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Epitopes of group A streptococcal M protein shared with antigens of articular cartilage and synovium
R W Baird1, M S Bronze, W Kraus
1Department of Veterans Affairs Medical Center, Memphis, TN 38104.
Abstract:
Rabbit antisera evoked by purified pepsin-extracted group A streptococcal M proteins were screened for the presence of joint cross-reactive antibodies by indirect immunofluorescence using thin sections of mouse knee joints. Pep M1, M5, and M18 antisera contained antibodies that cross-reacted with chondrocytes, cartilage, and synovium. Immunofluorescence inhibition assays showed that some of the joint cross-reactive epitopes were shared among the three heterologous serotypes of M protein. The pep M5 joint cross-reactive epitopes were localized to three different synthetic peptides of the C-terminal region of pep M5. Immunoblot analyses showed that the M5 joint cross-reactive antibodies recognized two proteins of human synovium and cartilage of molecular mass 56 and 58 kDa. The cross-reactive antibodies binding to the 56-kDa protein were inhibited by purified vimentin in immunoblot inhibition experiments. M protein-specific antibodies from patients with acute rheumatic fever were also shown to cross-react with joint tissue in a pattern similar to the rabbit antisera. Rabbit and human M protein-specific antibodies that were bound to articular cartilage activated significant levels of complement when compared to control serum, suggesting that M protein joint cross-reactive antibodies could potentially be involved in the pathogenesis of ARF and arthritis.
Insights
Group A Streptococcus M proteins trigger cross-reactive antibodies targeting joint tissues like cartilage. These findings suggest a potential role for these antibodies in the development of acute rheumatic fever (ARF) and arthritis.
Area of Science:
- Immunology
- Rheumatology
- Microbiology
Background:
- Group A Streptococcus (GAS) is a significant human pathogen.
- Rheumatic fever (ARF) is an inflammatory disease that can affect the heart, joints, brain, and skin.
- The role of GAS M proteins in autoimmune responses targeting joint tissues remains incompletely understood.
Purpose of the Study:
- To investigate whether antibodies against streptococcal M proteins cross-react with joint tissues.
- To identify specific M protein epitopes involved in joint cross-reactivity.
- To explore the potential role of these cross-reactive antibodies in the pathogenesis of ARF and arthritis.
Main Methods:
- Indirect immunofluorescence on mouse knee joint sections.
- Immunofluorescence inhibition assays.
- Immunoblot analyses of human synovium and cartilage proteins.
- Immunoblot inhibition experiments using purified vimentin.
- Complement activation assays.
Main Results:
- Rabbit antisera against M proteins (M1, M5, M18) showed cross-reactivity with chondrocytes, cartilage, and synovium.
- Shared epitopes between M protein serotypes and joint tissues were identified.
- Specific peptides in the C-terminal region of M5 were localized to joint cross-reactive epitopes.
- M5 cross-reactive antibodies recognized 56 and 58 kDa proteins in human joint tissues, with the 56 kDa protein identified as vimentin.
- Antibodies from ARF patients also cross-reacted with joint tissues.
- Bound M protein antibodies activated complement on articular cartilage.
Conclusions:
- Antibodies against group A Streptococcus M proteins can cross-react with joint components, including vimentin.
- Shared epitopes suggest a potential mechanism for autoimmune targeting of joints.
- Complement activation by these antibodies on cartilage indicates a potential role in ARF and arthritis pathogenesis.