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Chapter 16 : Countermeasures against Superantigens: Structure-Based Design of Bispecific Receptor Mimics
Superantigens (SAgs) are a family of highly potent immunostimulatory proteins produced by bacteria or viruses. The family includes many proteins that may be unrelated by sequence or structure and yet share the ability to bypass the mechanisms of conventional antigen processing and trigger excessive activation of T cells. The massive lymphokine release by the activated cells within hours and the excessive T-cell proliferation in 2 to 3 days could ultimately lead to an immunosuppressive state and favor the microbe. Human diseases caused by microbes that utilize SAgs as their major virulence factors are characterized by fever and shock. The Staphylococcus aureus enterotoxins A-1 are thought to be the causative agents in 33% of all food-poisoning cases and are the most frequent cause of hospital-acquired infections. Presently, the treatment of superantigen-mediated infections is limited to the administration of antibiotics and handling of the state of shock. Conventional antigens are phagocytosed by antigenpresenting cells (APCs) and are processed into discrete peptides. The SAgs of S. aureus and Streptococcus pyogenes share a common architecture despite their significant difference in sequence. SAgs are globular proteins of 22 to 29 kDa, composed of two domains, amino- and carboxy-terminal, that are separated by a long, solvent-accessible α- helix spanning the center of the molecule. The T-cell receptor is a transmembrane heterodimer, composed of α- and β-chains. Each chain is composed of constant (C) and variable (V) regions.