Superantigen

Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically it causes non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs are produced by some pathogenic viruses and bacteria most likely as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response where 0.0001-0.001% of the body’s T-cells are activated, these SAgs are capable of activating up to 20% of the body’s T-cells. Furthermore, Anti-CD3 and Anti-CD28 Antibodies (CD28-SuperMAB) have also shown to be highly potent superantigens (and can activate up to 100% of T cells). Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically it causes non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs are produced by some pathogenic viruses and bacteria most likely as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response where 0.0001-0.001% of the body’s T-cells are activated, these SAgs are capable of activating up to 20% of the body’s T-cells. Furthermore, Anti-CD3 and Anti-CD28 Antibodies (CD28-SuperMAB) have also shown to be highly potent superantigens (and can activate up to 100% of T cells). The large number of activated T-cells generates a massive immune response which is not specific to any particular epitope on the SAg thus undermining one of the fundamental strengths of the adaptive immune system, that is, its ability to target antigens with high specificity. More importantly, the large number of activated T-cells secrete large amounts of cytokines, the most important of which is Interferon gamma. This excess amount of IFN-gamma in turn activates the macrophages. The activated macrophages, in turn, over-produce proinflammatory cytokines such as IL-1, IL-6 and TNF-alpha. TNF-alpha is particularly important as a part of the body's inflammatory response. In normal circumstances it is released locally in low levels and helps the immune system defeat pathogens. However, when it is systemically released in the blood and in high levels (due to mass T-cell activation resulting from the SAg binding), it can cause severe and life-threatening symptoms, including shock and multiple organ failure. SAgs are produced intracellularly by bacteria and are released upon infection as extracellular mature toxins. The sequences of these toxins are relatively conserved among the different subgroups. More important than sequence homology, the 3D structure is very similar among different SAgs resulting in similar functional effects among different groups. Crystal structures of the enterotoxins reveals that they are compact, ellipsoidal proteins sharing a characteristic two-domain folding pattern comprising an NH2-terminal β barrel globular domain known as the oligosaccharide / oligonucleotide fold, a long α-helix that diagonally spans the center of the molecule, and a COOH terminal globular domain. The domains have binding regions for the Major Histocompatibility Complex Class II (MHC Class II) and the T cell receptor (TCR), respectively. Superantigens bind first to the MHC Class II and then coordinate to the variable alpha or beta chain of T-cell Receptors (TCR) SAgs show preference for the HLA-DQ form of the molecule. Binding to the α-chain puts the SAg in the appropriate position to coordinate to the TCR. Less commonly, SAgs attach to the polymorphic MHC class II β-chain in an interaction mediated by a zinc ion coordination complex between three SAg residues and a highly conserved region of the HLA-DR β chain. The use of a zinc ion in binding leads to a higher affinity interaction. Several staphylococcal SAgs are capable of cross-linking MHC molecules by binding to both the α and β chains. This mechanism stimulates cytokine expression and release in antigen presenting cells as well as inducing the production of costimulatory molecules that allow the cell to bind to and activate T cells more effectively.