Superantigen

Superantigens (SAG ) are toxins with unusual antigenic properties. They are the most potent activators of T- lymphocytes and are associated with a variety of diseases that can be transferred to T - cell toxicity and the lead back. With its two binding sites they link the immune system cells to each other, which leads to an uncontrolled Zytokinausstoß under which a targeted defense is no longer possible. For the produced streptococcal superantigen SMEZ -2 can be an activity in the area femtogram per milliliter detected, thus this is the most potent to date ( 2005), the bacterial SAG.

• 3.1 superantigens than conventional antigens

• 4.1 binding modes of superantigens with their target cells
• 4.2 interaction of superantigens with their target cells
• 4.3 Binding of superantigens to the target cells
• 4.4 Consequences of superantigen - mediated activation

• 6.1 diseases whose association is thought to superantigens
• 6.2 diseases that are related to superantigens

Superantigen producer

Bacterial superantigens

Most SAG are formed by bacteria, in particular gram-positive bacteria. The superantigens TSST ( Toxic shock syndrome toxin) of Staphylococcus aureus and SPE ( Streptococcus pyogenes exotoxin ) of invasive Streptococcus pyogenes apply to humans as well toxins with high mortality. Approx. 1% of Staphylococcus aureus form the TSST- 1 which operates on interleukin-1 and TNF- α release from macrophages septic shock. Other strains produce a toxin called exfoliant as SAG and thus cause in infants Ritter 's disease ( staphylococcal scalded skin syndrome, SSSS ). Streptococci of groups C and G were also identified as potential toxin producers, however, their importance appears to be restricted to animals. Among the gram- negative microorganisms, the toxins and YPM MAM of Mycoplasma arthritidis and Yersinia pseudotuberculosis have been identified as superantigens.

Viral superantigens

In addition to the bacterial SAG are super antigenic effects in infections with viruses of the herpes family, the mouse mammary tumor virus (MMTV ), Epstein- Barr virus ( EBV) ), and human immunodeficiency virus 1 (HIV -1) suspected.

Structure of superantigens

SAG are bifunctional molecules that can simultaneously connect the receptor binding site of class II MHC molecules in antigen -presenting cells (APCs ) with the T cell receptor Vβ elements (TCR Vβ ) of the T - cells. Thereby they can negatively modulate the interaction between class II MHC molecules and TCR by forming a trimer ( MHC II / SAG / TCR). Finally, the structure of superantigens is the cause of their high stability against proteases and heat.

Difference between superantigens and conventional antigens

In contrast to conventional antigens, whose size can vary greatly, are bacterial SAGs in terms of their molar mass, with a size of 20-30 kDa, quite constant molecules. When streptococci are found usually toxins ranging in size from 24-28 kDa. Most SAGs are globular proteins. Structural analyzes showed that they consist of a single chain, formed of two globular domains. It is assumed that the superantigens staphylococcal and streptococcal have common origins, especially since you can find at amino acid sequence comparisons matches from 20% to 90%.

Superantigens than conventional antigens

SAG also act to a lesser degree than conventional antigens. So you can also immunoglobulins IgE and IgG detected in patient sera against SAGs. The example of the staphylococcal enterotoxins A, B and TSST-1 has been shown that in this way takes place an IgE-mediated histamine release and thus inflammatory responses are enhanced. In other experiments, the effect was yet unsolved in that in patients with S. pyogenes infection occurred constitutive expression of SPEA ( Streptococcal Pyrogenic Exotoxin A). Due to the permanent formation of SPEA it is the infected organism permanently theoretically possible to develop neutralizing antibodies against the toxin. However, no antibody formation was detected in the case of SPEA in the course of an acute illness, which can have a more dramatic course of the effect. The fact that superantigens can also act as classical antigens, is interesting in that you can carry out a vaccination with small amounts or toxoids. This approach was verified on an animal model. The prognosis for a disease could thus be more positive.

Mechanism of immune stimulation by superantigens

Binding modes of superantigens with their target cells

For the interaction with the target cells SAG have at least two class II MHC molecule - binding sites, which differ among the SAG. To bind them are doing a low-affinity binding sites on the α - chain and / or high-affinity, zinc-dependent binding sites on the β - chain of class II MHC molecules are available. The zinc-dependent binding site can be crucial for the activity of the SAG. SAG, which are capable of binding zinc able to have C-terminal zinc binding motif HXD the primary, consisting of the amino acids histidine ( H), any (X) and aspartic acid ( D). Thus, the zinc binding, for example, dominant at the polymorphic β - chain of class II MHC molecules in the superantigens SPEC, SPEGGAS, SPEH, SPEJ and SMEZ. The only known streptococcal SAGs without zinc binding are SSA and SPEA. Of the staphylococcal enterotoxin A ( SEA) and E ( SEE), we know that they combine both forms of binding.

Interaction of superantigens with their target cells

Interacting with the T- cells is carried out in substantially the CDR2 and HV4 regions of the TCR Vβ elements, partly under slight influence of other variable regions of the TCR. This differs sag in their binding in comparison to conventional antigens, the use for the " complementarity determining region " (CDR). The Vβ elements are limited in humans to about 50 genes. Of these, a strong interaction is currently (2005) for only about 24 types described with SAG. SAG case all have a specific profile at different recognition sequences of Vβ elements, and thus independent of the antigen binding specificity to those T cells that express the appropriate Vβ elements. Allowing SAG with 5% to 20% of all T- cells to interact so that occurs due to a hyperproliferation. In contrast, most conventional antigens with 0.1 ‰ to 10 ‰ of all T cells.

Binding of superantigens to the target cells

Conventional antigens initially takes place at a recording processing of the exogenous into small peptide fragments 9-30 amino acids within the lysosomal compartment of the phagosome of the antigen- presenting cell. After fusion of the phagosome and endosome containing Class II MHC molecules is carried out the presentation of the antigen fragments to the cell surface. Due to a specific and controlled immunoreact with proliferation of T cells, cytokines, and ejection of antibodies is induced. SAG, however, are independent of processing and presentation and do not bind in the binding groove, but just outside of the DR or DQ domain of class II MHC molecules of APC (B cells, dendritic cells, monocytes ). There is no MHC restriction, as is typically found with peptide antigens.

Consequences of superantigen - mediated activation

Through the superantigen - mediated activation of APC and T cells occurs within the first hours to massive systemic Lymphokinausstößen. In particular, the cytokines TNF- α, followed by spurts of T- zellprolifertiven factors IL-1, 2, 6 and IFN -gamma, were documented in vivo and in vitro experiments in different. The interaction of the SAG and class II MHC molecules lead to the activation of phospholipase C and protein kinase C, increase in Zytokingenexpressionen (IL- 1, IL -12, TNF- α ) and phosphoinositol - collapse. The abnormal discharge of lymphokines seems to be the cause of toxic shock syndrome TSS and a number of other diseases.

Importance of superantigens for the microorganism

Why microorganisms have as potent activators of the immune system is still unclear, since blocking the immune response also seems to make sense. So it is believed that the superantigen -mediated stimulation of the consumption of locally produced interleukin-2 through T- cells, resulting in an effective immune response against pathogens is suppressed. The massive Zytokinausstoß also presumably leads to a delayed detection of the bacterium, thereby providing an effective propagation is possible. SAG can continue anergy and / or deletion of T-cells cause, which also leads to an effective protection for the agents. Of the streptococcal pyrogenic exotoxins A - and C and the staphylococcal enterotoxin B, there are in vitro studies showing that these toxins can suppress the humoral immune response in certain cases and thus prevent the formation of antibodies.

The involvement of superantigen in diseases

Diseases whose association is thought to superantigens

Several clues point to the implication of SAG with certain diseases or pulled back even as their etiology into consideration. However, the role of SAG is not yet proven for many diseases. In insulin- dependent diabetes mellitus is a relationship to the T-cell superantigen IDDMK1, 222 of the human - Endogenous retrovirus ( HERV ) K- 18 and enterotoxins from S. aureus discussed. The same applies to autoimmune reactions, such as rheumatic endocarditis, Sjögren's syndrome, acute rheumatic fever, rheumatoid arthritis, Kawasaki disease, and multiple sclerosis, for which a link with bacterial SAG is suspected. The pyrogenic exotoxins A, C, G to J, SSA and variants of SMEZ seem to have a significant role in acute tonsillitis to play necrotizing fasciitis, rheumatic fever and scarlet fever. The same unresolved is the role of SAG in cases of sudden infant death syndrome ( SIDS ), which often form conspicuous strains of S. aureus, pyrogenic exotoxins according to the autopsies could be isolated. It is believed that SAG also influence on some skin diseases such as atopic eczema, atopic dermatitis and psoriasis, as in patient samples significantly increased amounts of SAG could be isolated. For SPE A and C could be shown that these are associated with psoriasis guttata.

Diseases, which are in connection with superantigens

It is undisputed that can cause enterotoxins A to M and TSST -1 by S. aureus toxic shock syndrome ( TSS) with the following multi-organ failure as well as food poisoning (except TSST -1). The same applies to SAG Streptococcus, which are also called pyrogenic exotoxins. They cause streptococcal toxic shock syndrome and scarlet fever induced.