Иммундық жүйені күшті жақтыратын антигендер

Antigen which strongly activates the immune system

Superantigens (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 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.

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.

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.

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.