Superantigens (SAgs) – Definition, Types, Structure, Examples

Superantigens (SAgs) are a special type of powerful toxins. These are produced by some bacterial and viral pathogens. It causes very strong and uncontrolled activation of immune system.

The superantigens are different from normal antigens. Normal antigens are taken inside the antigen-presenting cells and broken into small pieces. But SAgs act as intact protein and they do not require normal processing.

They bind directly with the outside part of Major Histocompatibility Complex class II (MHC-II) molecule present on antigen-presenting cells. At the same time they also bind with T-cell receptor (TCR) present on T-lymphocytes. Thus they make a bridge between these two cells.

SAgs may also bind with costimulatory receptors like CD28 and B7. This increases the immune signal. Due to this, the normal specific antigen recognition is bypassed.

In normal antigen reaction, only very few T-cells are activated. But in case of superantigens, about 20% to 30% of total T-cell population may be activated. So the response becomes very high and non-specific.

This massive activation of T-cells causes release of many cytokines. This is called cytokine storm. The important cytokines are interleukin-2 (IL-2) and tumor necrosis factor (TNF).

The cytokine storm causes fever, inflammation and tissue injury. In severe condition, it may produce toxic shock syndrome and multiple organ failure. Thus superantigens are important virulence factors of pathogens and they can cause life threatening condition.

Superantigens (SAgs) are powerful toxins produced by some bacteria and viruses. They activate large number of T-cells without normal antigen processing. This causes excessive immune response and cytokine storm.

Discovery and Historical Background of Superantigens

• In 1924, Dick and colleagues discovered a toxin from culture filtrates of scarlet fever patients. This toxin was called scarlet fever toxin. It was one of the earliest toxin which later considered as superantigen (SAg).
• In 1928, the Toxic Shock Syndrome Toxin-1 (TSST-1) was found retrospectively in a strain of Staphylococcus aureus. This strain was related with fatal Bundaberg disaster in Australia. So this toxin was already present before it was properly named.
• In 1934 and 1960, other streptococcal toxins were discovered. These toxins were named as Toxin B and Toxin C. They were later included in the group of streptococcal pyrogenic toxins.
• In 1965 and 1966, Staphylococcal enterotoxin B (SEB) and Staphylococcal enterotoxin A (SEA) were isolated and characterized. These were among the first superantigens which were formally identified.
• In 1970, Kim and Watson renamed the scarlet fever toxins. They named them as streptococcal pyrogenic exotoxins (SPE) A, B and C. This name was given because these toxins can produce fever and increase sensitivity to shock.
• In 1973, the first evidence of viral superantigens was observed in mice. These were called minor lymphocyte stimulating (Mls) antigens. Later it was proved that they were encoded by endogenous mouse mammary tumor virus (Mtv).
• In 1984, after international symposium on toxic shock syndrome, the name Toxic Shock Syndrome Toxin-1 (TSST-1) was officially accepted. Older names like pyrogenic exotoxin serotype C and staphylococcal enterotoxin F were not used.
• In 1989, the term superantigen was coined by Philippa Marrack and John Kappler. This term was used because these proteins can activate very large number of T-lymphocytes in non-specific way.
• In 1990s, cloning of toxin genes helped in functional studies of these toxins. It was found that SPE-A was same as a previously known T-cell mitogen, called Blastogen A.
• In 1993, streptococcal superantigen (SSA) was discovered by traditional isolation method. In 1997, streptococcal mitogenic exotoxin Z (SMEZ) was also discovered. These added more members in streptococcal superantigen group.
• In 2001 and after this, microbial genomics started to give more information. From the genome of Streptococcus pyogenes, many new superantigen genes were identified such as spe-G, spe-H, spe-I, spe-J, spe-K, spe-L and spe-M.
• Later, similar genes were also found in other species such as Streptococcus equi. Thus the discovery of superantigens increased from toxin isolation to gene-based identification.

Characteristics of Superantigens

• Superantigens (SAgs) do not follow the normal antigen processing method. They are not engulfed and degraded by antigen-presenting cells. They act as intact extracellular proteins.
• They bind directly with outer lateral surface of Major Histocompatibility Complex class II (MHC-II) molecule. They also bind with variable region of T-cell receptor (TCR). Thus they form a direct bridge between antigen-presenting cell and T-cell.
• Superantigens also interact with costimulatory receptors. They bind with CD28 on T-cells and B7 molecules on antigen-presenting cells. This binding makes the immune signal more strong.
• They produce massive and non-specific activation of T-cells. In normal antigen response, only very few T-cells are activated. But SAgs can activate about 20% to 30% of total T-cell population.
• This large activation causes release of many inflammatory cytokines. This is called cytokine storm. The important cytokines are interleukin-2 (IL-2), interferon-gamma (IFN-γ) and tumor necrosis factor (TNF).
• The cytokine storm causes fever, capillary leakage, tissue damage and shock. In severe cases, it may become lethal to the host.
• Most superantigens are compact and highly stable proteins. They resist heat, drying, acid and host protease enzymes. Due to this, they can survive in harsh conditions like gastrointestinal tract.
• Superantigens can increase the toxicity of bacterial endotoxins. They act together with lipopolysaccharide (LPS) of Gram-negative bacteria. This can increase shock producing effect in very high amount.
• After the first strong inflammatory response, superantigens may produce immune suppression. They cause T-cell anergy or T-cell apoptosis. This helps pathogen to escape from immune clearance.
• Some superantigens act on B-cells also. Example is Staphylococcal Protein A of Staphylococcus aureus. It binds with immunoglobulin region outside the normal antigen-binding site and may cause B-cell apoptosis or complement activation.

Sources and Types of Superantigens

The following are the sources and types of Superantigens (SAgs)-

1. Bacterial T-cell superantigens
   • Staphylococcus aureus produces Toxic shock syndrome toxin-1 (TSST-1), Staphylococcal enterotoxins (SE-A to SE-E and SE-G) and Staphylococcal superantigen-like toxins (SEls H-X).
   • Streptococcus pyogenes is also called Group A Streptococcus. It produces Streptococcal pyrogenic exotoxins (SPE-A, C, G, H, I, J, K, L and M), Streptococcal superantigen (SSA) and Streptococcal mitogenic exotoxin Z (SMEZ).
   • Non-Group A Streptococci include Streptococcus equi and Streptococcus dysgalactiae. These produce related superantigens like SePE-H, SePE-I and Streptococcus dysgalactiae-derived mitogen (SDM).
   • Metamycoplasma arthritidis produces M. arthritidis-derived mitogen (MAM). It is a different type of superantigen. It is composed of alpha-helical domains and can crosslink receptors into large assemblies.
   • Yersinia pseudotuberculosis produces Y. pseudotuberculosis-derived mitogen (YPM). It is the only Gram-negative bacterium known to produce classical T-cell superantigen. The variants are YPM-a, YPM-b and YPM-c.
   • Enterotoxigenic E. coli (ETEC) produces ETEC enterotoxin. It is recognized as Type I superantigen.
2. Viral T-cell superantigens
   • Mouse Mammary Tumor Virus (MMTV) encodes a superantigen (Sag) in its long terminal repeat region. It is present as milk transmitted virus and also as endogenous Mtv provirus in host genome.
   • Rabies virus nucleoprotein or nucleocapsid acts as potent superantigen. It targets some specific T-cells and it has T-dependent adjuvant property.
   • Human Endogenous Retroviruses such as HERV-K18 produces envelope protein Env. This protein acts as superantigen. It remains dormant in human genome and becomes active during Epstein-Barr Virus (EBV) infection.
3. B-cell superantigens
   • B-cell superantigens are unlike T-cell superantigens. They bind with framework regions of immunoglobulins on B-cell receptors. This binding is not done through normal antigen binding site.
   • Staphylococcal Protein A (SpA) is a cell wall associated protein of Staphylococcus aureus. It binds with Fab region of VH3 family immunoglobulins on B-cells and also binds with Fc region of IgG.
   • Peptostreptococcal Protein L (PpL) is produced by Peptostreptococcus magnus. It binds with variable light chain (VL) of kappa subclass of human immunoglobulins.
   • Human Immunodeficiency Virus-1 (HIV-1) has envelope glycoprotein gp120. It acts as soluble B-cell superantigen. It binds with membrane bound IgM molecules of VH3 family.

Summary Table of Sources and Types of Superantigens

Structure of Superantigens

The following are the structure of Superantigens (SAgs)-

• Overall shape and size – Most bacterial superantigens are compact and ellipsoidal proteins. Their molecular weight is generally about 22 to 29 kDa. They are highly stable and resist heat, acid and other denaturing conditions.
• Two-domain structure – Most pyrogenic superantigens like Staphylococcal and Streptococcal exotoxins have two globular domains. These two domains are connected by a long central α-helix, which passes diagonally through the middle of the molecule.
• N-terminal domain – The NH₂-terminal domain has Greek key motif and forms a globular β-barrel. This fold is called OB-fold or oligonucleotide/oligosaccharide fold. It contains low affinity binding site for Major Histocompatibility Complex class II (MHC-II) and also has conserved 12-amino acid motif for binding with CD28 and B7.
• C-terminal domain – The COOH-terminal domain has β-grasp fold. It is made up of twisted β-sheet capped by central α-helix. The deep cleft between N-terminal and C-terminal domain helps in specific binding with T-cell receptor (TCR).
• Metal-ion coordination – Many superantigens contain zinc binding site near the interface of two domains. The Zn²⁺ ion helps to form high affinity bridge with polymorphic β-chain of MHC-II molecule.
• Flexible loops and dimerization – Some superantigens contain flexible loop at the top of N-terminal β-barrel. This loop may be stabilized by intramolecular disulfide bond. In SpeA1, this loop helps in dimer formation through intermolecular disulfide linkage and may block low affinity MHC-II binding site.
• Unique structural exceptions – Some superantigens do not follow the common two-domain β-fold structure.
  • Metamycoplasma arthritidis-derived mitogen (MAM) does not have normal β-barrel and β-grasp fold. It has two α-helical domains and may form 3D domain-swapped dimer.
  • Yersinia pseudotuberculosis-derived mitogen (YPM) has jelly-roll fold structure. It contains nine β-strands arranged in two anti-parallel sheets and may form stable homotrimer.

Mechanism of Action of Superantigens

The following are the step by step mechanism of action of Superantigens (SAgs)-

1. Bypassing of antigen processing – Superantigens (SAgs) do not follow normal antigen processing. They are not engulfed and broken down inside antigen-presenting cells (APCs). They act as intact extracellular proteins.
2. Binding with MHC-II molecule – In this step, superantigen binds directly to the outer lateral surface of Major Histocompatibility Complex class II (MHC-II) molecule present on APC. It does not bind inside the peptide binding groove like normal antigen.
3. Binding with T-cell receptor – At the same time, superantigen also binds with variable region of T-cell receptor β-chain (TCR Vβ) present on T-cell. Thus it makes a bridge between APC and T-cell.
4. Hijacking of costimulatory receptors – The superantigen also binds with costimulatory receptors. It binds with CD28 present on T-cell and B7-1 (CD80) or B7-2 (CD86) present on APC. This makes the contact between the two cells more stable.
5. Strong intracellular signaling – After this binding, strong signals are produced inside the T-cell. The early signaling molecules such as ZAP-70 and PLC-γ1 become phosphorylated. Then transcription factors like NF-AT, AP-1, NF-κB and STAT3 are activated and move into nucleus.
6. Massive T-cell activation – In normal antigen response, only selected T-cell clones are activated. But superantigen acts on many TCR Vβ families. Due to this, about 20% to 30% of total T-cells may be activated at a time.
7. Cytokine storm formation – The activated T-cells and APCs release large amount of cytokines. This is called cytokine storm. The major cytokines are interleukin-2 (IL-2), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6).
8. Systemic toxicity and shock – The cytokines enter into blood and produce systemic effects. It causes fever, epithelial barrier damage, vasodilation, capillary leakage and severe hypotension. In severe case, it leads to multiple organ failure and toxic shock.
9. Immune suppression after activation – After the first strong inflammatory phase, many T-cells become unresponsive. This is called anergy. Some T-cells are also removed by apoptosis.
10. Pathogen escape – Due to T-cell anergy and apoptosis, adaptive immunity becomes weak. This helps the pathogen to escape from immune clearance and continue infection.

Interaction of Superantigens with MHC Molecules and T Cells

The following are the step by step interaction of Superantigens with MHC molecules and T-cells-

1. Evading normal antigen processing – Superantigens (SAgs) do not enter into the normal antigen processing pathway. They are not engulfed and broken into peptide fragments by antigen-presenting cells (APCs). They remain as intact extracellular proteins.
2. Binding with MHC class II molecule – In this step, superantigen first bind with the outer lateral surface of Major Histocompatibility Complex class II (MHC-II) molecule. This binding helps the toxin to collect on the surface of APC.
3. Type of MHC-II binding – The binding may occur with MHC-II α-chain by low affinity interaction or with MHC-II β-chain by high affinity zinc coordinated interaction. Some superantigens can bind with both sites and they are called bivalent superantigens.
4. Binding with T-cell receptor – After binding with MHC-II, the superantigen also binds with T-cell receptor (TCR) present on nearby T-cell. Most of them bind with variable domain of TCR β-chain (Vβ). Some exceptions like Staphylococcal enterotoxin H (SEH) can bind with TCR Vα chain.
5. Formation of ternary complex – The superantigen makes a bridge between MHC-II molecule and TCR. This forms a ternary complex of MHC-II-SAg-TCR. In this condition, the TCR does not need to recognize any specific peptide antigen.
6. Hijacking of costimulatory receptors – For strong activation, superantigen also bind with costimulatory molecules. It uses conserved β-strand(8)/hinge/α-helix(4) region to bind with CD28 on T-cell and B7-1 (CD80) or B7-2 (CD86) on APC.
7. Stabilization of immunological synapse – Binding with TCR, MHC-II, CD28 and B7 makes the contact zone more stable. This contact zone is called immunological synapse. More TCRs may also come into this region.
8. Strong intracellular signaling – The stable receptor cross linking gives strong signals inside the T-cell. Signaling molecules like ZAP-70 and PLC-γ1 are activated. Then transcription factors like NF-AT and NF-κB are activated inside the cell.
9. Massive T-cell activation – The superantigen does not activate only one specific clone of T-cell. It activates many T-cells having selected Vβ regions. Due to this, large number of T-cells are activated in non-specific way.
10. Cytokine storm – The activated T-cells and APCs release high amount of cytokines. The important cytokines are interleukin-2 (IL-2), interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). This uncontrolled release is called cytokine storm.
11. Systemic effect – The cytokine storm produces systemic inflammation. It causes barrier damage, vascular changes and toxic shock. In severe condition, it may become lethal to host.

Activation of T Cells by Superantigens

The following are the step by step process of T-cell activation by Superantigens (SAgs)-

1. Evading antigen processing – Superantigens (SAgs) are not processed like normal antigens. They are not engulfed and degraded by antigen-presenting cells (APCs). They act as intact and unprocessed protein.
2. Attachment with MHC-II molecule – In this step, SAg binds directly with the outside lateral surface of Major Histocompatibility Complex class II (MHC-II) molecule present on APC. It does not bind in normal peptide binding groove.
3. Binding with T-cell receptor – The same SAg also binds with T-cell receptor (TCR) present on T-cell. It mainly bind with variable domain of TCR β-chain (Vβ). Some SAgs may bind with TCR α-chain (Vα) also.
4. Binding with costimulatory receptors – Superantigen also binds with important costimulatory receptors. It binds with CD28 on T-cell and B7-1 (CD80) or B7-2 (CD86) on APC. This makes the activation signal more strong.
5. Stabilization of immunological synapse – By binding with TCR, MHC-II, CD28 and B7, the SAg works as a bridge between T-cell and APC. This stabilizes the contact zone. This contact zone is known as immunological synapse.
6. Intracellular signaling – In this step, strong intracellular signals are started inside the T-cell. ZAP-70 and PLC-γ1 are phosphorylated rapidly. Calcium influx occurs and transcription factors like NF-AT, AP-1 and NF-κB become activated.
7. Massive polyclonal T-cell proliferation – Normal antigen activates only selected T-cell clone. But SAg bypasses this specific clonal selection. It activates very large number of T-cells, about 20% to 30% of total T-cell population.
8. Cytokine storm – The activated T-cells release large amount of cytokines into blood. This is called cytokine storm. The important cytokines are interleukin-2 (IL-2), interferon-gamma (IFN-γ) and tumor necrosis factor (TNF).
9. Systemic inflammatory effect – The cytokines produce severe inflammation in body. It causes tissue damage, vascular leak, toxic shock and sometimes multiple organ failure. Thus SAg-mediated T-cell activation becomes harmful for host.

Cytokine Release and Cytokine Storm Induced by Superantigens

The following are the cytokine release and cytokine storm induced by Superantigens (SAgs)-

• Massive T-cell activation – Superantigens (SAgs) activate very large number of T-cells by bypassing normal antigen processing. About 20% to 30% of total T-cell population may be activated. This causes uncontrolled release of cytokines.
• Primary cytokines released – The main cytokines released are interleukin-2 (IL-2), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) and TNF-β. These are mainly pro-inflammatory and Th1 type cytokines.
• Secondary cytokines and mediators – Some other inflammatory mediators are also released in high amount. These include IL-1, IL-1β, IL-6, IL-8, IL-17A, IL-22 and platelet-activating factor (PAF).
• Sequential release of cytokines – The cytokines are not released at same time. First TNF-α and TNF-β are released rapidly, mainly from T-cells of spleen. After this IL-2, IL-6, IL-1 and then IFN-γ are released.
• Formation of cytokine storm – Due to continuous and excessive cytokine release, a massive inflammatory condition is formed. This is called cytokine storm. It is not a controlled immune response and it affects whole body.
• Early physical symptoms – High level of cytokines in blood produces fever and malaise. IL-2 is important in this early symptoms. Nausea, vomiting and diarrhea may also occur.
• Tissue and barrier damage – The strong inflammatory condition damages the host tissues. In intestine, it disrupts epithelial barrier. The cell adhesion molecules are reduced, so gaps are formed between epithelial cells and severe leakiness occurs.
• Vascular leakage – Cytokines like TNF damage endothelial cells and increase capillary permeability. This causes capillary leak and fluid loss from blood vessels. Due to this, blood pressure may fall severely.
• Systemic complications – The cytokine storm affects cardiovascular and respiratory systems. It may cause acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), severe hypotension and toxic shock.
• Final harmful effect – If the cytokine storm is not controlled, it causes multiple organ system failure. Thus superantigen-induced cytokine storm is a dangerous immune reaction and may become lethal to the host.

Difference Between Conventional Antigens and Superantigens

Examples of Important Superantigens

The following are the important examples of Superantigens (SAgs)-

1. Bacterial T-cell superantigens
   • Toxic Shock Syndrome Toxin-1 (TSST-1) is produced by Staphylococcus aureus. It is a very potent superantigen and it is the common cause of toxic shock syndrome.
   • Staphylococcal Enterotoxins (SE) are also produced by Staphylococcus aureus. Important types are SEA, SEB and SEC. These are major cause of staphylococcal food poisoning and non-menstrual toxic shock syndrome.
   • Streptococcal Pyrogenic Exotoxins (SPE) are produced by Streptococcus pyogenes or Group A Streptococcus. Important examples are SPE-A, SPE-C and other types. These are mainly responsible for scarlet fever and streptococcal toxic shock syndrome.
   • Streptococcal Mitogenic Exotoxin Z (SMEZ) is present in Streptococcus pyogenes. It is a very strong superantigen and has more than 50 allelic variants.
   • Streptococcal Superantigen (SSA) is produced by Streptococcus pyogenes. It shows high structural similarity with staphylococcal superantigens.
   • Yersinia pseudotuberculosis-derived mitogen (YPM) is produced by Yersinia pseudotuberculosis. It is the classical T-cell superantigen of Gram-negative bacterium and has special jelly-roll fold structure.
   • Metamycoplasma arthritidis-derived mitogen (MAM) is a soluble superantigen. It causes inflammatory polyarthritis in rodents. It has only alpha-helical domains and not the common beta-grasp fold.
   • ETEC enterotoxin is produced by enterotoxigenic E. coli. It acts as Type I superantigen and is a common cause of traveller’s diarrhea.
2. B-cell superantigens
   • Staphylococcal Protein A (SpA) is a cell wall associated protein of Staphylococcus aureus. It acts as B-cell superantigen by binding directly with Fab region of VH3 family immunoglobulins.
   • Peptostreptococcal Protein L (PpL) is produced by Peptostreptococcus magnus. It binds with framework region of variable light chains of kappa subclass of human immunoglobulins.
   • Human Immunodeficiency Virus-1 (HIV-1) gp120 is envelope glycoprotein of HIV-1. It acts as soluble B-cell superantigen and binds with membrane-bound IgM molecules of VH3 heavy-chain family.
3. Viral T-cell superantigens
   • Mouse Mammary Tumor Virus (MMTV) superantigen is encoded in the long terminal repeat of the virus. It affects the T-cell repertoire of host and helps in transmission of virus to mammary glands.
   • Rabies Virus Nucleoprotein (N) is the nucleocapsid protein of rabies virus. It acts as superantigen and also has T-dependent adjuvant property. It may cause severe neuro-immunopathology and immune-mediated paralysis.
   • Human Endogenous Retrovirus-K18 (HERV-K18) envelope protein is a dormant viral superantigen present in human genome. It can be activated by Epstein-Barr Virus (EBV) and its expression is linked with risk of Multiple Sclerosis.

Diseases and Disorders Associated with Superantigens

Superantigens (SAgs) are associated with many acute and chronic diseases. These diseases are produced due to excess activation of T-cells and release of cytokines. The effect may be local or it may affect the whole body.

Acute and systemic infections

Toxic Shock Syndrome (TSS) is a severe systemic condition. It is mainly caused by Staphylococcus aureus superantigens such as TSST-1, SEB and SEC. High fever, rash, hypotension and shock are seen in this disease. It may occur as menstrual or non-menstrual type.

Streptococcal Toxic Shock Syndrome (STSS) is caused by Streptococcus pyogenes. The important superantigens are SPE-A, SPE-C and SMEZ. It is a rapidly progressive disease. Shock and multi-organ failure may occur.

Sepsis and Systemic Inflammatory Response Syndrome (SIRS) are also related with superantigens. In this condition, cytokines are released in very high amount. The immune response becomes uncontrolled and systemic inflammation is produced.

Gastrointestinal disorders

Staphylococcal food poisoning is caused by preformed staphylococcal enterotoxins present in food. Mainly SEA is involved. Vomiting and diarrhea are produced. This occurs by stimulation of neural receptors on vagus nerve.

Traveler’s diarrhea is caused by enterotoxigenic E. coli (ETEC). The ETEC enterotoxin acts as Type I superantigen. It produces diarrheal condition.

Respiratory and cardiovascular diseases

Necrotizing pneumonia is a severe lung infection. It is commonly seen after influenza infection. Staphylococcus aureus superantigens are involved in this condition.

Infective endocarditis is infection of heart valves. In this disease, Staphylococcus aureus superantigens help in vegetative lesion formation. Severe sepsis may also develop.

Kawasaki disease is an acute multisystem vasculitis. It mainly occurs in young children. Coronary artery damage may occur. It is linked with SPE-C, SPE-J and Yersinia superantigens.

Skin and tissue infections

Scarlet fever is caused by streptococcal pyrogenic exotoxins of Streptococcus pyogenes. Fever and characteristic skin rash are present. It is one of the classical disease related with streptococcal toxin.

Far East scarlet-like fever and Izumi fever are caused by Yersinia pseudotuberculosis-derived mitogen (YPM). Fever, rash and appendicitis like symptoms are seen. Mesenteric lymphadenitis may be present.

Necrotizing fasciitis is a destructive soft tissue infection. It is caused by invasive strains of Streptococcus pyogenes. Superantigens help in rapid tissue damage. It is also called flesh-eating infection.

Chronic skin conditions

Atopic dermatitis and eczema herpeticum are associated with Staphylococcus aureus colonization. Continuous exposure to superantigens increases the inflammation of skin. The immune response becomes more Th2 type.

Guttate psoriasis and chronic plaque psoriasis are often seen after Streptococcus pyogenes throat infection. Superantigens stimulate reactive T-cells in the skin. So skin inflammation is increased.

Bullous pemphigoid is a blistering autoimmune disease. It is usually seen in old people. It is associated with Staphylococcus aureus and TSST-1 production.

Autoimmune and inflammatory diseases

Acute rheumatic fever is a post-streptococcal autoimmune disease. It may produce rheumatic heart disease. SPE-L and SPE-M are associated with this disease.

Rheumatoid arthritis and inflammatory polyarthritis are joint inflammatory diseases. Superantigen activity may be involved. Metamycoplasma arthritidis-derived mitogen (MAM) causes inflammatory polyarthritis in rodents.

Systemic Lupus Erythematosus (SLE) and autoimmune enterocolitis are autoimmune diseases. Superantigens may act as triggering factor or worsening factor in these diseases.

Neurological and metabolic disorders

Multiple Sclerosis (MS) is a neuroinflammatory disease. It is linked with endogenous retroviral superantigens such as HERV-K18 and pHERV-W. These may become active after Epstein-Barr Virus (EBV) or Human Herpesvirus 6 (HHV-6) infection. Then self reactive T-cells damage the myelin sheath.

Immune-mediated paralysis in rabies is due to rabies virus nucleoprotein acting as superantigen. It may cause severe neuro-immunopathology. Paralysis may occur.

Diabetes Mellitus Type 2 (DM2) is associated with superantigen producing Staphylococcus aureus. These bacteria may colonize diabetic foot ulcers and skin. Their toxins may cause systemic immune dysregulation and disease become worse.

Immunological Significance of Superantigens

The following are the immunological significance of Superantigens (SAgs)-

• Triggering of cytokine storm – Superantigens (SAgs) activate very large number of T-cells without normal antigen presentation. About 20% to 30% of host T-cell population may be activated. This causes release of many cytokines like interleukin-2 (IL-2), interferon-gamma (IFN-γ) and tumor necrosis factor (TNF).
• Excess inflammatory response – The cytokines are released in uncontrolled amount. This condition is called cytokine storm. It produces fever, inflammation, vascular leakage and shock like condition.
• Hijacking of costimulatory receptors – Superantigens bind with CD28 present on T-cells and B7 present on antigen-presenting cells (APCs). This binding is not normal. It makes the immunological synapse more stable and produces strong inflammatory signal.
• Immune evasion – After first strong activation, many T-cells become weak or unresponsive. This condition is called T-cell anergy. Some T-cells are also destroyed by apoptosis.
• Suppression of adaptive immunity – Superantigens may also increase regulatory T-cells (Tregs). These cells suppress specific adaptive immune response. Due to this, pathogen can escape from normal immune clearance.
• B-cell disruption – Some superantigens act on B-cells also. Staphylococcal Protein A (SpA) and HIV gp120 bind with framework regions of immunoglobulins. They do not bind through normal antigen-binding site.
• Complement activation – Binding of B-cell superantigens may form large pseudo-immune complexes. These complexes can activate classical complement pathway. This may cause tissue inflammation like Arthus-type reaction.
• Amplification of endotoxin toxicity – Superantigens act together with Gram-negative bacterial endotoxins such as lipopolysaccharide (LPS). They reduce the level needed for endotoxin action and increase shock producing effect many times.

Clinical Significance of Superantigens

The following are the clinical significance of Superantigens (SAgs)-

• Acute systemic shock syndromes – Superantigens (SAgs) are important cause of severe shock diseases. Toxic Shock Syndrome (TSS) is caused by Staphylococcus aureus toxins. Streptococcal Toxic Shock Syndrome (STSS) is caused by Streptococcus pyogenes toxins. High fever, erythematous rash, capillary leak, hypotension and multi-organ failure are seen.
• Gastrointestinal illnesses – Staphylococcal enterotoxins are important cause of food poisoning. They also act as superantigens. These toxins stimulate neural receptors on vagus nerve present in gastric mucosa. Severe vomiting and diarrhea are produced.
• Traveler’s diarrhea – Some superantigens are also associated with traveler’s diarrhea. The toxin produced by enterotoxigenic E. coli (ETEC) acts as Type I superantigen. It produces diarrheal illness.
• Autoimmune diseases – Superantigens can produce excessive T-cell stimulation. Sometimes immune response cross reacts with host tissues. This is referred to as molecular mimicry. Due to this, autoimmune conditions may be started or worsened.
• Multiple Sclerosis (MS) – MS is linked with endogenous retroviral superantigens. These dormant viral SAgs may be activated by Epstein-Barr Virus (EBV). Then abnormal T-cell response may damage myelin sheath.
• Other autoimmune diseases – Acute rheumatic fever, Kawasaki disease, rheumatoid arthritis and guttate psoriasis are also linked with superantigens. In these diseases, activated immune cells reacts with host tissues and inflammation occurs.
• Exacerbation of chronic diseases – Long exposure to superantigens damages epithelial and mucosal barriers. It increases chronic inflammation. Atopic dermatitis, bullous pemphigoid and Diabetes Mellitus type 2 (DM2) may become worse due to these toxins.
• Therapeutic importance – Superantigens are also important for development of new treatment. Some synthetic peptide mimetics are made to block CD28/B7 interaction. This may reduce cytokine storm and protect from lethal shock.
• Use of IVIG – Intravenous Immunoglobulin (IVIG) is used in some severe conditions. It contains pooled neutralizing antibodies. These antibodies can neutralize many superantigen toxins and reduce their harmful effect.

Prevention and Therapeutic Approaches Against Superantigen-Mediated Diseases

The following are the prevention and therapeutic approaches against Superantigen-mediated diseases-

• Standard medical and surgical treatment – In acute superantigen-mediated diseases, the patient is first maintained by fluid resuscitation and vasopressors. These are used for maintaining blood pressure and circulation. Antibiotics are used for killing the toxin producing bacteria. In necrotizing soft tissue infection, the infected tissue is removed by surgery. This is necessary to reduce bacteria and toxin from the affected site.
• Intravenous Immunoglobulin (IVIG) therapy – Intravenous Immunoglobulin (IVIG) is a pooled human antibody preparation. It has neutralizing antibodies against many staphylococcal and streptococcal superantigens. In toxic shock syndrome, early use of IVIG helps in neutralization of circulating toxins. So the toxin effect is decreased in blood.
• Immunosuppressants and cytokine inhibitors – Superantigens produce excess inflammation by release of cytokines. Corticosteroids are used to suppress this inflammatory effect. Anakinra is an IL-1 receptor antagonist. It is used to reduce T-cell activation and cytokine production. Thus the cytokine storm is controlled.
• Peptide antagonists – Peptide antagonists are short synthetic peptides. These are made like CD28 receptor interface or like conserved β-strand(8)/hinge/α-helix(4) part of superantigen. These peptides compete with superantigen. They block the binding with costimulatory receptors. So the inflammatory signaling becomes less.
• Receptor mimics – Receptor mimics are soluble decoy receptors. They bind with superantigens in circulation. Due to this, the toxin cannot bind properly with MHC-II and TCR on immune cells. Some receptor mimics contain both MHC-II and TCR parts. Some are soluble high affinity TCR mutants.
• Toxoid vaccines – Toxoid vaccines are made from genetically changed superantigens. Mutation is made in TCR, MHC-II or costimulatory receptor binding region. Therefore the toxin becomes non-toxic but it remains antigenic. It stimulates formation of neutralizing antibodies against toxins such as TSST-1, SPE-A and SPE-C.
• Targeted monoclonal antibodies – Targeted monoclonal antibodies are used against some viral superantigen proteins. Temelimab is an IgG4 humanized monoclonal antibody. It is studied in Multiple Sclerosis (MS) linked with pHERV-W protein. It neutralizes the proinflammatory viral protein.
• Prevention of infection and toxin exposure – Proper hygiene, wound care and safe food handling are important. Early treatment of bacterial infection is also required. These help to stop the growth of toxin producing organisms. Thus superantigen-mediated diseases can be reduced.

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