Superantigen In Human Diseases

Widodo Judarwanto

Superantigens are a class of immunostimulatory molecules produced by bacteria and viruses. Their potent immune effects are due to their unique ability to bind to the major histocompatibility complex (MHC) outside the antigen-binding cleft and to stimulate T cells in a T-cell receptor (TCR) Vbeta-specific manner. Structural studies have revealed the binding sites involved in the MHC/superantigen/TCR complex. The bacterial superantigens are responsible for a number of syndromes, including food poisoning and toxic shock syndrome, but their effects may be not only acute but also chronic and complex.  They include pyrogenic toxins (streptococcal scarlet fever toxins of serotypes A, B, and C, toxic shock syndrome toxin 1, and staphylococcal enterotoxin serotypes A, B, D, E, and G), streptococcal M protein, staphylococcal exfoliative toxin, and recently identified pyrogenic toxins made by groups B, C, F, and G streptococci and Streptococcus sanguis. Pyrogenic toxin superantigens cause acute toxic shock syndrome and are associated with toxic shock-like syndromes. Superantigens cause symptoms via release of immune cytokines. These proteins should be considered potential causes of illnesses such as rheumatic fever, arthritis, Kawasaki syndrome, atopic dermatitis, and guttate psoriasis because of their potent immune system-altering capacity. 

Conventional antigens bind to a subset of MHC molecules and to a very small fraction of the huge array of TCRs. Thus a conventional peptide antigen activates only a very small fraction of the total pool of T cells. Superantigens, in contrast, are microbial products that bind to large subsets of TCR proteins and MHC molecules, so that a single superantigen can activate up to 20% or more of the total T cells in the body. The superantigen does this by binding without proteolytic processing to the MHC molecule outside of the antigen-binding groove and to TCR proteins outside of their antigen-MHC binding site . For example, the toxic shock syndrome toxin 1 produced by Staphylococcus aureus can activate all T cells with TCRs that use the Vβ2 and Vβ5.1 chains. The activation of large numbers of T cells induced by superantigens results in the massive release of cytokines producing clinical conditions, such as toxic shock syndrome 

Superantigens (SAgs) are the most powerful T cell mitogens ever discovered. Concentrations of less than 0·1 pg/ml of a bacterial superantigen are sufficient to stimulate the T lymphocytes in an uncontrolled manner resulting in fever, shock and death . SAgs bind, as intact molecules to the class II major histocompatibility complex (MHC) antigens expressed on professional antigen presenting cells (APCs) outside the peptide-binding groove then sequentially bind the T cell receptor (TcR) via the variable region of the TcR β-chain. Every SAg binds a subset of TcR Vβ domains and as the number of different Vβ regions in the human T cell repertoire is restricted to approximately 50, comprising about 24 major types of Vβ elements, a substantial number of T cells are activated by SAgs. This can be as high as 20% compared with only 1 in 10⁵−10⁶ naive T cells that are responsive to conventional peptide antigen. This results in massive systemic release of pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-α) and interleukin-beta (IL-1β), and T cell mediators, such as IL-2, which can lead to fever and shock 

Over the last 4 years the number of known bacterial SAgs has increased sharply, due mainly to various microbial genome sequencing projects . There are now 41 bacterial SAgs described in the literature  and the number is growing steadily. In addition, a new family of SAg-related proteins has been identified in Staphylococcus aureus that show sequence and structural homology to the ‘classical’ SAgs, but appear to have a quite different role. This review provides a summary of the field to date with some of the more recent discoveries that shed light on the how superantigens are able to trigger such strong T cell responses and the diseases related to SAg intoxication. 

Superantigen  

 

Superantigens (SAgs) are a class of antigens which cause non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs can be produced by pathogenic microbes (including viruses mycoplasma, and bacteria) as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response where .001-.0001% 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 TNF-alpha). TNF-alpha is particularly important as a part of the body’s inflammatory response, and in normal circumstances (where it is released locally in low levels) 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 shock and multiple organ failure. 

Presentation of Superantigens 

Superantigens are antigens that can polyclonally activate T cells  to produce large quantities of cytokines that can have pathological effects.  These antigens must be presented to T cells in association with class II MHC molecules but the antigen does not need to be processed.  Figure 5 compares how conventional antigens and superantigens are presented to T cells.  In the case of a superantigen, the intact protein binds to class II MHC molecules and to one or more V_β regions of the TCR.  The antigen is not bound to the peptide binding groove of the MHC molecule or to the antigen binding site of the TCR.  Thus, any T cell that uses a particular V_β in its TCR will be activated by a superantigen, resulting in the activation of a large numbers of T cells.  Each superantigen will bind to a different set of V_β regions. 

Types of superantigens 

A microbial example is a secreted protein (exotoxin) which exhibits highly potent lymphocyte-transforming (mitogenic) activity directed towards T lymphocytes.  The most well characterized superantigens are secreted by the bacteria Staphylococcus aureus, and Streptococcus pyogenes. These bacteria produce more than 20 different SAgs. 

Five groups have been proposed for classifying these toxins based on the specific variable region of the β chain of the human T cell receptor (TCR) to which they bind. Group I, for example, contains Toxic Shock Syndrome Toxin 1 (TSST-1) Other non-bacterial SAgs have been discovered and are discussed in the section on endogenous superantigens. 

Most of the genes encoding SAgs are located in close proximity to each other on mobile elements of bacterial genomes such as plasmids or “pathogenicity islands”. An operon known as the enterotoxin gene cluster was found to be common in most SAg-producing bacterial strains. 

SAgs are produced intracellularly by bacteria and are released upon infection as extracellular mature toxins. The sequences of these 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. 

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 domains have binding regions for the Major Histocompatibility Complex Class II (MHC Class II) and the T-cell Receptor (TCR), respectively . Superantigens bind first to the MHC Class II and then coordinate to a T-cell Receptor (TCR) with a specific Variable β motif 

MHC Class II

 

SAgs show preference for the HLA-DQ form of the molecule. 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. The use of a zinc ion in binding leads to a higher affinity interaction. Several staphylococcal SAgs are capable of cross-linking 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. 

T-cell receptor

 

The T-cell binding region of the SAg interacts with the Variable region on the Beta chain 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 VB regions. This interaction varies slightly among the different groups of SAgs. Variability among different people in the types of T-cell regions that are prevalent explains why some people respond more strongly to certain SAgs. Group I SAgs contact the Vβ at the CDR2 and framework region 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 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. 

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. 

T-cell signaling

 

The SAg cross-links the MHC and the TCR inducing a signaling pathway that results in the proliferation of the cell and production of cytokines. Low levels of Zap-70 have been found in T-cells activated by SAgs, indicating that the normal signaling pathway of T-cell activation is impaired. 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. 

Mechanism Of Action SAgs

SAgs are characterized by their ability to bind both MHC class II molecules and T cell receptors . This occurs in a sequential fashion. The sole purpose of SAgs appears to be to bring these two critical molecules together in order to activate as many T cells as possible. The net result is the release of a large and sudden bolus of cytokines which causes the acute condition toxic shock  The histocompatibility class II molecule, despite its polymorphism, is the principal cell receptor for all SAgs but the affinity for MHC class II varies depending on the class II molecule and the SAg . All SAgs examined so far display higher affinities towards human MHC class II molecules than mouse class II, which explains partly why SAgs are several orders of magnitude more potent on human T cells than mouse T cells. A variety of binding modes exist to both MHC class II and TcR (described in more detail below) which indicates the lengths that the bacteria have gone to target these two critical molecules of the adaptive immune response.

 

Viral Superantigens

  

Mouse mammary tumour virus (MMTV)

MMTV, a milk-transmitted B-type retrovirus, causes murine mammary carcinomas. The MMTV SAgs were discovered first by Felstenstein in 1974 and were referred to as minor lymphocyte stimulating (Mls) antigens. The T cell response to Mls antigens is similar to the response to bacterial SAgs with expansion of unique TcR Vβ subsets. The SAg gene was identified later within the 3′ long-terminal repeat (LTR) of the MMTV genome and did not show any homology to the bacterial SAg genes . The gene product is a 45-kDa type II transmembrane protein with a 10–14 amino acid polymorphic region at the C-terminus, which is responsible for the TcR Vβ specificity. Infectious MMTV is present in mammary tissue and breast milk of only a few mouse strains. The SAg molecule is an essential component of the virus life cycle, providing efficient viral replication in newly infected gut B cells by recruiting Vβ mediated T cell ‘help’ and promoting B cell proliferation. The endogenous SAg is inherited in Mendelian fashion and causes T cell deletion as a result of self-tolerance induction in the thymus. As a result, the transmission of an infectious virus carrying the identical SAg will be hampered by the lack of responder T cells, thereby protecting the mouse from MMTV infection.

 

Endogenous SAgs in humans

For many years, MMTV was the only virus that was known for certain to express a SAg. In 1996, Sutkowski et al. observed that Epstein–Barr virus (EBV) infected human B cell lines induced into the lytic cycle with a B cell mitogen that selectively stimulate Vβ13 bearing T cells suggesting the existence of a EBV encoded SAg . More recently, the same group showed that the previously described EBV-related SAg activity is in fact encoded by alleles of the human endogenous retrovirus (HERV)-K18 env gene, which is transcriptionally activated by EBV. HERV-K18 is located on chromosome 1 within the first intron of CD48, which possesses an upstream EBV-inducible enhancer. Furthermore, expression of HERV-K18 is strongly induced by IFN-α . Three alleles of HERV-K18 env were identified (K18·1–3) and all of them had mitogenic activity towards Vβ7 and Vβ13·1 T cells. HERV-K18·1 is identical to the previously identified insulin-dependent diabetes mellitus associated retrovirus IDDMK_1,222 . The authors propose that endogenous SAgs might facilitate the transmission of the EBV virus, similar to MMTV in mice and could contribute to viral pathogenesis, e.g. the extensive T cell infiltrates in EBV-associated tumours.

 

  

The Bacterial Superantigens

 

The prototype SAgs from S. aureus and Streptococcus pyogenes

The first bacterial SAg was isolated in the late 1960s by Bergdoll and coworkers as a secreted toxin of S. aureus and was named staphylococcal enterotoxins A (SEA) for its potent enterotoxic properties. The staphylococcal enterotoxins (SE) are the causative agent in staphylococcal food poisoning and induce vomiting and diarrhoea within 1–2 h following ingestion. The mitogenic activity of SEs was discovered many years later, but the term ‘superantigen’ was not coined until 1989 when Marrack and coworkers found that the mitogenic activity was a result of a massive expansion of T cells that all shared the same T cell receptor Vβ chain domains. Today, 18 different SEs have been described in the literature  and all are potent T cell mitogens with half maximum stimulation values as low as 0·1 pg/ml. The SAg family also includes the S. aureus toxic shock syndrome toxin (TSST) which is the causative agent in toxic shock syndrome .

 

Twelve SAgs have been identified in Group A Streptococci (GAS), predominantly but not exclusively produced by S. pyogenes. These are the streptococcal pyrogenic exotoxins (SPEs) A, C, G-M, the streptococcal superantigen (SSA) and the streptococcal mitogenic exotoxin (SMEZ) 1 and 2. Many new SAgs have been identified by screening the completed S. pyogenes genomes; serotypes M1 (Oklahoma University, USA), M3 and M18 (Rocky Mountain Laboratories, NIH, USA) with conserved sequence motifs . The sudden explosion of new superantigen sequences has resulted in confusing nomenclature where some sequences have been given two different names. For example, SPE-K identified in a serotype M3 strain from the United States is identical to SPE-L found in an M3 strain from Japan and an M89 strain from New Zealand. The superantigen gene spe-l found in an M18 strain from the United States is identical to a gene named spe-m found in New Zealand. For the purposes of this review, spe-m* is the gene described in the United States as spe-m.

The mitogenic potency varies between both the streptococcal SAgs and the staphylococcal SAgs. The least potent of all superantigens so far examined is SPE-H, which produces a 50% maximal response (P₅₀) in human PBL of 50 pg/ml, while SMEZ-2 is the most potent SAg known thus far with a P₅₀ of 0·08 pg/ml. This is equivalent to 8 × 10⁻¹⁴ gm/ml or 21 000 molecules/ml.

 

By structural comparison, the staphylococcal and streptococcal superantigens build a large protein family, indicating that they have all evolved from a single primordial superantigen. Primary amino acid sequence homologies vary greatly from as low as 15·5% sequence identity, e.g. between SEB and SEK to over 90% (SEA versus SEE). Nevertheless, all SAgs possess a characteristic PROSITE amino acid sequence signature K-X(2)-[LIVF]-X(4)-[LIVF]-D-X(3)-R-X(2)-L-X(5)-[LIV]-Y (PS00278). So far, 11 superantigens have been crystallised and all show remarkable similarities in their overall structure despite very different primary amino acid sequences.

The streptococcal SAgs SPE-A, SPE-H, SPE-I and SSA are related more closely to the staphylococcal SAgs than to any other streptococcal SAg  and the genes for these toxins are all located on mobile elements, so it is likely that this SAg subgroup in S. pyogenes arose through the horizontal transfer from S. aureus rather than evolving from existing streptococcal superantigen genes.

For many years the streptococcal proteins SPE-B and SPE-F were considered to be SAgs but have since been shown to be due to contamination from the potent SAg SMEZ-2. SPE-B is a cysteine protease and SPE-F (also known as mitogenic factor or MF) is in fact streptococcal DNase.

  

The non-GAS superantigens

SAgs have also been found in two different group C streptococci. The Streptococcus equi pyrogenic exotoxins (SePE) H, I, L and M are homologous to their S. pyogenes counterparts SPE-H, I, L and M (>98% sequence identity) indicating another horizontal transfer from S. pyogenes to S. equi or vice versa. Another two SAgs have been identified from S. dysgalactiae called SDM  and SPE-G^dys . SDM is most similar to SPE-M* and SPE-G^dys is most similar to SPE-G. Amino acid exchanges are outside the MHC class II and TcR binding sites suggesting that the GAS toxins and the non-GAS toxins are orthologues with identical functions. This suggests that horizontal gene transfer between GAS and non-GAS occurred more recently than between GAS and S. aureus.

 

SAgs in other bacteria

SAgs have also been isolated from the Gram-negative bacteria Yersinia pseudotuberculosis and Mycoplasma arthritidis. The Y. pseudotuberculosis mitogens (YPM) A and B are 21 kDa proteins, which both target human TcR Vβ3, 9, 13·1 and 13·2 regions. The M. arthritidis mitogen (MAM) is a 25-kDa protein that targets T cells bearing the Vβ6 and Vβ8 TcR.  These Vβ profiles differ from any profile of the ‘classical’ SAgs.MAM and YPM-A/B are unrelated by amino acid sequence to the ‘classical’ SAgs and also lack the SAg family signature sequence. The protein structures of these SAgs have yet to be solved, so their mode of action remains a mystery. However, functional studies have shown that MAM binds preferentially to murine I-E or its human equivalent HLA-DR. The DR4, DR7 and DR12 subtypes present MAM most efficiently. A study published in 1998 on the interaction between MAM and TcR indicated that MAM might contact not only the germ-line encoded TcRVβ region, but also the hypervariable CDR3 region.

Direct effects

 

SAg stimulation of antigen presenting cells and T-cells elicits a response that is mainly inflammatory, focused on the action of Th1 T-helper cells. Some of the major products are IL-1, IL-2, IL-6, TNF-α, gamma interferon (IFN-γ), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and monocyte chemoattractant protein 1 (MCP-1). 

This excessive uncoordinated release of cytokines, (especially TNF-α), overloads the body and results in to 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-10 from prolonged exposure to the toxin. IL-10 downregulates production of IL-2, 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 prolong 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. 

Superantigenicity independent (indirect) effects

 

Apart from their mitogenic activity, SAgs are able to cause symptoms that are characteristic of infection. One such effect is emesis. 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 20-35ug 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. 

Diseases associated with superantigen production

• Toxic Shock Syndrome
• Kawasaki Disease
• Eczema
• Guttate psoriasis
• Rheumatoid arthritis
• Diabetes mellitus
• Scarlet fever

Superantigens In Human Disease

 

Food poisoning

The staphylococcal superantigens SEA-SEE and SEG-SEI are potent gastrointestinal toxins responsible for staphylococcal food poisoning. Quantities of less than 1 µg of toxin are sufficient to trigger vomiting in humans. This enterotoxin function appears to be distinct from the SAg activity but this remains controversial. A highly flexible disulphide-loop within the N-terminal domain has been implicated with the emetic properties, but the exact mechanism that leads to the disease or a specific receptor molecule have not yet been identified .

 

Toxic shock syndrome (TSS)

Classical toxic shock syndrome (TSS) caused by S. aureus can be considered as a capillary leak syndrome and includes symptoms, such as hypotension, rash, desquamation, fever and major organ involvement . Like endotoxic shock, TSS is mediated through TNF-α. TSST is regarded as the primary causative agent for menstrual TSS, which is associated with the use of certain tampons, particularly those of high absorbency that promotes the growth of S. aureus. In contrast to other staphylococcal SAgs, TSST has the ability to cross the mucosa. TSST and other staphylococcal SAgs have been associated with non-menstrual TSS, which can occur in any patient population . This is supported by the observation that these toxins induce TSS-like symptoms in animal models in the rabbit and in rodents .

  

Streptococcal toxic shock syndrome (STSS)

STSS, caused by S. pyogenes, is the most severe form of invasive streptococcal disease, with mortality rates of up to 50%. The clinical symptoms are very similar to those in TSS, but STSS is often associated with bacteraemia, myositis or necrotizing fasciitis. Streptococcal SAgs have been implicated in STSS and supporting evidence includes the following. The spe-a and spe-c genes were found at higher frequencies in isolates from STSS patients compared to control groups , lack of protective anti-SAg antibodies was found to be associated with an increased risk for STSS  and circulating SAgs were found in several patients suffering from STSS .

 

Acute rheumatic fever (ARF)

ARF, a post-infection sequelae, is the leading cause of preventable paediatric heart disease. It usually occurs in school-age children and young adults after pharyngeal infection with S. pyogenes. ARF is a cross-reactive immune response to the host’s cardiac tissue and it has been proposed that the reactive T cells might be driven by SAgs. Recently, several novel streptococcal SAgs have been identified from ARF-associated serotypes. The genes for SPE-K/L were found in high frequencies on serotypes M3 (USA and Japan)  and on M89 (New Zealand), while SPE-M and SPE-M* were found in M18 (USA). Smoot et al. showed that antibodies against SPE-M and SPE-M* were more common in convalescent sera from ARF patients compared to patients with pharyngitis. Interestingly, a common target of the SAgs SPE-K/L, SPE-M and SPE-M* are T cells bearing the TcRs with Vβ1·1.

 

Kawasaki disease (KD)

KD is an acute multi-system vasculitis of unknown aetiology that affects mainly young children and is now recognized as the leading cause of acquired heart disease in children in the developed world.

KD is associated with marked activation of T cells and monocytes and there is a remarkable similarity among KD, TSS, STSS and scarlet fever in the clinical symptoms. Intravenous immunoglobulin therapy is highly effective when given early, suggesting that the causative agent is a toxin. Several investigators reported the selective expansion of T cells bearing the Vβ2·1 TcR, which points towards a SAg involvement in the disease . A potential association between KD and the Y. pseudotuberculosis mitogenic factor (YPM) has also been reported .

Autoimmune diseases

It has been proposed that SAgs might contribute to the pathogenesis of autoimmune disease by activating T cells that are specific for self antigens. Although there is no direct evidence of SAg involvement, it has been suggested that SAgs could, under the right conditions, break the tolerance or suppression of auto-reactive T cell clones and induce a state of autoimmunity. Evidence for this hypothesis came from an animal model of multiple sclerosis: experimental autoimmune encephalomyelitis (EAE), where it was shown that administration of SEB to mice recovering from EAE triggered direct stimulation of the Vβ3 positive auto-reactive MBP peptide specific T cells resulting in a rapid relapse of the disease .

Conrad and colleagues found a biased TcR usage in T cells from IDMM patients towards Vβ7 suggesting the activity of a SAg [58]. They showed that the mitogenic activity was encoded by a gene residing on an endogenous retrovirus, named IDDMK_1,222 and that viral expression occurred only in IDMM patients. It was shown later by the same group that IDDMK_1,222 is identical to one allele of the EBV-inducible HERV-K18 carrying the Vβ7-specific SAg K18·3

 

Superantigens and streptococcal disease susceptibility

One of the most intriguing questions is why do some patients develop severe diseases after GAS infections, while others show only minor symptoms, such as pharyngitis? Several investigators have shown an association between severe streptococcal disease and spe-a or spe-c genotype of the disease causing GAS isolate. However, most experiments were carried out before the majority of streptococcal SAgs were discovered and more recent genotyping has not confirmed those preliminary results. Moreover, the genes for some potent SAgs, such as SMEZ and SPE-J, are present in virtually all GAS isolates.

A lack of protective neutralizing antibodies against individual SAgs has also been proposed as a possible risk factor for the development of severe SAg-mediated disease . Unfortunately, to date, interpretations of experiments aimed at examining neutralizing responses in patient sera have been limited by the number of known SAgs available. Now that most of the SAgs have been identified from the various completed staphylococcal and streptococcal genomes, a larger cohort of disease sera should be examined to test this theory.

HLA alleles differ in their ability to present different SAgs and recent structural analysis revealed that the bound peptide also plays a role in modulating SAg binding to the MHC molecule (see above), implying an MHC linkage with susceptibility to SAg toxicity. Recently, Kotb and colleagues showed that indeed the immunogenetics of the host strongly influence the outcome of invasive streptococcal infection. Specific human HLA haplotypes conferred strong protection from severe systemic disease caused by invasive streptococcal infection, whereas other haplotypes actually increased the risk of severe disease . This was the first clearly identifiable link between MHC class II polymorphism and the activity of individual SAgs. It now remains to match the MHC susceptible alleles with individual SAgs expressed by the invading bacteria.

Superantigens have received a great deal of attention since the discovery of their mechanisms in 1989. Since then, a wealth of knowledge about their structure and molecular mechanisms has been presented, yet little information has been forthcoming on their direct role in diseases, other than the obvious food poisoning and toxic shock. Nevertheless, there has been considerable speculation that they are involved in other immune-related diseases. They are a remarkably family of molecules, refined to subvert the adaptive immune response ruthlessly by targeting the two most important antigen recognition molecules the TcR and MHC class II. They are clearly designed as a defence against a hostile immune system: of this much we are certain. What is not certain is exactly how this random stimulation of many T cells results in protection for the microbe. Both S. aureus and S. pyogenes are commensal organisms in humans, so the fact that they have the potential to activate the immune response in such a dramatic fashion means that their expression must be tightly controlled and that the immune system must deal with their continuous presence. Perhaps this continual subliminal T cell activation is of some benefit to the host as well.

 

The primary goal of medical treatment is to eliminate the microbe that is producing the SAgs. This is accomplished through the use of vasopressors, fluid resuscitation and antibiotics. 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. 

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. Lussow and MacDonald demonstrated this by systematically exposing animals to a streptococcal antigen. They found that exposure to other antigens after SAg infection failed to elicit an immune response. In another experiment, Watson and Lee discovered that 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. 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. 

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 B-strand motifs. 

Endogenous 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. 

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 

Staphylococcal superantigen 

Studies of microbial superantigens that target large clonal sets of B cells through conserved antigen-receptor-variable-region sites are providing new insights into the mechanisms of B-cell activation-induced cell death. These investigations have shown differences between the clonal regulation of follicular B cells (B2 cells) and the innate-like marginal-zone B cells and B1 cells, and have also shown how B-cell superantigens can affect specialized host defences against infection. Agents designed to emulate the properties of B-cell superantigens might also provide new approaches for the treatment of B-cell-mediated autoimmune and neoplastic diseases. 

 

Confounding B-cell defences: lessons from a staphylococcal superantigen, Gregg J. Silverman and Carl S. Goodyear, Nature Reviews Immunology 6, 465-475 (June 2006) 

The general structural and genetic principles that underlie antigen recognition by an antibody are well known. In general, the binding of an antigen involves contacts from both the heavy-chain variable region (V_H) and light-chain variable region (V_L). In each V region there are three non-contiguous linear intervals of greatest variability, which have been termed hypervariable regions or complementarity-determining regions (CDRs). Separating these CDRs are more highly conserved intervals termed framework regions. In the -barrel structure of an antibody, the framework regions fold into relatively rigid strands that maintain the overall antibody structure, whereas the CDRs form bends (or loops) that are juxtaposed to form a composite surface at one end of the Fab to provide the contacts for antigen. The recognition of an antigen requires a combinatorial interaction of residues from two or more of these loops, with contributions that always include the somatically generated CDR3 subdomains. By contrast, superantigens bind outside this conventional binding site through conformational framework sites. Here, the Fab-mediated binding interactions of the B-cell superantigens, Staphylococcal protein A (SpA) and Peptostreptococcus magnus protein L (PpL), are compared with a conventional antigen. The heavy chain (V_H and constant (C_H1)) is cyan and the light chain (V_L and C_L) is blue. SpA is shown interacting with the framework regions of the heavy chain whereas PpL is interacting with the light chain. By contrast, the conventional antigen interacts with the CDR loops (pink). Adapted from reports of crystallographic structural analyses^{2, 3}, and kindly provided by E. Stura. 

 

Confounding B-cell defences: lessons from a staphylococcal superantigen, Gregg J. Silverman and Carl S. Goodyear, Nature Reviews Immunology 6, 465-475 (June 2006) 

Superantigens can interact with a large proportion of the B-cell compartment. a | The superantigen can interact with all clones of a particular family (green) no matter what their conventional antigen specificity is. The conventional antigen, however, might be able to interact with only certain clones of a defined binding-specificity (brown) and of a particular family (green). b | On initial B-cell exposure to a superantigen, the B-cell receptor (BCR) of all susceptible clones are recruited into complexes that appear as membrane-associated caps. This is followed by the subsequent clustering of the CD21 and CD19 co-receptors and the resulting activation of the B cell, which is associated with early upregulation of CD69 and CD86 expression. Later activation events include the upregulation of CD40, CD54, CD80 and CD95. At early time points, migration of B cells to the spleen is observed. Several outcomes have been shown to follow this exposure, the main one being apoptosis, which is first observed within 4 hours of superantigen exposure. Although some proliferation occurs following superantigen encounter, if an appropriate second signal, such as CD40 ligand or interleukin-4, is delivered, increased proliferation and survival of clones results. Alternative outcomes, such as the induced differentiation of clones into memory cells, functional inactivation (anergy) or receptor editing, have not yet been documented, but based on B-cell responses to conventional antigenic-ligands, these are also possible outcomes after superantigen exposu 

 Superantigen-induced cell death through B-cell receptor engagement. 

 

 

On engagement of a superantigen, the B-cell receptors (BCRs) are recruited into complexes that include CD19, CD21 and other co-receptors, and this results in capping on the B-cell surface. This engagement leads to signalling events for cellular activation that end with the death of the B cell between several hours and several days. These interactions cause a series of intracellular events that remain unclear, which lead to changes in mitochondrial membrane potential and ultimately to the release of cytochrome c and pro-apoptotic factors. This results in the release of active caspase-9, which activates caspase-3 that is responsible for downstream DNA fragmentation and nuclear fragmentation. Although the signals between the BCR and the mitochondria still need to be identified, recent studies indicate that BCR-induced cell death recruits pro-death BCL-2-homology domain 3-only (BH3-only) B-cell lymphoma 2 (BCL-2) family members (C.S.G. and G.J.S., unpublished observations). This induction might occur either through post-transcriptional pathways such as the release of active BH3-only protein from sequestration at sites such as the dynein motor complex or through transcriptional regulation. APAF1, apoptotic-protease-activating factor 1; BAK, BCL-2 antagonist/killer; BAX, BCL-2-associated X protein; TNFR, tumour-necrosis factor receptor 

Gregg J. Silverman and Carl S. Goodyear.Confounding B-cell defences: lessons from a staphylococcal superantigen .Nature Reviews Immunology 6, 465-475 (June 2006) 

 

SEB, A typical bacterial superantigen (PDB:3SEB) The β-grasp domain is shown in red, and the β-barrel in green: The “disulfide loop” is shown in yellow 

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