Superantigen
From Wikipedia, the free encyclopedia
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.
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[edit] Symptoms
Characteristic symptoms of superantigen-mediated diseases include:
Chronic infection can cause autoimmune diseases and glomerulonephritis.
[edit] Mode of Action
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.
[edit] Structural Information
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]
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]).
[edit] Clinical notes
[edit] Diseases associated with superantigen production
- 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)"
[edit] Diseases in which superantigen production is suspected
- Kawasaki disease
- Allergic sinusitis
- Cytomegalovirus (with HIV)
- Epstein-Barr Virus (with HIV)
- Type I diabetes mellitus
- vasculitis and other unexplained inflammatory diseases
[edit] References
- ^ Papageorgiou AC, Tranter HS, Acharya KR Crystal structure of microbial superantigen staphylococcal enterotoxin B at 1.5 A resolution: implications for superantigen recognition by MHC class II molecules and T-cell receptors J. Mol. Biol. v277, p.61-79
- ^ Sundstrom M, Hallen D, Svensson A, Schad E, Dohlsten M, Abrahmsen L The Co-crystal structure of staphylococcal enterotoxin type A with Zn2+ at 2.7 A resolution. Implications for major histocompatibility complex class II binding J. Biol. Chem. v271, p.32212-32216
[edit] External links
Adaptive immune system - Innate immune system - Humoral immune system - Cellular immune system
Lymphatic system - Inflammation - Complement system (Classical, Alternative, Lectin) - Cytokines - White blood cells - Antibody - Antigen - APC - MHC
Immunity - Autoimmunity - Tolerance (Central) - Immunodeficiency
