gram - positive infections account for up to 50% of cases of severe sepsis in the modern intensive care unit . the complex processes by which gram - positive organisms cause sepsis are poorly understood by comparison with gram - negative sepsis .
much interest is currently focused on the role of certain protein exotoxins synthesized by staphylococcus aureus and streptococcus pyogenes , which share the immunological property of being super - antigens .
superantigens are characterized by the ability to bypass normal major histocompatibility complex ( mhc)-restricted , intracellular , antigen processing and presentation . through direct binding to the mhc class ii molecule and the t cell receptor , at sites away from those involved in conventional antigen binding ,
superantigens activate up to 50% of the whole t cell repertoire rather than the 1% fraction stimulated by conventional antigens .
such toxins are , however , believed to have a role in causation of two classic superantigen - mediated diseases , staphylococcal and streptococcal toxic shock syndromes , that kill 5000 americans per annum .
they may also contribute to the pathogenesis of other forms of gram - positive shock .
in addition to intensive care support and antimicrobial therapy , various adjunctive treatments for toxic shock syndrome have been evaluated both in vitro and in clinical trials ( table 1 ) .
nevertheless , the treatment of toxic shock syndrome , like that of conventional forms of sepsis , remains suboptimal and the disease is still associated with mortality in the region of 50% and associated with considerable morbidity .
they identified a dodecapeptide that is highly conserved among different bacterial superantigens and lies in a region of the super - antigen molecule away from sites involved with either mhc class ii or t cell receptor interaction .
several modified forms of this peptide acted as antagonists to a range of bacterial superantigens against which they were tested in vitro .
one dodecapeptide , which was a particularly effective antagonist , was administered to mice challenged with bolus doses of bacterial superantigen .
arad et al speculate that the mechanism of inhibition may involve co - stimulatory pathways of t cell activation .
interestingly , protection against subsequent challenges , at 3-weekly intervals , improved with each challenge . this improved protection correlated with antibody production against the whole challenge superantigen , while antibody against the dodecapeptide was not detected .
this finding is in keeping with the previously observed correlation between lack of antibody against streptococcal pyrogenic exotoxin a and development of invasive s. pyogenes infection .
one consequence of the cytokine storm induced by superantigens may be to disrupt the development of antibody - mediated immunity . by switching off superantigenicity , the dodecapeptide may be allowing normal antibody production to occur .
although the prospect of drugs to switch off superantigenicity is exciting , there have been many false dawns in the field of sepsis research .
all laboratory animals are intrinsically resistant to the effects of bacterial superantigens . the mouse model , while being one of the best established systems for studying toxic shock , requires far higher doses of superantigen than are needed to induce shock in humans , and prior ' sensitization ' of the animal with the hepatotoxin d - galactosamine .
we have recently demonstrated , in a mouse model of invasive streptococcal infection , that other properties of these toxins may be more important than their superantigenicity and , paradoxically , such effects may in fact be advantageous to the host . furthermore , administration of bolus doses of superantigen probably does not reflect the pattern of toxin production in clinical cases .
certain findings of the report by arad et al are at odds with our current understanding of bacterial superantigens .
the study found that animals protected from one super - antigen in an initial challenge were cross - protected against different superantigens in subsequent challenges .
this effect was observed for toxins as dissimilar as staphylococcal exotoxin b and toxic shock syndrome toxin 1 , which have only 6% sequence homology .
this is hard to understand in terms of neutralizing antibody since no cross - reactivity between toxic shock syndrome toxin 1 and other superantigens has been demonstrated in serological or neutralization assays .
the paper by arad et al is the first published report of superantigen antagonist peptides .
encouragingly , at least one other group is making progress in the same area , and have demonstrated a protective effect not only against bolus doses of superantigen , but also in a model of co - challenge with endotoxin .
further studies to address the mode of action of these peptides , particularly in super - antigen - sensitive animal models ( sriskandan et al , manuscript submitted ) , are necessary before speculation about clinical trials is warranted .
specific approaches to treatment of toxic shock syndromes spea , streptococcal pyrogenic exotoxin a ; spec , streptococcal pyrogenic exotoxin c.
 the production of superantigenic exotoxins by gram positive bacteria underlies the pathology of toxic shock syndrome . 
 future treatment strategies for superantigen - mediated diseases are likely to be directed at blocking the three - way interaction between superantigen , t cell receptor and major histocompatibility class ii molecule , which inititates an excessive and disordered inflammatory response . in this article , we review the first published data to address one such strategy in the context of other recognised and experimental treatments . 
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