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Superantigens ( SAgs) are a class of that result in excessive activation of the immune system. Specifically they cause non-specific activation of resulting in polyclonal T cell activation and massive cytokine release. Superantigens act by binding to the MHC proteins on antigen-presenting cells (APCs) and to the T-cell receptor on their adjacent helper T-cells, bringing the signaling molecules together, and thus leading to the activation of the T-cells, regardless of the peptide displayed on the MHC molecule. SAgs are produced by some 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 , the most important of which is Interferon gamma. This excess amount of IFN-gamma in turn activates the . 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 septic shock and multiple organ failure.
The sequences of these bacterial 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. There are at least 5 groups of superantigens with different binding preferences.
Crystal structures of the enterotoxins reveals that they are compact, ellipsoidal sharing a characteristic two-Protein 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. By bridging these two together, the SAg causes nonspecific activation.
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 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.
The biological strength of the SAg (its ability to stimulate) is determined by its affinity for the TCR. SAgs with the highest affinity for the TCR elicit the strongest response. SPMEZ-2 is the most potent SAg discovered to date.
It is hypothesized that FYN rather than Lck is 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.
This excessive uncoordinated release of cytokines, (especially TNF-α), overloads the body and results in rashes, fever, and can lead to multi-organ failure, coma and death.
Deletion or anergy of activated T-cells follows infection. This results from production of IL-4 and IL-10 from prolonged exposure to the toxin. The IL-4 and IL-10 downregulate production of IFN-gamma, MHC Class II, and costimulatory molecules on the surface of APCs. These effects produce memory cells that are unresponsive to antigen stimulation.
One mechanism by which this is possible involves cytokine-mediated suppression of T-cells. MHC crosslinking also activates a signaling pathway that suppresses hematopoiesis and upregulates Fas-mediated apoptosis.
IFN-α is another product of prolonged SAg exposure. This cytokine is closely linked with induction of autoimmunity, and the autoimmune disease Kawasaki disease is known to be caused by SAg infection.
SAg activation in T-cells leads to production of CD40 ligand which activates isotype switching in B cells to IgG and IgM and 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.
One such effect is vomiting. 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 gastrointestinal toxicity. This activity is also highly potent, and quantities as small as 20-35 μg of SAg are able to induce vomiting.
SAgs are able to stimulate recruitment of neutrophils to 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 monocytic cells, 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 inflammation can lead to tissue destruction.
One of the more dangerous indirect effects of SAg infection concerns the ability of SAgs to augment the effects of endotoxins in 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 synergistic relationship 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 sepsis in patients with bacterial infections.
The body naturally produces antibodies to some SAgs, and this effect can be augmented by stimulating B-cell production of these antibodies.
Immunoglobulin pools 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.
Immunosuppressants are also employed to prevent T-cell activation and the release of cytokines. Corticosteroids are used to reduce inflammatory effects.
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 homology suggests that the SAgs evolved through the recombination of two smaller β-strand motifs.
"Staphylococcal Superantigen-Like" (SSL) toxins are a group of secreted proteins structurally similar to SAgs. Instead of binding to MHC and TCR, they target diverse components of innate immunity such as complement, , and . One way SSL targets myeloid cells is by binding the siallylactosamine glycan on surface glycoproteins. In 2017, a superantigen was found to also have a glycan-binding ability.
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. In 2001, it was found that EBV actually transactivates a superantigen encoded by the env gene () of HERV-K18. In 2006, it was found that EBV does so by docking to CD2.
The two viral superantigens have no homology to aforementioned bacterial superantigens, nor are they homologous to each other.
Rasooly, R., Do, P. and Hernlem, B. (2011) Auto-presentation of Staphylococcal enterotoxin A by mouse CD4+ T cells. Open Journal of Immunology, 1, 8-14.
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