thumb|Figure_1._Schematic_of_Superantigen_stimulation_compared_to_normal_antigen_presentation_and_activation__.]_Superantigens (SAgs) are secreted proteins (
exotoxins) that exhibit highly potent lymphocyte-transforming ( mitogenic) activity directed towards T lymphocytes[2,4,6] . Compared to a normal antigen-induced T-cellresponse where .001-.0001% of the body’s T-cells are activated, SAgs are capable of activating up to 20% of the body’s T-cells  . This causes a massive immune response that is not specific to any particular epitopeon the SAg. Since one of the fundamental strengths of the adaptive immune systemis its ability to target antigens with high specificity, SAgs produce an immune response that is effectively useless. Microbes(including viruses, mycoplasma, and bacteria ) produce SAgs as a defense mechanism to aid them in evading the immune system  .
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 [12, 14] .
Crystal structuresof the enterotoxins reveals that they are compact, ellipsoidal proteinssharing a characteristic two-domain folding pattern comprising an NH2-terminal β barrel globular domainknown as the oligosaccharide/ oligonucleotidefold, a long α-helixthat 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 (see Figure 2)  .
Superantigens bind first to the MHC Class II and then coordinate to a T-cell Receptor (TCR) with a specific Variable β motif [4,14,15] .
MHC Class II
[Figure 4. Ribbon diagrams showing three classes of SAg (red) binding to MHC Class II molecules (blue and yellow). SEB shows binding to α-chain; TSST shows binding at a different location on the α-chain; SPE-C shows binding to the β chain mediated by a zincst SAgs show preference for the
HLA-DQform 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 polymorphicMHC class II β-chain in an interaction mediated by a zincion coordination complex between three SAg residues and a highly conserved region of the HLA-DRβ chain  . The use of a zinc ion in binding leads to a higher affinity interaction  . Several staphylococcal SAgs are capable of cross-linkingMHC molecules by binding to both the α and β chains [12,14] . This mechanism stimulates cytokineexpression 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  .
The T-cell binding region of the SAg interacts with the Variable region on the Beta chain of the T-cell Receptor. A given SAg can activate a large proportion of the T-cell population because the human T-cell repertoire comprises only about 50 types of Vβ elements and some SAgs are capable of binding to multiple types of VB regions. This interaction varies slightly among the different groups of SAgs  . Variability among different people in the types of T-cell regions that are prevalent explains why some people respond more strongly to certain SAgs. Group I SAgs contact the Vβ at the
CDR2and framework region of the molecule [1,9] . SAgs of Group II interact with the Vβ region using mechanisms that are conformation-dependent. These interactions are for the most part independent of specific Vβ amino acid side-chains. Group IV SAgs have been shown to engage all three CDR loops of certain Vβ forms [1,9] . The interaction takes place in a cleft between the small and large domains of the SAg and allows the SAg to act as a wedge between the TCR and MHC. This displaces the antigenic peptide away from the TCR and circumvents the normal mechanism for T-cell activation [14, 23] .
The biological strength of the SAg (its ability to stimulate) is determined by its
affinityfor the TCR. SAgs with the highest affinity for the TCR elicit the strongest response  . SPMEZ-2 is the most potent SAg discovered to date  .
The SAg cross-links the MHC and the TCR inducing a signaling pathway that results in the
proliferationof the cell and production of cytokines. Low levels of Zap-70have been found in T-cells activated by SAgs, indicating that the normal signaling pathway of T-cell activation is impaired  . It is hypothesized that Fynrather than Lckis activated by a tyrosine kinase, leading to the adaptive induction of anergy  . Both the protein kinase C pathway and the protein tyrosine kinase pathways are activated, resulting in upregulating production of proinflammatory cytokines  . This alternative signaling pathway impairs the calcium/calcineurin and Ras/MAPkinase pathways slightly  , but allows for a focused inflammatory response.
SAg stimulation of antigen presenting cells and T-cells elicits a response that is mainly inflammatory, focused on the action of Th1
T-helpercells. Some of the major products are IL-1, IL-2, IL-6, TNF-α, gamma interferon (IFN-γ), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and monocytechemoattractant protein 1 ( MCP-1)  . This excessive uncoordinated release of cytokines, (especially TNF-α), overloads the body and results in to rashes, fever, and can lead to multi-organ failure, coma and death [9, 15] . Deletion or anergyof activated T-cells follows infection. This results from production of IL-10from prolonged exposure to the toxin. IL-10 downregulates production of IL-2, MHC Class II, and costimulatory molecules on the surface of APCs. These effects produce memory cells that are unresponsive to antigen stimulation [8, 19] . One mechanism by which this is possible involves cytokine-mediated suppression of T-cells. MHC crosslinking also activates a signaling pathway that suppresses hematopoiesisand upregulates Fas-mediated apoptosis . IFN-α is another product of prolong SAg exposure. This cytokine is closely linked with induction of autoimmunity  , and the autoimmune disease Kawasaki Diseaseis known to be caused by SAg infection  . SAg activation in T-cells leads to production of CD40ligand which activates isotype switching in B cells from to IgGand IgMand IgE . To summarize, the T-cells are stimulated and produce excess amounts of cytokine resulting in cytokine-mediated suppression of T-cells and deletion of the activated cells as the body returns to homeostasis. The toxic effects of the microbe and SAg also damage tissue and organ systems, a condition known as Toxic Shock Syndrome . If the initial inflammation is survived, the host cells become anergic or are deleted, resulting in a severely compromised immune system.
Superantigenicity independent Effects (Indirect Effects)
Apart from their mitogenic activity, SAgs are able to cause symptoms that are characteristic of infection [as cited by 2] .
One such effect is
emesis. This effect is felt in cases of food poisoning, when SAg-producing bacteria release the toxin, which is highly resistant to heat. There is a distinct region of the molecule that is active in inducing gastrointestinaltoxicity [as cited by 2] . This activity is also highly potent, and quantities as small as 20-35ug of SAg are able to induce vomiting  .
SAgs are able to stimulate recruitment of
neutrophilsto the site of infection in a way that is independent of T-cell stimulation. This effect is due to the ability of SAgs to activate monocyticcells, stimulating the release of the cytokine TNF-α, leading to increased expression of adhesion molecules that recruit leukocytes to infected regions. This causes inflammation in the lungs, intestinal tissue, and any place that the bacteria have colonized . While small amounts of inflammation are natural and helpful, excessive inflammationcan lead to tissue destruction.
One of the more dangerous indirect effects of SAg infection concerns the ability of SAgs to augment the effects of
endotoxinsin the body. This is accomplished by reducing the threshold for endotoxicity. Schlievert demonstrated that, when administered conjunctively, the effects of SAg and endotoxin are magnified as much as 50 000 times  . This could be due to the reduced immune system efficiency induced by SAg infection. Aside from the synergisticrelationship between endotoxin and SAg, the “double hit” effect of the activity of the endotoxin and the SAg result in effects more deleterious that those seen in a typical bacterial infection. This also implicates SAgs in the progression of sepsisin patients with bacterial infections  .
Diseases Associated with Superantigen production 
Toxic Shock Syndrome
The primary goal of medical treatment is to eliminate the microbe that is producing the SAgs. This is accomplished through the use of
vasopressors, fluid resuscitationand antibiotics . The body naturally produces antibodiesto some SAgs, and this effect can be augmented by stimulating B-cellproduction of these antibodies  . Immunoglobulinpools are able to neutralize specific antibodies and prevent T-cell activation. Synthetic antibodies and peptides have been created to mimic SAg-binding regions on the MHC class II, blocking the interaction and preventing T cell activation [as cited by 2] . Immunosuppressantsare also employed to prevent T-cell activation and the release of cytokines. Corticosteroidsare used to reduce inflammatory effects  .
Evolution of Superantigen Production
SAg production effectively corrupts the immune response, allowing the microbe secreting the SAg to be carried and transmitted unchecked. One mechanism by which this is done system is through inducing
anergyof the T-cells to antigens and SAgs [8, 10] . Lussow and MacDonald demonstrated this by systematically exposing animals to a streptococcal antigen. They found that exposure to other antigens after SAg infection failed to elicit an immune response  . In another experiment, Watson and Lee discovered that memory T-cellscreated by normal antigen stimulation were anergic to SAg stimulation and that memory T-cells created after a SAg infection were anergic to all antigen stimulation. The mechanism by which this occurred was undetermined  . The genes that regulate SAg expression also regulate mechanisms of immune evasion such as M proteinand capsuleexpression, supporting the hypothesis that SAg production evolvedprimarily as a mechanism of immune evasion  .
When the structure of individual SAg domains has been compared to other immunoglobulin-binding streptococcal proteins (such as those toxins produced by
"E. coli") it was found that the domains separately resemble members of these families. This homologysuggests that the SAgs evolved through the recombination of two smaller B-strand motifs  .
Minor lymphocyte stimulating (Mls) exotoxins were originally discovered in the
thymic stromalcells of mice. These toxins are encoded by SAg genes that were incorporated into the mouse genome from the mouse mammary tumour virus ( MMTV). The presence of these genes in the mouse genome allows the mouse to express the antigen in the thymusas a means of negatively selecting for lymphocytes with a variable Beta region that is susceptible to stimulation by the viral SAg. The result is that these mice are immuneto infection by the virus later in life [as cited by 2] .
Similar endogenous SAg-dependent selection has yet to be identified in the human genome, but endogenous SAgs have been discovered and are suspected of playing an integral role in viral infection. Infection by the
Epstein-Barr virus, for example, is known to cause production of a SAg in infected cells, yet no gene for the toxin has been found on the genome of the virus. The virus manipulates the infected cell to express its own SAg genes, and this helps it to evade the host immune system. Similar results have been found with rabies, cytomegalovirus, and HIV[as cited by 2] .
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# Lussow AR, MacDonald HR. 1994. Differential effects of superantigen-induced “anergy” on priming and effector stages of a T cell-dependent antibody response. Eur J Immunol; 24: 445–49.
# Rebecca A. Buonpane1, Beenu Moza, Eric J. Sundberg and David M. Kranz. 2005. Characterization of T Cell Receptors Engineered for High Affinity Against Toxic Shock Syndrome Toxin-1. J. Mol. Biol. 353; 308–321
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* [http://public-1.cryst.bbk.ac.uk/sagdb/sagdb.html Superantigen Web Database] at
Birkbeck, University of London
** [http://public-1.cryst.bbk.ac.uk/sagdb/intro.html Introduction to SAgs at Superantigen Web Database]
* [http://www.expasy.org/cgi-bin/get-entries?KW=Superantigen List of Superantigen Proteins] from
Wikimedia Foundation. 2010.
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