers to capture this heterogeneity.