The antigenic relatedness of surface-exposed portions of M
protein molecules derived from group A streptococcal isolates representing more than 50 distinct serotypes was examined. The data indicate that the majority of serotypes fall into two major classes. Class I M
protein molecules share a surface-exposed, antigenic domain comprising the C repeat region defined for M6
protein. The C repeat region of M6
protein is located adjacent to the COOH-terminal side of the
pepsin-susceptible site. In contrast, Class I M
proteins display considerably less antigenic relatedness to the B repeat region of M6
protein, which lies immediately NH2-terminal to the
pepsin site. Surface-exposed portions of Class II M
proteins lack antigenic
epitopes that define the Class I molecules. Studies in the 1970s demonstrated that M
protein serotypes can be divided into two groups based on both immunoreactivity directed to an unknown
surface antigen (termed M-associated
protein) and production of
serum opacity factor. These two groups closely parallel our current definition of Class I and Class II serotypes. Both classes retain the antiphagocytic property characteristic of M
protein, and Class II M
proteins share some immunodeterminants with Class I M
proteins, although the shared determinants do not appear to be exposed on the streptococcal surface. Nearly all streptococcal serotypes associated with outbreaks of
acute rheumatic fever express M
protein of a Class I serotype. Thus, the surface-exposed, conserved C repeat domain of Class I serotypes may be a virulence determinant for
rheumatic fever.