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IJMS Journal Spring 2003

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Editorial

Systemic inflammatory response syndrome: a new direction?

Systemic inflammatory response syndrome: a new direction? MR Kell, BD Barry, HP Redmond Department of Surgery, Cork University Hospital, University College Cork, Ireland

Sepsis, septic shock and the ensuing multiple organ failure continue to be the most common causes of death in the surgical intensive care unit. This syndrome is characterised by deterioration in several organ systems and also by the development of systemic inflammation. Systemic inflammation of this type has been described as the systemic inflammatory response syndrome (SIRS) and frequently occurs without evidence of infection or a septic focus. The pathogenesis of SIRS is unclear but much work has focused on the gastrointestinal tract as a possible source of bacteria or bacterial products that could trigger SIRS. One concept is that the gut acts as an undrained abscess that could drive immune activation in SIRS patients.1 Supporting this concept, critically ill patients have specific GI colonisation, which can precede signs of systemic inflammation by the same organisms.2 The bacterial product, which most research has focused on, is the Gram-negative cell wall endotoxin lipopolysaccharide (LPS). This was initially discovered in conjunction with Coley’s work on bacterial toxins in the treatment of malignancy.3 Carswell then identified tumour necrosis factor as the link between endotoxin and tumour cachexia.4 Endotoxin has been firmly regarded as the principal bacterial product involved in the innate immune activation which occurs in SIRS. This concept has been questioned: in humans there is no clear link between endotoxin, gut barrier function, systemic cytokine levels and outcome.5 Recent studies to address the microbiology of gut translocation have found that one-third of translocated organisms are Gram-positive, though the question of whether these organisms initiate SIRS has not been addressed.6 Gut barrier function does decline following surgical insult and this may therefore be a potential portal of entry for Gram-positive and other bacterial products to enter the circulation and activate the immune system, though this hypothesis has not been tested.7 It is clear, however, that current data in humans do not support endotoxin as the sole bacterial mediator of SIRS. The ability of Gram-positive organisms to produce systemic inflammation has been attributed to the production of superantigens (SAgs). These are potent exotoxin antigens with the capacity to activate large numbers of T-cells. The response ratio of T-cells responding to SAgs is in the order of 1:5 whereas normal antigen activates only 1:10,000.8 Induction of T-cells by SAg is the major histocompatibility class II molecule (MHCII) dependent on antigen presenting cells (APCs).8 SAg binds directly to the MHCII with high affinity for the HLADR type. It also binds in a unique fashion outside the

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conventional T-cell receptor grove.8 SAgs do not therefore require processing by the APCs in contrast to the conventional antigen. This allows rapid T-cell activation. Tcell recognition of antigen requires contribution from all the variable components of the T-cell receptor. However, SAgs stimulate T-cells in a Vβ specific manner. Therefore, SAg is specific to individual Vβ T-cell subsets. Since the Vβ T-cell repertoire is phenotypically varied between individuals it is likely that some patients have a genetic predisposition to SAg and possibly SIRS.9 SAg has been linked to a number of human diseases including staphylococcal food poisoning, toxic shock syndrome and Kawasaki syndrome. Additionally SAg has been linked with autoimmune disease such as rheumatoid arthritis and demyelinating diseases. However, the possibility of SAg mediating disease after severe injury has only been suggested.10 Animal studies have shown that following severe injury, the response to SAg is enhanced, and so predisposed to lethal shock. Therefore severe injury may not only cause the release of microbial products but may also sensitise the immune system to the effects of these products.10 Injured patients who develop Gram-positive sepsis have a worse outcome when compared to patients with Gramnegative sepsis.11 Such patients have a more profound state of shock and greater metabolic disturbance than patients with Gram-negative sepsis. These results suggest that Gram-positive bacterial products can create a more profound systemic immune activation and cytokine release than is produced by Gram-negative endotoxin in similar patients. Although SAg and endotoxin have very different mechanisms of immune activation; both may be present during polymicrobial sepsis. Furthermore, low doses of SAg combined with endotoxin have a synergistic effect.12 Murine models of sepsis demonstrate that, when combined, SAg and endotoxin create a lethal immune activation, which outweighs the sum of their individual effects. However, the reverse does not occur suggesting that there may be some common site of immune activation between SAg and endotoxin distinct from T-cells. Such a common site of interaction could be a valuable target for therapeutic intervention. Conceptually Gram-positive SIRS or a synergistic mixed bacterial SIRS would seem to fit clinical scenarios more closely than an isolated endotoxin-driven process. In addition, SAginduced SIRS introduces the possibility that the adaptive immune system may be a key regulator of systemic inflammation following injury; however, the role of alternative

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IJMS Journal Spring 2003

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MR Kell et al

bacterial products and T-cells in SIRS has, to date, been largely ignored in humans.

dysfunction. Eur J Vasc Endovasc Surg 2000; 19 (6): 619-24. 8.

Johnson HM, Torres BA, Soos JM. Superantigens: structure and relevance to human disease. Proc Soc Exp Biol Med 1996; 212: 99-109.

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Correspondence to: MR Kell, Department of Surgery, Mater Misericordiae Hospital, Eccles Street, Dublin 7, Ireland. Tel. (01) 830 1122.

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