Despite remarkable increases in our knowledge of the biology of the group A streptococcus and of the human host and despite important observations about the epidemiologic association between group A streptococci and the human host, the pathogenetic mechanism responsible for the development of acute rheumatic fever remains unknown.

There have been two basic theories attempting to explain the development of this sequel to group A streptococcal pharyngitis: a toxic effect produced by an extracellular toxin of group A streptococci on target organs such as myocardium, valves, synovium, and brain; and an abnormal immune response by the human host. The search for the correct hypothesis has been severely hampered by the fact that there is no adequate animal model.

 

The hypotheses suggesting that rheumatic fever may be related to a direct effect of a streptococcal extracellular toxin have not been proved. For example, although streptolysin O, an extracellular product of group A streptococci, is cardiotoxic in animals, it has not been possible to establish a direct in vivo toxic effect by streptolysin O on the myocardium and valves or an injury of host tissue by streptolysin O resulting in "neoantigen" formation, with a subsequent immunologic response and damage to the host tissues.

 

The most popular hypotheses are those that postulate an abnormal immune response by the human host to some still, undefined component of the group A streptococcus. The resulting antibodies might then cause the immunologic damage leading to clinical manifestations. The latent period, usually 1{endash}–3 wk between the onset of the actual group A streptococcal infection and the onset of symptoms of acute rheumatic fever, lends support to an immunologic mechanism of tissue damage. Although the specific antigen or antigens responsible for inciting such an immune response have still to be identified, several possibilities exist.

 

The group A streptococcus is a complex microorganism producing a large number of somatic and extracellular antigens that evoke brisk immune responses. This theory is further supported by the observation that different humans appear to respond quantitatively differently to streptococcal antigens. For example, in in vitro studies with human lymphocytes, individuals can be divided into high and low responders to streptococcal blastogen A, an extracellular product of the organism. This finding is compatible with the clinical and epidemiologic observations that not all people appear to be susceptible to developing rheumatic fever (see later).

 

Two streptococcal antigens are excellent examples of how an abnormal immunologic response might cause the clinical manifestations. First, the group-specific polysaccharide of the group A b{beta}-hemolytic streptococcal cell wall is antigenically similar to the glycoprotein found in human and bovine cardiac valves. There is prolonged persistence of antibody against the group A polysaccharide in individuals with chronic rheumatic valvular heart disease compared with individuals recovering from uncomplicated streptococcal infection or those with acute nephritis. When rheumatic mitral valves were surgically removed and replaced with prosthetic valves, serum antibody levels against the group A polysaccharide fell, as if the antigenic stimulus had been removed. However, important questions remain about whether this antigen is responsible for the valvulitis of rheumatic heart disease.

For example, it has been shown that antibodies to group-specific carbohydrate develop after group A streptococcal skin infection, and rheumatic fever does not follow group A streptococcal skin infection (pyoderma). A second so-called cross-reactive antigen was originally described in the cell wall or cell membrane. Antibodies to this (these) somatic antigen(s) are found in sera of patients with rheumatic fever (i.e., heart-reactive antibodies), and it has been postulated that the myocarditis of acute rheumatic fever is related to an abnormal or autoimmune response against sarcolemma membrane. However, the significance of these observations has been questioned because these serum antibodies also develop after uncomplicated pharyngitis in individuals without evidence of rheumatic carditis.

 

The possibility of an abnormal immune response is also based on cross-reactivity between group A streptococci M protein and human tissue. The M protein is the virulence factor that is responsible for the organism's ability to resist phagocytosis. In addition, following infections with group A streptococci, type-specific immunity is conferred against the specific M protein type. The group A streptococcal M protein shares certain amino acid sequences with some human tissues, and this has been proposed as a possible source of cross-reactivity between the organism and its human host, leading to the abnormal immune response. One of the two classes of M protein correlates with serotypes of group A streptococci that are frequently isolated from patients with acute rheumatic fever.

 

In patients with Sydenham chorea, common antibodies to antigens are found in the group A streptococcal cell membrane and the caudate nucleus of brain. This observation further supports the concept of an abnormal autoimmune mechanism for the central nervous system manifestations of rheumatic fever and Sydenham chorea.

 

An understanding of the pathogenesis of rheumatic fever must encompass the fact that there are differences in human susceptibility to the development of acute rheumatic fever, including an unusual incidence of rheumatic fever and rheumatic heart disease among members of certain family groups. In regard to this genetic influence, there is a specific alloantigen present on the surface of non{endash}–T lymphocytes in 70{endash}–90% of rheumatic individuals, but fewer than 30% of "control" nonrheumatic individuals have the marker. The marker is more common in family members in which there is an index case of rheumatic fever than in nonaffected members of "control" families.

 

Although there may be genetic differences in rheumatic susceptibility among humans, the exact mechanism remains unknown. It is unlikely that the recent outbreaks of acute rheumatic fever in the United States are caused by an increasingly susceptible population based only on genetics. It is most likely that the pathogenetic mechanism for the development of rheumatic fever after upper respiratory tract infection with group A b{beta}-hemolytic streptococci involves a combination of specific characteristics of the organism and some as yet incompletely defined genetic predisposition in the human host.