Molecular mimicry between streptococcal pyrogenic exotoxin B and endothelial cells

Area of Science:

• Immunology
• Microbiology
• Cardiovascular Research

Background:

• Group A Streptococcus (GAS) infections can lead to autoimmune sequelae like rheumatic heart disease (RHD).
• Molecular mimicry between GAS antigens and host tissues is a proposed mechanism for RHD pathogenesis.
• Previous research implicated M proteins and carbohydrate antigens in RHD etiology.

Purpose of the Study:

• To investigate the role of antibodies against streptococcal pyrogenic exotoxin B (SPE B) in post-streptococcal sequelae.
• To identify the specific epitopes on SPE B involved in cross-reactivity with host antigens.
• To explore the potential for molecular mimicry between SPE B and host components.

Main Methods:

• Immunization of mice with SPE B and analysis of resulting antibodies.
• Assessment of immunoglobulin G (IgG) deposition, complement activation, and apoptosis in heart valves.
• Characterization of a specific anti-SPE B monoclonal antibody (mAb 10G) for cross-reactivity.
• Peptide array and ELISA assays to map the SPE B epitope recognized by mAb 10G.
• Competition assays using peptides and N-acetyl-β-D-glucosamine (GlcNAc) to confirm molecular mimicry.

Main Results:

• Anti-SPE B antibodies demonstrated cross-reactivity with endothelial cells, including those in the heart valve.
• SPE B immunization and passive transfer with mAb 10G induced IgG deposition, complement activation, and apoptosis in mouse heart valves.
• The dominant epitope recognized by mAb 10G was mapped to amino acid residues 296-310 of SPE B (P7-8).
• mAb 10G also bound to N-acetyl-β-D-glucosamine (GlcNAc), and this binding was inhibited by GlcNAc and P7-8 peptides, suggesting conformational mimicry.

Conclusions:

• Antibodies targeting SPE B can cross-react with host endothelial cells, contributing to heart valve damage.
• A specific epitope within SPE B (residues 296-310) is crucial for this cross-reactivity.
• Conformational molecular mimicry between SPE B and GlcNAc is a likely mechanism driving autoimmune responses in post-streptococcal heart disease.