Superantigen

thumb|right|[[Staphylococcal Enterotoxin B|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.]]

thumb|right|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.]]

thumb|Schematic representation of [[MHC class II.]]

thumb|The [[T-cell receptor complex with TCR-α and TCR-β chains, CD3 and ζ-chain accessory molecules.]]

<span lang="fa">Superantigens</span> (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically they cause non-specific activation of T-cells 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 TCRs 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 pathogenic 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 cytokines, the most important of which is Interferon gamma. This excess amount of IFN-gamma in turn activates the macrophages. The activated macrophages, in turn, over-produce proinflammatory cytokines such as IL-1, IL-6 and TNF. TNF 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.

Structure

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

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 proteins sharing a characteristic two-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.

Binding

Superantigens bind first to the MHC class II and then coordinate to the variable alpha- or beta chain of T-cell Receptors (TCR)

MHC Class II

SAgs show preference for the HLA-DQ form of the molecule. 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.

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,

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.

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. 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.

Rheumatic fever
Rheumatoid arthritis
Scarlet fever

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 vasopressors, fluid resuscitation and antibiotics.

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.

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, Fc receptors, and myeloid cells. 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.

Endogenous and viral SAgs

Minor lymphocyte stimulating (Mls; ) exotoxins were originally discovered in the thymic stromal cells 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 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.

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

References

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.