Superantigen

Source: Wikipedia, the free encyclopedia.
SEB, a typical bacterial superantigen (PDB:3SEB). The β-grasp domain is shown in red, the β-barrel in green, the "disulfide
loop" in yellow.
SEC3 (yellow) complexed with an MHC class II molecule (green & cyan). The SAgs binds adjacent to the antigen presentation cleft (purple) in the MHC-II.
Schematic representation of MHC class II.
CD3
and ζ-chain accessory molecules.

Superantigens (SAgs) are a class of

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

multiple organ failure
.

Structure

SAgs are produced intracellularly by bacteria and are released upon infection as extracellular mature toxins.[4]

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.[5][6] There are at least 5 groups of superantigens with different binding preferences.[7]

α-helix that diagonally spans the center of the molecule, and a COOH terminal globular domain.[5]

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.[8]

Binding

Superantigens bind first to the MHC class II and then coordinate to the variable

beta chain of T-cell Receptors (TCR)[6][9][10]

MHC Class II

SAgs show preference for the HLA-DQ form of the molecule.[10] 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.[6] The use of a zinc ion in binding leads to a higher affinity interaction.[5] Several staphylococcal SAgs are capable of cross-linking MHC molecules by binding to both the α and β chains.[5][6] 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.[6]

T-cell receptor

T-cell binding region of the SAg interacts with the Variable region on the Beta chain (Vβ region) 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 Vβ regions. This interaction varies slightly among the different groups of SAgs.

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.[11][12] 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.[6][13]

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.[14] SPMEZ-2 is the most potent SAg discovered to date.[14]

T-cell signaling

The SAg cross-links the MHC and the TCR inducing a signaling pathway that results in the

Zap-70 have been found in T-cells activated by SAgs, indicating that the normal signaling pathway of T-cell activation is impaired.[15]

It is hypothesized that Fyn rather than Lck is activated by a tyrosine kinase, leading to the adaptive induction of anergy.[16]

Both the protein kinase C pathway and the protein tyrosine kinase pathways are activated, resulting in upregulating production of proinflammatory cytokines.[17]

This alternative signaling pathway impairs the calcium/calcineurin and Ras/MAPkinase pathways slightly,[16] but allows for a focused inflammatory response.

Effects

Direct effects

SAg stimulation of antigen presenting cells and T-cells elicits a response that is mainly inflammatory, focused on the action of

MCP-1).[17]

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.[10][12]

Deletion or

costimulatory molecules on the surface of APCs. These effects produce memory cells that are unresponsive to antigen stimulation.[18][19]

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.[20]

IFN-α is another product of prolonged SAg exposure. This cytokine is closely linked with induction of autoimmunity,[21] and the autoimmune disease Kawasaki disease is known to be caused by SAg infection.[14]

SAg activation in T-cells leads to production of

IgE.[22]

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.[22]

If the initial inflammation is survived, the host cells become anergic or are deleted, resulting in a severely compromised immune system.

Superantigenicity-independent (indirect) effects

Apart from their mitogenic activity, SAgs are able to cause symptoms that are characteristic of infection.[2]

One such effect is

gastrointestinal toxicity.[2] This activity is also highly potent, and quantities as small as 20-35 μg of SAg are able to induce vomiting.[10]

SAgs are able to stimulate recruitment of

colonized.[23] 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

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.[22]

Diseases associated with superantigen production

Treatment

The primary goals of medical treatment are to hemodynamically stabilize the patient and, if present, to eliminate the microbe that is producing the SAgs. This is accomplished through the use of

antibiotics.[2]

The body naturally produces

B-cell production of these antibodies.[26]

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.[2]

Corticosteroids are used to reduce inflammatory effects.[22]

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 is through inducing anergy of the T-cells to antigens and SAgs.

memory T-cells created 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.[15] The genes that regulate SAg expression also regulate mechanisms of immune evasion such as M protein and Bacterial capsule expression, supporting the hypothesis that SAg production evolved primarily as a mechanism of immune evasion.[27]

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.[28]

"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

myeloid cells. One way SSL targets myeloid cells is by binding the siallylactosamine glycan on surface glycoproteins.[29] In 2017, a superantigen was found to also have a glycan-binding ability.[30]

Endogenous and viral SAgs

Minor lymphocyte stimulating (Mls; P03319) exotoxins were originally discovered in the

mouse mammary tumour virus (MMTV). The presence of these genes in the mouse genome allows the mouse to express the antigen in the thymus as 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 immune to infection by the virus later in life.[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.[2] In 2001, it was found that EBV actually transactivates a superantigen encoded by the env gene (O42043) of HERV-K18. In 2006, it was found that EBV does so by docking to CD2.[31]

The two viral superantigens have no homology to aforementioned bacterial superantigens, nor are they homologous to each other.

References

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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.

Further reading

External links

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