PhIP-Seq uncovers marked heterogeneity in Acute Rheumatic Fever Autoantibodies

Reuben McGregor; Lauren H. Carlton; Timothy J. O'Donnell; Elliot Merritt; Campbell R. Sheen; Florina Chan Mow; William John Martin; Michael G. Baker; Nigel Wilson; Uri Laserson; Nicole J. Moreland

doi:10.1172/jci.insight.196619

PhIP-Seq uncovers marked heterogeneity in Acute Rheumatic Fever Autoantibodies

Reuben McGregor,¹ Lauren H. Carlton,¹ Timothy J. O'Donnell,² Elliot Merritt,² Campbell R. Sheen,³ Florina Chan Mow,⁴ William John Martin,⁵ Michael G. Baker,⁶ Nigel Wilson,⁷ Uri Laserson,² and Nicole J. Moreland¹

Published November 18, 2025 - More info

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Abstract

Acute rheumatic fever (ARF) and associated rheumatic heart disease are serious sequelae of a Group A Streptococcus (GAS/Strep A) infection. Autoantibodies are thought to contribute to pathogenesis, with deeper exploration of the autoantibody repertoire needed to improve mechanistic understanding and identify new biomarkers. Phage immunoprecipitation and Sequencing (PhIP-Seq) with the HuScan library (>250,000 overlapping 90-mer peptides spanning the human proteome) was utilised to analyse autoreactivity in sera from children with ARF, uncomplicated Strep A pharyngitis and matched healthy controls. A global proteome-wide increase in autoantigen reactivity was observed in ARF, as was marked heterogeneity between patients. Public epitopes, common between individuals with ARF were rare, and comprised < 1% of all enriched peptides. Differential analysis identified both novel and previously identified ARF autoantigens, including PPP1R12B, a myosin phosphatase complex regulatory subunit expressed in cardiac muscle, and members of the collagen-protein family, respectively. Pathway analysis found antigens from the disease-relevant processes encompassing sarcomere and heart-morphogenesis were targeted. In sum, PhIP-Seq has substantially expanded the spectrum of autoantigens in ARF, and reveals the rarity of public epitopes in the disease. It provides further support for the role of epitope spreading in pathogenesis and has identified PPP1R12B as a novel, enriched autoantigen.

PhIP-Seq uncovers marked heterogeneity in Acute Rheumatic Fever Autoantibodies

Reuben McGregor,¹ Lauren H. Carlton,¹ Timothy J. O'Donnell,² Elliot Merritt,² Campbell R. Sheen,³ Florina Chan Mow,⁴ William John Martin,⁵ Michael G. Baker,⁶ Nigel Wilson,⁷ Uri Laserson,² and Nicole J. Moreland¹

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PhIP-Seq uncovers marked heterogeneity in Acute Rheumatic Fever Autoantibodies

Reuben McGregor,1 Lauren H. Carlton,1 Timothy J. O'Donnell,2 Elliot Merritt,2 Campbell R. Sheen,3 Florina Chan Mow,4 William John Martin,5 Michael G. Baker,6 Nigel Wilson,7 Uri Laserson,2 and Nicole J. Moreland1

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Reuben McGregor,¹ Lauren H. Carlton,¹ Timothy J. O'Donnell,² Elliot Merritt,² Campbell R. Sheen,³ Florina Chan Mow,⁴ William John Martin,⁵ Michael G. Baker,⁶ Nigel Wilson,⁷ Uri Laserson,² and Nicole J. Moreland¹