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Superantigens elicit massive and often destructive immune responses by circumventing the usual rules of antigen presentation and T-cell recognition. Rather than binding to the cleft of major histocompatibility complex class II molecules, these microbial proteins bind directly to the outside of major histocompatibility complex molecules and then to the variable (Vβ) region of the T-cell receptor's beta chain, thus bridging the T cell and the antigen-presenting cells without a requirement for complex processing. Linkage to the Vp region allows superantigens to activate as many as one in five T cells. Although these proteins were identified more than two decades ago, their unique features giving rise to tissue destruction and other disorders are only beginning to be understood. For example, the ability of superantigens to induce toxic shock appears closely related to their stimulation of inflammatory cytokines. Less dramatic, but no less significant in terms of morbidity and health-care costs, is the association of superantigens with autoimmune disease. This relationship may reflect the expansion of superantigen-stimulated, self-reactive T-cell clones that were not deleted during thymic selection. Continued study of superantigens in clinical material will no doubt provide the necessary insights to begin effective intervention in disorders traceable to these substances.