Definition of a Superantigen Toxic shock syndrome (TSS) is a life-threatening, multi-system disease characterized by rapid onset of fever, hypotension, and multi-organ failure. This disease entity has received considerable attention in the past 15 yr as a result of the appearance of menstrual TSS associated with Staphylococcus aureus and, most recently, with the global appearance of a streptococcal toxic shocklike syndrome (TSLS) associated with particular strains of StreptococcuS pyogenes, i.e., group A streptococci (GAS) (1). Although there is some evidence that viridans streptococci and groups B, C, F, and G streptococci cause TSLS (2), this discussion will be limited to S. aweuS and GAS, These two organisms produce protein exotoxins that have been shown to be associated with the development of TSS. These exotoxins are known as super-antigens because their interaction with the human immune system results in overstimulation of the normal response to a foreign antigen. The discovery of the mechanism of action of these exotoxins has defined TSS at the cellular level and has shed light on the complex regulatory pathways of our immune system. An understanding of the immune response to conventional antigens is necessary before superantigens can be adequately defined (3,4). Conventional foreign antigens encountered by the immune system are recognized by antigenpresenting cells (APC) that are primarily B cells, monocytes, and dendritic cells (Fig. 1). The antigens are internalized and processed into small peptides within the lysosomal compartments of the APC. The small peptides are transported to the APC membrane, where they form complexes with the major histocompatibility (MHC) class II molecules on the surface of these cells. This complex is recognized by T cells with receptors specific for the antigen/MHC complex. T-cell binding to antigen/MHC complexes initiates a series of events in the T cell and APC that result in the release of inflammatory cytokines, the regulatory messengers of the immune system. Cytokines such as interferon gamma (lFNy), interleukin 1 (IL-l), IL-6, and tumor necrosis factor alpha (ma) orchestrate activation and differentiation of immune cells, thereby allowing the body to respond to foreign invaders. T-cell binding to antigen/MHC complexes is highly specific and results in activation of only 0.0001% of the T cells in the body. This exquisite specificity is a result of the composition of the 01 and p chains of the T-cell receptor. These chains possess variable elements VP, Dp, Jp, Va, Ja that are encoded by many different genes within the human genome. Reassortment of these genes produces the vast repertoire of T-cell receptor specificities. Although there are innumerable combinations of a and p and regions, there are only about 25 major families of VP elements. This limited diversity of VP elements plays a key role in the excessive immune activation caused by super-antigens.