Human Antibodies to Bacterial Superantigens and Their Ability To Inhibit T-Cell Activation and Lethality

Abstract

Bacterial superantigens (BSAgs) cause massive stimulation of the immune system and are associated with various pathologies and diseases. To address the role of antibodies in protection against BSAgs, we screened the sera of 29 human volunteers for antibodies to the SAgs staphylococcal enterotoxin A (SEA), SEB, SEC1, and toxic shock syndrome toxin 1 (TSST-1). Although all volunteers had detectable levels of antibodies against SEB and SEC1, many (9 out of 29 volunteers) lacked detectable antibody to SEA or had minimal titers. Antibody titers to TSST-1 were well below those to SEB and SEC1, and three volunteers lacked detectable antibody to this BSAg. In addition, pooled immunoglobulin preparations obtained from different companies had antibody titers against SEs and TSST-1. There was a good correlation between antibody titers and inhibition of superantigenic effects of these toxins. Transfer of SEB-specific antibodies, obtained from pooled sera, suppressed in vitro T-cell proliferation and totally protected mice against SEB. These data suggest that the inhibitory activity of human sera was specific to antibodies directed against the toxins. Thus, it may be possible to counteract with specific antibodies BSAg-associated pathologies caused by stimulation of the immune system.Bacterial superantigens (BSAgs), such as staphylococcal enterotoxins (SEs) and toxic shock syndrome toxin 1 (TSST-1), are pyrogenic virulence factors produced by Staphylococcus aureus (9,11,13,26). These microbial SAgs bind to both human major histocompatibility antigen class II molecules on the surface of antigen-presenting cells and germ line-encoded variable domain sequences of the specific T-cell receptor variable ␤ chain on T lymphocytes (9, 11). Thus, BSAgs bypass the normal antigen-specific restrictions by creating a wedge between T-cell receptor and class II molecules and hence activate significantly greater numbers of T lymphocytes. The majority of stimulated T cells are programmed to acquire susceptibility to cell death by Fas-and Fas ligand-mediated apoptosis, or alternatively they enter into a state of specific nonresponsiveness (anergy), which may last for several months after the initial encounter with the BSAg. The activation of antigenpresenting cells and T cells results in production of pathological levels of proinflammatory cytokines that contribute to several serious pathologies and lethal toxic shock syndrome (11,17,22,26).Low serum antibody titers to BSAgs have been associated with the recurrence of toxic shock syndrome (10,23,28). Vaccination with nonsuperantigenic forms of BSAgs mitigates many of the symptoms of SE exposure (4,14,27). Vaccinated animals had high protective antibody titers against SEs and were fully protected against lethal challenge (4, 27). Thus, antibody responses may play a major role in protection against BSAgs. Here, we studied the prevalence of anti-SE and anti-TSST-1 antibodies in normal human volunteers and several pooled intravenous immunoglobulin (IVIG) products and examined if there is a correla...

Development of serum IgM antibodies against superantigens ofStaphylococcus aureusandStreptococcus pyogenesin Kawasaki disease

“…Takei and colleagues [21] showed that IVIG contains anti-SE antibodies that suppress SE-induced T-cell stimulation in vitro. In vivo evidence also indicated that SE-specific antibodies obtained from pooled sera protected mice from a lethal dose of SE [22]. We showed that high concentrations of IgG antibodies against the staphylococcal and streptococcal toxins were present in the IVIG products.…”

“…We showed that high concentrations of IgG antibodies against the staphylococcal and streptococcal toxins were present in the IVIG products. These results indicate a high prevalence of antitoxin antibodies in Japanese adults as well as US populations [21,22], and may reflect the virtual absence of KD in adulthood due to widespread immunity. More importantly, we also showed that the administration of immunoglobulin products directly influenced serum IgGantitoxin antibody levels in KD patients.…”

Preclinical evaluation of superantigen (staphylococcal enterotoxin B) in the intravesical immunotherapy of superficial bladder cancer

“…Synthetic fusion proteins, MHC class II-independent and tumor-specific, have been evaluated successfully. 23,24,[51][52][53][54][55] In summary, the preclinical findings indicate that SEB could be a useful agent for treatment of bladder cancer and that a clinical phase I evaluation appears warranted. …”

“…Another issue which needs to be considered is the prevalence of anti-staphylococcal enterotoxins and anti-TSST-1 antibodies in humans. In a study by LeClaire and Bavari, 51 it was shown that detectable levels of antibodies against various staphylococcal enterotoxins (SEA, SEB, SEC1 and TSST-1) can potentially inhibit T-cell activation. This and the fact that the high toxicity of streptococcal and staphylococcal enterotoxins can result in significant human morbidity and mortality lead to the potential use of genetically engineered superantigens.…”

Mutational effects on protein folding stability and antigenicity: the case of streptococcal pyrogenic exotoxin A

“…To assay for neutralization of SPEA activity by serum antibodies, we used the T-lymphocyte proliferation assay [21]. To demonstrate SPEA-specific T-cell inhibition by pooled mouse sera obtained from vaccinated or control mice, sera were incubated (1 h/37°C) with a various doses of SPEA (20 or 200 ng/ml).…”