Comprehensive analysis of antibody responses to streptococcal and tissue antigens in patients with acute rheumatic fever

Abstract

Acute rheumatic fever (ARF) is an autoimmune disease occurring in individuals following untreated group A streptococcal infection believed to be triggered by antibodies to bacterial components that cross-react with human tissues. We developed a multiplexed immunoassay for the simultaneous quantitation of antibodies to nine streptococcal-related antigens including streptolysin O (SLO), DNase B, collagen I and IV, fibronectin, myosin, group A carbohydrate, M6 protein and streptococcal C5a peptidase. Utilizing this method, we examined serum from 49 ARF, 58 pharyngitis patients and age- and sex-matched controls in samples collected at initial disease onset, and at 4 weeks, 6 months and 1 year after diagnosis. Antibody responses were significantly higher for SLO, DNase B, M6 protein, group A carbohydrate and the cross-reactive antigens collagen I and myosin in ARF compared with pharyngitis patients (P <or= 0.05). Moreover, we found significantly elevated antibody responses in the ARF patients with rheumatic heart disease to fibronectin and collagen I compared with ARF patients without heart disease. The major differences between the ARF patients with and without carditis appear to be in the immune response to the putative heart valve components, collagen I and fibronectin.

Immune responsiveness during disease progression from acute rheumatic fever to chronic rheumatic heart disease

“…Although progress has been made in our understanding of disease pathogenesis, there is still much to be elucidated about the disease process. Auto-antibodies, which develop during streptococcal infection and rheumatic fever, are being investigated for their potential role [4,5,14], while it is evident that T lymphocytes play a key role in the pathogenesis of rheumatic carditis.…”

Strategies in the development of vaccines to prevent infections with group A streptococcus

“…36 Evidences suggest that streptococcal specific antibodies and T cells may contribute to this pathology. [37][38][39][40] In the case of RHD it has been suggested that antibodies to the streptococcal sugars damage the endothelial surface of the heart valves enabling the ingress of streptococcal-specific immune cells, including CD4 and CD8 T cells [41][42][43] which are activated by cross-reactive cardiac antigens leading to inflammation and scarring. 40,44 T cells taken from the excised heart valves of acute RF patients have been analyzed for specificity and some have been shown to respond to epitopes from the M protein, 45,46 raising potential concerns that vaccines containing those epitopes may induce pathology.…”

Novel Conserved Group A Streptococcal Proteins Identified by the Antigenome Technology as Vaccine Candidates for a Non-M Protein-Based Vaccine

“…Its variable N-terminal as well as its conserved carboxy-terminal region has been studied as a possible vaccine candidate (2,4,12). However, the existence of more than 100 M protein serotypes of S. pyogenes and the link between M protein-induced humoral and cellular immune responses and autoimmune poststreptococcal sequelae hinder M protein-based vaccine development (13,18,42). Several other group A streptococcal surface proteins were also shown to induce protective immune responses in animals and are therefore considered vaccine candidates; among them are the extracellular pyrogenic exotoxins, streptococcal superantigens, C5a peptidase, and the streptococcal fibronectin-binding protein SfbI (5,10,25,36,56).…”

“…on May 10, 2018 by guest http://iai.asm.org/ to induce both humoral and cellular immunological cross-reactivity, especially with heart and joint tissues, is the M protein (11,13,18,42). Besides this link of autoimmunity to poststreptococcal sequelae, the existence of more than 100 different M types hinders M protein-based vaccine development.…”