Holm, and M. rates ranging from 30 to 70% (9, 10, 12, 21). During the late AEE788 1980s, several outbreaks of severe invasive infections due to T1M1 GAS were reported worldwide. In Sweden, two outbreaks of streptococcal invasive disease occurred during the time span of the current study (1986 to 1996), one in 1988 and 1989 and a second in 1994 and 1995 (33, 34). The M-protein and streptococcal pyrogenic exotoxins (Spe) are considered important virulence factors in the pathogenesis of invasive disease. Spe belong to the superantigen (SAg) protein family that induces massive T-cell activation and subsequent launch of high levels of cytokines through cross-linking of the major histocompatibility complex class II proteins and T-cell receptor molecules bearing particular V chains (32). Several lines of evidence support the hypothesis of SAg involvement in the pathogenesis of STSS. In sera from individuals with shock, elevated levels of Th1 cytokines have been mentioned, along with depletion and suppression of particular V-expressing T cells (26, 29, 35). Moreover, studies with animal models have shown that SAgs induce shock-like symptoms in rabbits and rodents (6, 22, 31). The isolation of genetically identical GAS from individuals with different examples of severity of illness implies a role for host factors in determining the outcome of microbe-host connection (7, 24). Several studies of patient humoral immunity have demonstrated that the lack of protecting antibodies to M-protein and SAgs are risk factors for development of invasive disease (4, 28). Furthermore, the magnitude of Th1 cytokine response mounted during illness has been shown to be related to the severity of disease (26). SAgs of streptococcal source have been shown to preferentially bind HLA-DR and HLA-DQ, and in more recent studies, polymorphism within these genes offers been shown to influence the sponsor response to SAgs (19, 20, 27). Early administration of intravenous immunoglobulin (IVIG) has shown promising results in treatment of GAS invasive disease (8, 18). However, IVIG preparations differ in their capability to neutralize SAgs (25). A possible future restorative approach entails recognition of common epitopes on SAgs important for T-cell activation and HLA acknowledgement, which could be used in developing a vaccine against STSS (3). These different methods for treatment raise questions regarding the level and specificity of the individual humoral immune response induced during a GAS illness. With this retrospective study, we monitored the humoral immune responses in individuals with different medical manifestations of GAS infections over time. The purpose of the study was to measure the neutralization of the mitogenic activity and the enzyme-linked immunosorbent assay (ELISA) titers against EP produced by the patient’s personal infecting isolate during in vitro tradition. Furthermore, we also wanted to investigate whether GAS infections could trigger the development of SAg-inhibiting humoral response and to analyze whether the acquired immunity is definitely general or limited to the infecting isolate. MATERIALS AND METHODS Clinical material. Isolates and sera from individuals with different medical manifestations of GAS infections were collected in Sweden from 1986 to 1996 (12, 17, 28). A total of 84 isolates were used. Both acute- and convalescent-phase sera and the infecting isolate were from 75 individuals. Individuals were grouped relating to analysis: 20 experienced sepsis without shock, 23 experienced STSS, 21 experienced erysipelas, and 11 experienced tonsillitis; the imply age groups for the four patient groups were 60, 46, 59, and 18 years, respectively. The analysis was made by a physician. AEE788 Tonsillitis was defined as a sore throat with positive GAS tradition. Erysipelas was defined as a febrile condition having a reddish, well-demarcated, warm, and painful part of erythema. Individuals having a positive blood culture were included in the sepsis group, and STSS was defined according to standard criteria and in some cases was diagnosed retrospectively (36). Sera were collected at different time points and divided in organizations. Acute-phase sera were collected on days 0 to 7 AEE788 after the onset of disease; if the onset was not mentioned, day of admission to hospital was considered day time 1. Early convalescent-phase sera were collected from days 10 to 75, intermediate AEE788 convalescent-phase sera were collected from days 114 to 400, and late convalescent-phase sera were collected from days 696 RCBTB1 to 1 1,512. Sera were not.