Mapping Autoantibodies in Children With Acute Rheumatic Fever

Area of Science:

• Immunology
• Rheumatology
• Infectious Diseases

Background:

• Acute rheumatic fever (ARF) is a severe sequela of Group A Streptococcus (GAS) infection with high global mortality.
• Its pathogenesis is poorly understood, with molecular mimicry proposed as a mechanism involving cross-reactivity of anti-GAS antibodies with cardiac proteins.
• Further investigation into the autoantibody response in ARF is crucial for understanding pathogenesis and identifying biomarkers.

Purpose of the Study:

• To comprehensively profile circulating autoantibodies in ARF patients.
• To identify novel autoantigens and biomarkers for ARF.
• To elucidate the role of autoantibody heterogeneity in ARF pathogenesis.

Main Methods:

• Multi-platform autoantibody profiling using protein arrays (Protoarray, HuProt) and 2-D gel electrophoresis with mass spectrometry.
• Analysis of sera from ARF patients, healthy controls, and GAS pharyngitis patients.
• Orthogonal validation of selected autoantigens using conventional immunoassays.

Main Results:

• Increased total autoantigen reactivity and marked heterogeneity in autoantibody profiles were observed in ARF patients compared to controls.
• Previously implicated autoantigens (myosin, collagens) and novel candidates were identified.
• Three novel autoantigens (PTPN2, DMD, ANXA6) showed significantly elevated serum antibodies in ARF, with varied reactivity patterns among patients.

Conclusions:

• Broad, heterogeneous autoantibody elevation suggests epitope spreading and repertoire expansion play a significant role in ARF pathogenesis and progression.
• The heterogeneity highlights the potential need for multiple autoantigens as diagnostic biomarkers for ARF.
• Findings provide new insights into ARF pathogenesis and potential diagnostic strategies.