Protective and heart-crossreactive epitopes located within the NH2 terminus of type 19 streptococcal M protein.

Abstract

M protein was purified to homogeneity from limited pepsin digests of intact type 19 streptococci (pep M19). The purified pep M19 when emulsified in CFA and injected into rabbits evoked type-specific and crossreactive opsonic antibodies, as well as heart-crossreactive antibodies. The NH2-terminal primary structure of pep M19 was determined and a peptide copying the first 24 amino acids [SM19(1-24)C] was chemically synthesized. Rabbits that were immunized with the unconjugated peptide developed antibodies that recognized the native pep M19, as determined by ELISA, and opsonic antibodies against type 19 streptococci, as determined by in vitro opsonophagocytosis tests. The synthetic peptide also evoked antibodies that crossreacted with a 60-kD sarcolemmal membrane protein of human myocardium. By using overlapping synthetic subpeptides as immunoinhibitors, the opsonic and heart-crossreactive epitopes of SM19(1-24)C were localized to SM19(11-24)C. Our data confirm the presence of heart-crossreactive epitopes within the primary structure of pep M19 and show that these potentially harmful autoimmune epitopes may be located in the NH2-terminal regions of certain M proteins. We conclude that continued efforts to identify the primary structures of protective and heart-crossreactive epitopes will be necessary to elucidate the pathogenesis of acute rheumatic heart disease and to develop safe and effective streptococcal vaccines.

Systemic and Mucosal Immunizations with Fibronectin-Binding Protein FBP54 Induce Protective Immune Responses againstStreptococcus pyogenesChallenge in Mice

“…Mortality was monitored every day. 2 analysis was employed to analyze the significance of differences between the means of FBP54-immunized and nonimmunized mice on day 8. ‫,ء‬ P Ͻ 0.05; ‫,ءء‬ P Ͻ 0.001.…”

“…The other is that some M proteins share structural homology with cardiac proteins such as myosin and tropomyosin (10,17). The M19 protein possesses both a protective epitope and an autoimmune epitope in the amino terminus (2).…”

The Reactive Nature of Acute Rheumatic Fever: Evidence From Streptococcal Cell Wall Antigen Detection by Immunotechnology

“…Although still obscure, the pathogenesis of ARF requires primary infection (organism factor) of the throat by certain serotypes of group A strep (the concept of Rheumatogenicity). M serotypes 1,3,5,6,14,18,19,24,27 and 29 are the most frequently implicated. The pathogenic factor (s) are not known although M protein, the hyaluronic acid capsule, the cell wall-associated groupspecific carbohydrate, and the cell membrane have all been suggested (36).…”

“…The arthritogenicity of Strep pyogenes cell wall is attributed to an autoimmunelike disease (17) which for reasons still unclear predominantly manifests itself as ReA (18). The most virulent factor in strep cell wall is surface M protein (19) which immunologically cross-reacts with human tissues (20) including joints (21). An immunogenic factor in M proteins, peptidoglycan (PG), is covalently bound to a group specific polysaccharide (PS) and both (PG-PS) has been implicated in the pathogenesis of animal models of ReA (22).…”

Host–Pathogen Interactions in Streptococcal Immune Sequelae

“…Human and murine poly-reactive antibodies with myosin cross-reactivity, as suggested by their cytotoxicity and tissue localization, appear to contribute to the pathogenesis of carditis in ARF (Cunningham, 2000). Myosin cross-reactive antibodies recognize epitopes in M proteins M5, 6 and 19 (Bronze et al, 1988;Cunningham et al, 1989;Dale and Beachey, 1986). Further support for a role of molecular mimicry of M protein in ARF is the isolation of reactive T-cell clones that cross-react between M5 protein and cardiac myosin from myocardial and valvular lesions of RHD patients (Fae et al, 2006).…”