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SEB, A typical bacterial superantigen (PDB:3SEB) The β-grasp domain is shown in red, and the β-barrel in green: The "disulphide loop" is shown in yellow

Superantigens (SAgs) are a group of virulent toxins that indiscriminately activate T-cells of the immune system causing system-wide inflammation and other serious, potentially fatal symptoms. They are not quite the same as antigens-- though they almost all have antigenic properties-- but rather receive their name from their powers to stimulate a massive antigen-nonspecific immune response.

Characteristic symptoms of superantigen-mediated diseases include:

• fever
• mucus production
• diarrhea
• vomiting
• septic shock leading to death

Chronic infection can cause autoimmune diseases and glomerulonephritis.

Superantigens are secreted as exotoxins by bacteria or protozoa, alternatively viruses hijack our own molecular machinery to generate endotoxin forms of superantigens. They are mainly associated with species of Streptococcus and Staphylococcus infections, and are the contributing cause of toxic shock syndrome. Superantigens are also the suspected cause of numerous diseases displaying characteristic symptoms with unknown causes.

Rather than typical presentation by major histocompatibility complex type II molecules (MHC II) of antigen-presenting cells to T-cell receptors (TCXs) inside specialised clefts, superantigens bind externally to the Vβ region of the TCR and to the complementary chain of MHC II, the alpha chain region, causing inappropriate, antigen-dependent B-cell activation. In a typical infection, 0.01% of the body's T-cells are activated; superantigen-mediated infections commonly activate 20-50% of the T-cells in the region. These T-cells are of all populations (helper T cells, cytotoxic T cells, suppressor T cells, and as-yet-unidentified T-cell populations), and leads to a mass activation of multiple, often contradictory, chemical mediators that contribute to the severe unwellness of an individual. For example, massive production of IL-2 and TNF-alpha lead to extreme inflammation and septic shock.

Many superantigen structures have been solved by X-ray crystallography, including complexes between some SAgs and either the MHC-type II complexes and T-cell receptors. Bacterial SAgs typically consist of 2 domains: a 6-stranded β-barrel followed by a β-grasp domain. In the Zinc-independent superantigens, both the T-cell receptor and MHC-type II molecules are able to simultaneously bind the β-barrel domain: this simultaneous cross-linking of the molecules and their associated cells leads to the over-activation of T-cells which in turn leads to the over production of cytokines and other cell-signalling molecules. The so-called "disulphide loop", shown in yellow (upper figure), is thought to be sandwiched between the MHC-II and TCR and is implicated in mediating the response ^[1].

Some Sags co-ordinate a zinc-ion in their β-grasp domain. It has beeen shown that these zinc-dependent SAgs, such as SEC2, bind the MHC-II molecule in a different fashion, via this zinc ion. However, the cross-linking still occurs, albeit in a different fashion, and the immunological effect produced is similar.^[2]

SEC3 (yellow) complexed with an MHC-II molecule (green & cyan): The SAgs binds adjacent to the antigen (purple) presentation cleft in the MHC-II

Research into superantigen treatment focuses on the use of polyspecific immunologlobulin G, antagonistic peptides, and toxoid vaccines. There has also been some concern that bacterial superantigens may be mass-produced and used as bioweapons (Staphylococcus aureus B enterotoxin, for example - [1]).

• Food poisoning (Staphylococcus and Streptococcus)
• Toxic shock syndrome (Staphylococcus)
• Wegener's granulomatosis (Staphylococcus)
• Scarlet fever (Streptococcus)
• Yersinia pseudotuberculosis
• Mycoplasma arthriditis
• Linconegavnia oncothersis
• Necrotizing fasciitis (Streptococcus pyogenes)"

• Kawasaki disease
• Allergic sinusitis
• Cytomegalovirus (with HIV)
• Epstein-Barr Virus (with HIV)
• Type I diabetes mellitus
• vasculitis and other unexplained inflammatory diseases

• Superantigen Web Database at Birkbeck College

• Introduction to SAgs at Superantigen Web Database

• List of Superantigen Proteins from UniProt