Superantigens and Streptococcal Toxic Shock Syndrome

have been implicated with streptococcal toxic shock syndrome (STSS). We analyzed 19 acute-phase serum samples for mitogenic activity from patients with severe strepto-coccal disease. The serum samples from two patients in the acute phase of STSS showed strong proliferative activity. Streptococcal mitogenic exotoxin (SME) Z-1 and strep-tococcal pyrogenic exotoxin (SPE)-J were identified in one patient with peritonitis who recovered after 2 weeks in intensive care. SMEZ-16 was found in a second patient who died on the day of admission. Sequential serum samples taken on day 3 after admission from patient 1 showed clearance of mitogenic activity but absence of neutralizing anti-SMEZ antibodies. Serum samples taken on day 9 from this patient showed evidence of seroconversion with high levels of anti-SMEZ antibodies that neutralized SMEZ-1 and 12 other SMEZ-variants. These results imply that a high level of SMEZ production by group A streptococcus is a causative event in the onset and subsequent severity of STSS. S ince the 1980s, a marked increase has occurred in highly invasive group A streptococcal (GAS) infections, in particular streptococcal toxic shock syndrome (STSS) associated with necrotizing fasciitis or myositis (1–4). The classical case definition for STSS is similar to staphylo-coccal toxic shock, caused by Staphylococcus aureus, but the outcome is more serious in STSS, with a reported death rate of 30% to 70% (2,5,6). The multiorgan involvement in STSS suggests that a toxin produced by GAS might be involved in pathogene-sis. Prime candidates are the streptococcal superantigens (SAgs), a family of highly mitogenic proteins secreted individually or in certain combinations by many Streptococcus pyogenes strains (7–10), although other vir-ulence factors, such as streptolysin O and various cell wall antigens can also cause toxic shock (11). Superantigens simultaneously bind to major histocompatibility complex class II molecules and T-cell receptor molecules bearing a particular V-β region. This binding results in the activation of a large proportion of antigen-presenting cells and T cells, with subsequent release of high systemic levels of cytokines (12–15). Several lines of evidence support the hypothesis of SAg involvement in STSS. Toxic shock syndrome (TSS) toxin, produced by S. aureus, has been associated with most menstrual TSS cases (7). TSS toxin is a typical SAg that is functionally and structurally related to the staphylococcal and streptococcal SAgs (16). Moreover, animal models have shown that TSS toxin and other SAgs induce TSS-like symptoms in rabbits and rodents (17,18). The lack of neutralizing anti-SAg antibodies appears …