Acute rheumatic fever is a sequel only of pharyngeal infections, but acute glomerulonephritis can follow infections of the pharynx or the skin. Although there is no adequate explanation for the precise pathogenesis of acute rheumatic fever, an abnormal or enhanced immune response seems essential. Also, persistence of the organism on pharyngeal tissues (i.e., the tonsils) is associated with an increased likelihood of rheumatic fever. Acute rheumatic fever can result in permanent damage to the heart valves. Less than 1% of sporadic streptococcal pharyngitis infections result in acute rheumatic fever; however, recurrences are common, and life-long antibiotic prophylaxis is recommended following a single case.

The occurrence of cross-reactive antigens in S. pyogenes and heart tissues possibly explains the autoimmune responses that develop following some infections. The antibody mediated immune (AMI) response (i.e., level of serum antibody) is higher in patients with rheumatic fever than in patients with uncomplicated pharyngitis. In addition, cell-mediated immunity (CMI) seems to play a role in the pathology of acute rheumatic fever.

Acute glomerulonephritis results from deposition of antigen-antibody-complement complexes on the basement membrane of kidney glomeruli. The antigen may be streptococcal in origin or it may be a host tissue species with antigenic determinants similar to those of streptococcal antigen (cross-reactive epitopes for endocardium, sarcolemma, vascular smooth muscle). The incidence of acute glomerulonephritis in the United States is variable, perhaps due to cycling of nephritogenic strains, but it appears to be decreasing. Recurrences are uncommon, and prophylaxis following an initial attack is unnecessary.

The host phagocytic system is a second line of defense against streptococcal invasion. Organisms can be opsonized by activation of the classical or alternate complement pathway and by anti-streptococcal antibodies in the serum. S. pyogenes is rapidly killed following phagocytosis enhanced by specific antibody. The bacteria do not produce catalase or significant amounts of superoxide dismutase to inactivate the oxygen metabolites (hydrogen peroxide, superoxide) produced by the oxygen-dependent mechanisms of the phagocyte. Therefore, they are quickly killed after engulfment by phagocytes. The streptococcal defense must be one to stay out of phagocytes.

In immune individuals, IgG antibodies reactive with M protein promote phagocytosis which results in killing of the organism. This is the major mechanism by which AMI is able to terminate Group A streptococcal infections. M protein vaccines are a major candidate for use against rheumatic fever, but certain M protein types cross-react antigenically with the heart and themselves may be responsible for rheumatic carditis. This risk of autoimmunity has prevented the use of Group A streptococcal vaccines. However, since the cross-reactive epitopes of the M-protein  are now known, it appears that limited anti-streptococcal vaccines are on the horizon.

FIGURE 4. Phagocytosis of Streptococcus pyogenes by a macrophage. CELLS alive!

The hyaluronic acid capsule allows the organism to evade opsonization. The capsule is also an antigenic disguise that hides bacterial antigens and is non antigenic to the host. Actually, the hyaluronic acid outer surface of S. pyogenes is weakly antigenic, but it does not result in stimulation of protective immunity. The only protective immunity that results from infection by Group A streptococcus comes from the development of type-specific antibody to the M protein of the fimbriae, which protrude from the cell wall through the capsular structure. This antibody, which follows respiratory and skin infections, is persistent. Presumably, protective levels of specific IgA is produced in the respiratory secretions while protective levels of IgG are formed in the serum. Sometimes, intervention of an infection with effective antibiotic treatment precludes the development of this persistent antibody. This accounts, in part, for recurring infections in an individual by the same streptococcal strain. Antibody to the erythrogenic toxin involved in scarlet fever is also long lasting.

Adherence (colonization) surface macromolecules
M protein

Lipoteichoic acid (LTA)

Protein F and Sfb (fibronectin-binding proteins)
 

Enhancement of spread in tissues
Hyaluronidase hydrolyses hyaluronic acid, part of the ground substance in host tissues.

Proteases

Streptokinase lyses fibrin

Evasion of phagocytosis
Capsule: hyaluronic acid is produced.

C5a peptidase: C5a enhances chemotaxis of phagocytes .

M protein is a fibrillar surface protein. Its distal end bears a negative charge that interferes with phagocytosis. It also blocks complement deposition on the cell surface. Mutations during the course of infection alter the structure of M proteins, rendering some antibodies ineffective. Strains that persist in carriers frequently exhibit altered M proteins.

Leukocidins, including streptolysin S and streptolysin O, are proteins secreted by the streptococci to kill phagocytes (and probably to release nutrients for their growth)

Defense against host immune responses
Antigenic disguise and tolerance provided by hyaluronic acid capsule

Antigenic variation. Antibody against M protein (antigen) is the only effective protective antibody, but there are more than 50 different M types, and subsequent infections may occur with a different M serotype.

Production of toxins and other systemic effects
Toxic shock: Exotoxin is superantigen that binds directly to MHC II (without being processed) and binds abnormally to the T cell receptor of many (up to 20% of) T cells. Exaggerated production of cytokines causes the signs of shock: fever, rash, low blood pressure. aberrant interaction between toxin, macrophage, and T cells.

Induction of circulating, cross-reactive antibodies
Some of the antibodies produced during infection by certain strains of streptococci cross-react with certain host tissues. These antibodies can indirectly damage host tissues, even after the organisms have been cleared, and cause autoimmune complications.

Suppurative conditions (active infections associated with pus) occur in the throat, skin, and systemically.

Throat
Streptococcal pharyngitis is acquired by inhaling aerosols emitted by infected individuals. The symptoms reflect the inflammatory events at the site of infection. A few (1-3%) people develop rheumatic fever weeks after the infection has cleared.

Skin
Impetigo involves the infection of epidermal layers of skin. Pre-pubertal children are the most susceptible. Cellulitis occurs when the infection spreads subcutaneous tissues. Erysipelas is the infection of the dermis. About 5% of patients will develop more disseminated disease. Necrotizing fasciitis involves infection of the fascia and may proceed rapidly to underlying muscle.

Systemic
Scarlet fever is caused by production of erythrogenic toxin by a few strains of the organism.

Toxic shock is caused by a few strains that produce a toxic shock-like toxin.

Non-suppurative Sequelae
Some of the antibodies produced during the above infections cross-react with certain host tissues. These can indirectly damage host tissues, even after the organisms have beencleared, and cause non suppurative complications.

Rheumatic fever. M protein cross reacts with sarcolemma. Antibodies cross-react with heart tissue, fix complement, and cause damage.