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T cell-mediated lethal shock triggered in mice by the superantigen staphylococcal enterotoxin B: critical role of
1Institute of Medical Microbiology and Hygiene, Technischen, Universität Munich, Germany.
Abstract:
Because mice are more resistant than humans to the pathogenic effects of bacterial toxins, we used D-Galactosamine- (D-Gal) sensitized mice as a model system to evaluate potential toxic shock symptoms triggered by the superantigen staphylococcal enterotoxin B (SEB). We show that similar to endotoxin (lipopolysaccharide) [LPS], the exotoxin SEB causes lethal shock within 8 h in D-Gal-sensitized mice, inducing 100% and about 50% lethality with 20 and 2 micrograms SEB, respectively. The lethal shock triggered by the superantigen SEB is mediated by T cells, a conclusion based on the observation that T cell repopulation of SCID mice conferred sensitivity to SEB. Since CSA also conferred protection, the role of T cell-derived lymphokines in mediating lethal shock was evaluated. Within 30-60 min after SEB injection, serum tumor necrosis factor (TNF) levels peaked, followed immediately by interleukin-2 (IL-2). Serum-borne lymphokines were detected well in advance of signs of T cell activation, as assessed by IL-2 receptor expression of SEB-reactive V beta 8+ T cells. Passive immunization with anti-TNF-alpha/beta-neutralizing monoclonal antibody also conferred protection, indicating that it is TNF which is critical for initiating toxic shock symptoms. Taken together, this study defines basic differences between endotoxin (LPS)- and exotoxin (SEB)-mediated lethal shock, in that the former is mediated by macrophages and the latter by T cells. Yet the pathogenesis distal to the lymphokine/cytokine-producing cells appears surprisingly similar in that TNF represents a key mediator in inducing shock.
Insights
Staphylococcal enterotoxin B (SEB) causes lethal toxic shock in D-Galactosamine-sensitized mice, mediated by T cells and tumor necrosis factor (TNF). This reveals key differences in lethal shock pathways compared to endotoxin.
Area of Science:
- Immunology
- Toxicology
- Microbiology
Background:
- Mice exhibit higher resistance to bacterial toxins than humans.
- D-Galactosamine-sensitized mice serve as a model for human responses to toxins.
- Staphylococcal enterotoxin B (SEB) is a superantigen with potent toxic effects.
Purpose of the Study:
- To investigate toxic shock symptoms induced by SEB in a mouse model.
- To elucidate the mechanisms underlying SEB-induced lethal shock.
- To compare SEB-induced shock with endotoxin (lipopolysaccharide)-induced shock.
Main Methods:
- Administration of SEB to D-Galactosamine-sensitized mice.
- Evaluation of lethality and shock symptoms.
- T cell repopulation of SCID mice to assess T cell mediation.
- Measurement of serum cytokine levels (TNF, IL-2).
- Passive immunization with anti-TNF-alpha/beta monoclonal antibodies.
Main Results:
- SEB caused lethal shock in D-Gal-sensitized mice, with dose-dependent lethality.
- T cell mediation of SEB-induced shock was confirmed by SCID mouse experiments.
- Tumor necrosis factor (TNF) peaked early after SEB injection and was critical for shock.
- Interleukin-2 (IL-2) levels followed TNF, preceding T cell activation markers.
- Anti-TNF antibodies protected mice, highlighting TNF's central role.
Conclusions:
- SEB-induced lethal shock is T cell-mediated, distinct from macrophage-mediated endotoxin shock.
- TNF is a critical initiator of SEB-induced toxic shock symptoms.
- Despite differing cellular mediators, the downstream pathogenesis of SEB and LPS shock converges on TNF.