Purpose Acute rheumatic fever (ARF) remains a major problem worldwide. We have seen over 600 cases of ARF in the past 15 years (NEJM 316:421-427, 1987, J. Peds. 124:9-15 1994, Ped. 113:168-172, 2004). The specific pathogenesis of ARF and especially rheumatic heart disease (RHD) remains unknown. Previous studies have suggested molecular mimicry between components of strains of the group A streptococcus (GAS) and human tissue resulting in an immune response directed at these tissues.
Methods We employed a multiplexed fluorescent microsphere system to develop an assay requiring only 5 μl of serum to simultaneously assess the serum concentration of two non-specific streptococcal antibodies (anti-streptolysin O (ASO), anti-DNase B) and four antibodies specific to human tissues (myosin, collagen I, collagen IV, and fibronectin).
Results We found significantly higher antibody activity in the ARF patients (n=20) to nonspecific streptococcal enzymes ASO and DNase B compared to pharyngitis patients (n=10) (ASO: 2519 mean fluorescent intensity vs. 1412 MFI p=0.005, anti-DNase B: 4795 MFI vs. 2268 MFI p=0.0006). We also found significant increases in antibody to collagen I, a component of heart valves, collagen IV, a component of basement membrane in several tissues, and fibronectin (anti-collagen I: 277 MFI vs. 136 MFI p=0.029, anti-collagen IV: 200 MFI vs. 50 MFI p=0.005, anti-fibronectin 1279 MFI vs. 1169 MFI p=0.007). In contrast, we did not see significantly elevated antibody to myosin which is associated with myocarditis (anti-myosin 649 MFI vs. 310 MFI p=0.069). In 10 patients with ARF with carditis vs. 10 patients with ARF without carditis, we found significantly higher levels of ASO, anti-DNase B, and anti-myosin (ASO: 2968 MFI vs. 2071 MFI p=0.035, anti-DNase B: 6037 MFI vs. 3554 MFI p=0.015, anti-myosin: 1037 MFI vs. 262 MFI p=0.019).
Conclusion Employing this system, we have shown that ARF patients are hyper-responsive to all of these antigens, and carditis patients have a higher response to specific antigens than non-carditis patients. Such data derived from this multi-analyte system, may allow us to dissect the critical role of this molecular mimicry in the pathogenesis of acute rheumatic fever and rheumatic heart disease.
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