Streptococcal superantigens: categorization and clinical associations.

Superantigens are key virulence factors in the immunopathogenesis of invasive disease caused by group A streptococcus. These protein exotoxins have also been associated with severe group C and group G streptococcal infections. A number of novel streptococcal superantigens have recently been described with some resulting confusion in their classification. In addition to clarifying the nomenclature of streptococcal superantigens and proposing guidelines for their categorization, this review summarizes the evidence supporting their involvement in various clinical diseases including acute rheumatic fever.

Clinical significance of immunoglobulin E responses to staphylococcal superantigens in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Previous studies have reported a higher prevalence of immunoglobulin E (IgE) specific for staphylococcal superantigens (SAg) in the nasal mucosa of patients with aspirin-exacerbated respiratory disease (AERD), associated with eosinophilic inflammation and leukotriene production. However, the role of SAg-specific IgE in the pathogenesis of AERD is not well understood. We evaluated the clinical significance of serum IgE specific for three types of SAg, namely staphylococcal enterotoxins A and B (SEA and SEB) and toxic shock syndrome toxin-1 (TSST-1) in AERD. METHODS: We enrolled 147 patients with AERD confirmed by a lysine-acetyl salicylic acid bronchoprovocative test and compared them with 147 patients with aspirin-tolerant asthma (ATA) and 141 healthy controls (NC). The levels of serum total IgE and SAg-specific IgE were measured using an ImmunoCAP system. Other clinical parameters were analyzed retrospectively. RESULTS: The prevalences of SEA-, SEB- and TSST-1-specific IgE in the AERD and ATA groups were significantly higher than those in the NC group (p < 0.05, respectively). The total IgE level was significantly higher in patients with AERD with high levels of SEA-specific IgE than in those with lower levels (p < 0.05), with significant positive correlations between total and SAE-specific IgE levels (p < 0.05). The PC20 methacholine level was significantly lower in patients with AERD with high levels of SEA-specific IgE, while a significantly higher eosinophil count was noted in patients with AERD with high levels of SEB-specific IgE (p < 0.05, respectively). CONCLUSIONS: Specific IgE responses to SAg may increase the serum total IgE level, airway hyperresponsiveness and eosinophil activation, leading to more severe clinical symptoms in AERD.

Evolutionary paths of streptococcal and staphylococcal superantigens.

BACKGROUND: Streptococcus pyogenes (GAS) harbors several superantigens (SAgs) in the prophage region of its genome, although speG and smez are not located in this region. The diversity of SAgs is thought to arise during horizontal transfer, but their evolutionary pathways have not yet been determined. We recently completed sequencing the entire genome of S. dysgalactiae subsp. equisimilis (SDSE), the closest relative of GAS. Although speG is the only SAg gene of SDSE, speG was present in only 50% of clinical SDSE strains and smez in none. In this study, we analyzed the evolutionary paths of streptococcal and staphylococcal SAgs. RESULTS: We compared the sequences of the 12-60 kb speG regions of nine SDSE strains, five speG(+) and four speG(-). We found that the synteny of this region was highly conserved, whether or not the speG gene was present. Synteny analyses based on genome-wide comparisons of GAS and SDSE indicated that speG is the direct descendant of a common ancestor of streptococcal SAgs, whereas smez was deleted from SDSE after SDSE and GAS split from a common ancestor. Cumulative nucleotide skew analysis of SDSE genomes suggested that speG was located outside segments of steeper slopes than the stable region in the genome, whereas the region flanking smez was unstable, as expected from the results of GAS. We also detected a previously undescribed staphylococcal SAg gene, selW, and a staphylococcal SAg -like gene, ssl, in the core genomes of all Staphylococcus aureus strains sequenced. Amino acid substitution analyses, based on dN/dS window analysis of the products encoded by speG, selW and ssl suggested that all three genes have been subjected to strong positive selection. Evolutionary analysis based on the Bayesian Markov chain Monte Carlo method showed that each clade included at least one direct descendant. CONCLUSIONS: Our findings reveal a plausible model for the comprehensive evolutionary pathway of streptococcal and staphylococcal SAgs.

Association of staphylococcal superantigen-specific immunoglobulin e with mild and moderate atopic dermatitis.

OBJECTIVE: To examine the frequency of allergic sensitization to staphylococcal superantigens in young children with mild to moderate atopic dermatitis (AD). STUDY DESIGN: AD severity was assessed with objective Scoring AD. Serum IgE to staphylococcal enterotoxin (SE) A, SEB, SEC, SED, and toxic shock syndrome toxin-1 were measured with ImmunoCAP. Comparisons between mild AD and moderate AD were performed by using logistic regressions. RESULTS: The prevalence of allergic sensitization to staphylococcal superantigens in patients with mild and moderate AD was 38% and 63%, respectively. Allergic sensitization to staphylococcal superantigens, particularly SEA and SED, was found to be associated with moderate AD, compared with mild AD. CONCLUSIONS: Our results suggest that allergic sensitization to staphylococcal superantigens is common even in young children with mild to moderate AD, and such sensitization may contribute to the disease severity of these patients.

Strain prevalence, rather than innate virulence potential, is the major factor responsible for an increase in serious group A streptococcus infections.

BACKGROUND: It is postulated that the surge in incidence and severity of group A streptococcus (GAS) infections since the 1980s is due to the emergence of strains of GAS with increased virulence. We used active, population-based surveillance of invasive GAS disease, serologically confirmed pharyngitis, and carriage to determine whether particular strains were associated with invasive disease. METHODS: Two hundred twenty GAS isolates were collected--78 invasive, 34 pharyngitis, and 108 carriage. Isolates were characterized using emm typing, random amplification of polymorphic DNA (RAPD) profiling, and superantigen genotyping. RESULTS: emm1, emm12, and emm28 predominated in invasive disease and accounted for 30.8%, 12.8%, and 12.8% of all isolates, respectively. emm1, emm75, emm28, and emm4 were the most frequently isolated emm types in pharyngitis, and emm12 and emm1 predominated in carriage. emm12 was significantly associated with carriage rather than disease. There were no other significant associations between emm type and disease or carriage. There were no associations between any RAPD profile or superantigen genotype and invasive disease, pharyngitis, or carriage. One RAPD profile accounted for most cases of necrotizing fasciitis, which suggests that this strain might have particular features promoting connective-tissue infection. CONCLUSIONS: These data suggest that the emergence of GAS strains with increased virulence is not the main factor responsible for the surge in GAS-related infections. The prevalence of particular emm types, RAPD profiles, or superantigen genes in invasive disease may simply indicate widespread transmission of these strains in the population, rather than a particular ability to cause disease.

Comprehensive analysis of classical and newly described staphylococcal superantigenic toxin genes in Staphylococcus aureus isolates.

We describe a comprehensive detection system for 18 kinds of classical and newly described staphylococcal superantigenic toxin genes using four sets of multiplex PCR. Superantigenic toxin genotyping of Staphylococcus aureus for 69 food poisoning isolates and 97 healthy human nasal swab isolates revealed 32 superantigenic toxin genotypes and showed that many S. aureus isolates harbored multiple toxin genes. Analysis of the relationship between toxin genotypes and toxin genes encoding profiles of mobile genetic elements suggests its possible role in determining superantigenic toxin genotypes in S. aureus as combinations of toxin gene-encoding mobile genetic elements.

Functional characterization of streptococcal pyrogenic exotoxin J, a novel superantigen.

Streptococcal toxic shock syndrome (STSS) is a highly lethal, acute-onset illness that is a subset of invasive streptococcal disease. The majority of clinical STSS cases have been associated with the pyrogenic toxin superantigens (PTSAgs) streptococcal pyrogenic exotoxin A or C (SPE A or C), although cases have been reported that are not associated with either of these exotoxins. Recent genome sequencing projects have revealed a number of open reading frames that potentially encode proteins with similarity to SPEs A and C and to other PTSAgs. Here, we describe the cloning, expression, purification, and functional characterization of a novel exotoxin termed streptococcal pyrogenic exotoxin J (SPE J). Purified recombinant SPE J (rSPE J) expressed from Escherichia coli stimulated the expansion of both rabbit splenocytes and human peripheral blood lymphocytes, preferentially expanded human T cells displaying Vbeta2, -3, -12, -14, and -17 on their T-cell receptors, and was active at concentrations as low as 5 x 10(-6) microg/ml. Furthermore, rSPE J induced fevers in rabbits and was lethal in two models of STSS. Biochemically, SPE J had a predicted molecular weight of 24,444 and an isoelectric point of 7.7 and lacked the ability to form the cystine loop structure characteristic of many PTSAgs. SPE J shared 19.6, 47.1, 38.8, 18.1, 19.6, and 24.4% identity with SPEs A, C, G, and H, streptococcal superantigen, and streptococcal mitogenic exotoxin Z-2, respectively, and was immunologically cross-reactive with SPE C. The characterization of a seventh functional streptococcal PTSAg raises important questions relating to the evolution of the streptococcal superantigens.

Conservation and variation in superantigen structure and activity highlighted by the three-dimensional structures of two new superantigens from Streptococcus pyogenes.

Bacterial superantigens (SAgs) are a structurally related group of protein toxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They are implicated in a range of human pathologies associated with bacterial infection whose symptoms result from SAg-mediated stimulation of a large number (2-20%) of T-cells. At the molecular level, bacterial SAgs bind to major histocompatability class II (MHC-II) molecules and disrupt the normal interaction between MHC-II and T-cell receptors (TCRs). We have determined high-resolution crystal structures of two newly identified streptococcal superantigens, SPE-H and SMEZ-2. Both structures conform to the generic bacterial superantigen folding pattern, comprising an OB-fold N-terminal domain and a beta-grasp C-terminal domain. SPE-H and SMEZ-2 also display very similar zinc-binding sites on the outer concave surfaces of their C-terminal domains. Structural comparisons with other SAgs identify two structural sub-families. Sub-families are related by conserved core residues and demarcated by variable binding surfaces for MHC-II and TCR. SMEZ-2 is most closely related to the streptococcal SAg SPE-C, and together they constitute one structural sub-family. In contrast, SPE-H appears to be a hybrid whose N-terminal domain is most closely related to the SEB sub-family and whose C-terminal domain is most closely related to the SPE-C/SMEZ-2 sub-family. MHC-II binding for both SPE-H and SMEZ-2 is mediated by the zinc ion at their C-terminal face, whereas the generic N-terminal domain MHC-II binding site found on many SAgs appears not to be present. Structural comparisons provide evidence for variations in TCR binding between SPE-H, SMEZ-2 and other members of the SAg family; the extreme potency of SMEZ-2 (active at 10(-15) g ml-1 levels) is likely to be related to its TCR binding properties. The smez gene shows allelic variation that maps onto a considerable proportion of the protein surface. This allelic variation, coupled with the varied binding modes of SAgs to MHC-II and TCR, highlights the pressure on SAgs to avoid host immune defences.

Role of the immune response induced by superantigens in the pathogenesis of microbial infections.

Superantigens (SAgs) are microbial proteins which have potent effects on the immune system. They are presented by major histocompatibility complex (MHC) class II molecules and interact with a large number of T cells expressing specific T cell receptor V beta domains. Encounter of a SAg leads initially to the stimulation and subsequently to the clonal deletion of reactive T cells. SAgs are expressed by a wide variety of microorganisms which use them to exploit the immune system to their own advantage. Bacterial SAgs are exotoxins which are linked to several diseases in humans and animals. A classical example is the toxic shock syndrome in which the massive release of cytokines by SAg-reactive cells is thought to play a major pathogenic role. The best characterized viral SAg is encoded by mouse mammary tumour virus (MMTV) and has proved to have a major influence on the viral life cycle by dramatically increasing the efficiency of viral infection. In this paper, we review the general properties of SAgs and discuss the different types of microorganisms which produce these molecules, with a particular emphasis on the role played by the SAg-induced immune response in the course of microbial infections.

[Superantigens and their implication in autoimmune diseases]. / Super-antigènes et leur implication dans les maladies auto-immunes.

Superantigens, unlike conventional antigens, are capable of stimulating cell growth and differentiation of a large proportion of T cells (10 -40%). There are two types of superantigens: endogenous retroviral superantigens (described only in mice) and bacterial superantigens. Bacterial superantigens are heat-resistant enterotoxins responsible for Staphylococcus food poisoning or toxic shock syndromes. T lymphocyte proliferation is associated with production of large quantities of cytokines, including interleukin-1, 2, 4, 6 and tumour necrosis factor which induce the symptoms observed in toxic syndromes. These superantigens form trimolecular complexes with the beta chains on the outer peptide pouch of class II HLA molecules and with certain families of V beta chains of the T-cell receptors on CD4 and CD8 lymphocytes. Unlike conventional antigens, superantigens do not have to be processed in small-sized peptides before presentation to T-cell receptors by the class II HLA molecules. The late consequences of T-cell activation by superantigens are either a deletion of the T-lymphocytes carrying V beta chains in families specific for a superantigen, or an anergy. The oligoclonal characteristic of T-lymphoid populations infiltrating the central nervous system, the synovial membrane or the salivary glands suggests that superantigens are implicated in the pathogenesis of certain autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and Sjögren's syndrome. Certain Staphylococcus superantigens could be the cause of Kawasaki's syndrome.

Superantigens. Do they have a role in skin diseases?

Superantigens are a group of bacterial and viral proteins that are characterized by their capacity to stimulate a large number of T cells. They bind directly to the major histocompatibility complex class II molecule on the antigen-presenting cell and cross-link the antigen-presenting cell with T cells expressing certain T-cell receptors, leading to polyclonal T-cell activation. They have been shown to play a role in toxic shock syndrome and mucocutaneous lymph node syndrome and are postulated to play a role in other systemic diseases. Because inflammatory skin diseases such as atopic dermatitis and psoriasis are often known to be colonized with superantigen-releasing Staphylococcus aureus, the role of superantigens in skin diseases is of major importance. Recent studies have demonstrated that if a staphylococcal superantigen is applied on intact human skin, a clinical picture of dermatitis evolves. Furthermore, in the presence of superantigens, epidermal cells potently activate T cells. Thus, superantigens may play a role in the induction and exacerbation of inflammatory skin diseases.