T cell-mediated lethal shock triggered in mice by the superantigen staphylococcal enterotoxin B: critical role of tumor necrosis factor.

Miethke, Thomas; Wahl, Christian; Heeg, Klaus; Echtenacher, Bernd; Krammer, Peter H.; Wagner, Hermann

doi:10.1084/jem.175.1.91

Cited by 542 publications

(489 citation statements)

References 39 publications

(51 reference statements)

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“…Meanwhile, regular laboratory mice, which share B85% gene content with humans, 42 are not sensitive to invasive GAS infections 43,44 just as certain human populations are not good models for certain human diseases because of their genetic resistance. This natural resistance of mice to severe GAS sepsis can be overcome by the use of high infectious doses, less resistant strains or transgenic mice carrying human HLA class II 18 or human plasminogen.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

et al. 2007

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Variation in responses to pathogens is influenced by exposure history, environment and the host's genetic status. We recently demonstrated that human leukocyte antigen class II allelic differences are a major determinant of the severity of invasive group A streptococcal (GAS) sepsis in humans. While in-depth controlled molecular studies on populations of genetically wellcharacterized humans are not feasible, it is now possible to exploit genetically diverse panels of recombinant inbred BXD mice to define genetic and environmental risk factors. Our goal in this study was to standardize the model and identify genetic and nongenetic covariates influencing invasive infection outcomes. Despite having common ancestors, the various BXD strains (n strains ¼ 33, n individuals ¼ 445) showed marked differences in survival. Mice from all strains developed bacteremia but exhibited considerable differences in disease severity, bacterial dissemination and mortality rates. Bacteremia and survival showed the expected negative correlation. Among nongenetic factors, age -but not sex or weight -was a significant predictor of survival (P ¼ 0.0005). To minimize nongenetic variability, we limited further analyses to mice aged 40-120 days and calculated a corrected relative survival index that reflects the number of days an animal survived post-infection normalized to all significant covariates. Genetic background (strain) was the most significant factor determining susceptibility (Pp0.0001), thus underscoring the strong effect of host genetic variation in determining susceptibility to severe GAS sepsis. This model offers powerful unbiased forward genetics to map specific quantitative trait loci and networks of pathways modulating the severity of GAS sepsis.

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Section: Discussionmentioning

confidence: 99%

Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

et al. 2007

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“…For example, in studies using D-galN-sensitized mouse models, TNF-␣ blockade completely prevented SAg-induced TSS and death in conventional mice. 37 However, TNF-␣ blockade is ineffective or even counterproductive in S. aureus-induced sepsis in humans. 38 These discrepancies warrant an animal model that better recapitulates the disease in humans.…”

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confidence: 99%

Human Leukocyte Antigen Class II Transgenic Mouse Model Unmasks the Significant Extrahepatic Pathology in Toxic Shock Syndrome

Tilahun

Marietta

et al. 2011

The American Journal of Pathology

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Among the exotoxins produced by Staphylococcus aureus and Streptococcus pyogenes, the superantigens (SAgs) are the most potent T-cell activators known to date. SAgs are implicated in several serious diseases including toxic shock syndrome (TSS), Kawasaki disease, and sepsis. However, the immunopathogenesis of TSS and other diseases involving SAgs are still not completely understood. The commonly used conventional laboratory mouse strains do not respond robustly to SAgs in vivo. Therefore, they must be artificially rendered susceptible to TSS by using sensitizing agents such as D-galactosamine (D-galN), which skews the disease exclusively to the liver and, hence, is not representative of the disease in humans. SAg-induced TSS was characterized using transgenic mice expressing HLA class II molecules that are extremely susceptible to TSS without D-galN. HLA-DR3 transgenic mice recapitulated TSS in humans with extensive multiple-organ inflammation affecting the lung, liver, kidneys, heart, and small intestines. Heavy infiltration with T lymphocytes (both CD4 ؉ and CD8؉), neutrophils, and macrophages was noted. In particular, the pathologic changes in the small intestines were extensive and accompanied by significantly altered absorptive functions of the enterocytes. In contrast to massive liver failure alone in the D-galN sensitization model of TSS, findings of the present study suggest that gut dysfunction might be a key pathogenic event that leads to high morbidity and mortality in humans with

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“…Systemic injection of a superantigen leads to acute weight loss due to in vivo stimulation of T cells and release of interleukin-2 (IL2), IL6, and tumor necrosis factor a (TNFa) (40)(41)(42). The activation of macrophages by a superantigen is increased in the presence of T cells that bind the superantigen (57,58).…”

Section: Discussionmentioning

confidence: 99%

“…Superantigens are a group of molecules which, when bound to class I1 MHC molecules, stimulate T cells bearing particular TCR V, elements (39)(40)(41)(42)(43)(44)(45)(46). In addition, superantigens can transmit signals directly through class I1 MHC molecules, resulting in transcription of cytokines in monocytes (47) and T cells (48,49).…”

mentioning

confidence: 99%

T Cell Influence on Superantigen‐Induced Arthritis in MRL‐lpr/lpr Mice

Mountz

Zhou

Long

et al. 1994

Arthritis & Rheumatism

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Objective. To define the influence of the T cell receptor (TCR) and the lpr autoimmune gene on the induction and progression of superantigen-induced arthritis in V,8 transgenic MRL-lprllpr mice.Methods. The time to onset and the extent of synovial hyperplasia after the induction of arthritis by intraarticular injection of staphylococcal enterotoxin B (SEB) were compared in mice having T cells that bear the V, $ transgene alone (V@ TCR transgenic M R G +/+), the lpr gene without the Vs8 gene (nontransgenic MRL-lpr/lpr), both the Vs8 gene and the lpr gene Results. At day 30, increased synovial cells were observed in all SEB-treated mice, but the increase was greatest in the V@ transgenic MRGlprllpr mice. T cell involvement was indicated by the inability of either heat-denatured SEB or SEA to induce severe arthritis, the reduction in the severity of the arthritis on systemic treatment with CSA or anti-VgS, and the correlation of synovial hyperplasia with in vitro SEB reactivity of T cells.Conclusion. Theseobservations suggest that superantigens can induce chronic arthritis and that the induction and progression of the arthritis requires an underlying T cell defect in anergy induction in addition to exposure to the superantigen.

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T cell-mediated lethal shock triggered in mice by the superantigen staphylococcal enterotoxin B: critical role of tumor necrosis factor.

Cited by 542 publications

References 39 publications

Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

Human Leukocyte Antigen Class II Transgenic Mouse Model Unmasks the Significant Extrahepatic Pathology in Toxic Shock Syndrome

T Cell Influence on Superantigen‐Induced Arthritis in MRL‐lpr/lpr Mice

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