Transcytosis of Staphylococcal Superantigen Toxins

Hamad, Abdel Rahim A.; Marrack, Philippa; Kappler, John W.

doi:10.1084/jem.185.8.1447

Cited by 124 publications

(99 citation statements)

References 46 publications

(41 reference statements)

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Section: Discussionmentioning

confidence: 99%

“…However, we also investigated the effect of SEB pretreatment in our model of oral tolerance and airway allergy and found that SEB was less effective and less reliable in improving oral tolerance compared with SEA (unpublished data). The greater efficiency of SEA might be due to the fact that SEA can reside in the gut, whereas SEB is more readily transcytosed over the gut epithelium and enters the blood stream [33].Extensive variability between individual mice in the response to antigen challenge characterised the orally tolerised sham pretreated mice, wheras SEA pre-treated mice were remarkably tolerant with a minimal spread among individual animals. It seems as though SEA pre-treatment maximises the capacity to develop tolerance after feeding, whereas the process is more variable in efficiency in control mice, probably due to individual differences regarding conditions prevailing in the gut at the time point for tolerisation.…”

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Neonatal exposure to staphylococcal superantigen improves induction of oral tolerance in a mouse model of airway allergy

et al. 2009

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The hygiene hypothesis suggests that lack of microbial stimulation in early infancy may lead to allergy, but it has been difficult to identify particular protective microbial exposures. We have observed that infants colonised in the first week(s) of life with Staphylococcus aureus have lower risk of developing food allergy. As many S. aureus strains produce superantigens with T-cell stimulating properties, we here investigate whether neonatal mucosal exposure to superantigen could influence the capacity to develop oral tolerance and reduce sensitisation and allergy. BALB/c mice were exposed to staphylococcal enterotoxin A (SEA) as neonates and fed with OVA as adults, prior to sensitisation and i.n. OVA challenge. Our results show that SEA pre-treated mice are more efficiently tolerised by OVA feeding, as shown by lower lung-cell infiltration and antigen-specific IgE response in the SEA pre-treated mice, compared with sham-treated mice. This was not due to deletion or anergy of lymphocytes by SEA treatment, because the SEA pre-treated mice that were fed with PBS showed similar inflammatory response as the sham-treated PBS-fed mice. Our results suggest that strong T-cell activation in infancy conditions the mucosal immune system and promotes development of oral tolerance.Key words: Allergic sensitisation . Mucosal immunity . Staphylococcal enterotoxin A . Tolerance Supporting Information available online IntroductionAllergies have increased markedly in Western industrialised countries, where they now afflict every third child. Allergies are linked to wealth, good education and small families, observations that have given rise to the hygiene hypothesis, according to which the developing immune system should be exposed to appropriate microbial stimulation in early childhood in order to mature correctly and for allergies to be avoided [1,2]. The hygiene hypothesis is also supported by experimental data. Germ-free animals are less prone to develop oral Ã These author contributed equally to this work. Eur. J. Immunol. 2009. 39: 447-456 DOI 10.1002 Immunomodulation 447 tolerance than animals reared conventionally [3,4]. Oral tolerance is induced by passage of antigens over the gut mucosa, prevents against both Th1-and Th2-dominated immune responses [5] and includes development of Treg [6,7]. Natural thymic-dependent Treg (CD4 1 CD25 hi FoxP3 1 ) are fundamental in protection against autoimmunity, gut inflammation and IgE responses. This cell subset has reduced functional capacity in germ-free animals [8].The strongest T-cell activators known are the ''superantigens'', exotoxins produced by certain pathogenic bacteria such as Staphylococcus aureus. These include staphylococcal enterotoxin A, B, C, D and E, as well as toxic shock syndrome toxin-1. The superantigen binds to the variable part of the TCR and to the MHC class II molecule, thereby ''mimicking'' antigen recognition, which leads to T-cell activation [9][10][11][12]. As many as 10-30% of all T cells can become activated by a certain superantigen compared with o0...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Neonatal exposure to staphylococcal superantigen improves induction of oral tolerance in a mouse model of airway allergy

et al. 2009

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“…Moreover, multiple lines of evidence have accumulated to suggest that staphylococcal enterotoxins can cross the epithelial barrier in an immunologically intact form through transcytosis (33,34). Thus, the probability that staphylococcal enterotoxin can directly interact with the second layer of nonprofessional immunological defense, e.g., IMFs, is high.…”

Section: Discussionmentioning

confidence: 99%

“…IMFs form an interface between the epithelium and lamina propria immune cells and have been implicated in the regulation of mucosal inflammation (31,32). Thus, given the unique subepithelial location of MHC class II ϩ IMFs with respect to mucosal lymphocytes, as well as the fact that staphylococcal enterotoxins can cross the intestinal epithelial barrier in immunologically active form (33,34) and increase epithelial permeability (35)(36)(37), it is important to study the role of IMFs in the initiation of the staphylococcal enterotoxin-associated immunopathogenesis.…”

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confidence: 99%

Monocyte Chemoattractant Protein-1 Production by Intestinal Myofibroblasts in Response to Staphylococcal Enterotoxin A: Relevance to Staphylococcal Enterotoxigenic Disease

Pinchuk¹,

Beswick²,

Saada³

et al. 2007

The Journal of Immunology

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Food poisoning due to staphylococcal enterotoxins A and B (SEA and SEB) affects hundreds of thousands of people annually. SEA and SEB induce massive intestinal cytokine production, which is believed to be the key factor in staphylococcal enterotoxin enteropathy. MHC class II molecules are the major receptors for staphylococcal enterotoxins. We recently demonstrated that normal human subepithelial intestinal myofibroblasts (IMFs) express MHC class II molecules. We hypothesized that IMFs are among the first cells to respond to staphylococcal enterotoxins and contribute to the cytokine production associated with staphylococcal enterotoxin pathogenesis. We demonstrated here that primary cultured IMFs bind staphylococcal enterotoxins in a MHC class II-dependent fashion in vitro. We also demonstrated that staphylococcal enterotoxins can cross a CaCo-2 epithelial monolayer in coculture with IMFs and bind to the MHC class II on IMFs. IMFs responded to SEA, but not SEB, exposure with 3- to 20-fold increases in the production of proinflammatory chemokines (MCP-1, IL-8), cytokines (IL-6), and growth factors (GM-CSF and G-CSF). The SEA induction of the proinflammatory mediators by IMFs resulted from the efficient cross-linking of MHC class II molecules because cross-linking of class II MHC by biotinylated anti-HLA-DR Abs induced similar cytokine patterns. The studies presented here show that MCP-1 is central to the production of other cytokines elicited by SEA in IMFs because its neutralization with specific Abs prevented the expression of IL-6 and IL-8 by IMFs. Thus, MCP-1 may play a leading role in initiation of inflammatory injury associated with staphylococcal enterotoxigenic disease.

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“…Recently, SEB has been shown to cross the intestinal epithelial cell barrier (38) and stimulate T cells (39 -41), leading to the activation of T cells producing IFN-␥ and IL-2 (42). Based on the results presented in this report, any stimulation that activates a relatively large subset of T cells generates autoreactive T cells that proliferate when re-exposed to self Ags expressing class II MHC.…”

Section: Discussionmentioning

confidence: 99%

Staphylococcal Enterotoxin B Stimulates Expansion of Autoreactive T Cells That Induce Apoptosis in Intestinal Epithelial Cells: Regulation of Autoreactive Responses by IL-10

Ito

Takaishi

Jin

et al. 2000

The Journal of Immunology

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T cell responses to self Ags and normal microbial flora are carefully regulated to prevent autoreactivity. Because IL-10-deficient mice develop colitis, and this response is triggered by luminal flora, we investigated whether IL-10 regulates the ability of microbial Ags to induce autoreactive T cells that could contribute to intestinal inflammation. T cells from wild-type mice were primed with staphylococcal enterotoxin B (SEB) in vitro, which induced an autoreactive proliferative response to syngeneic feeder cells. The cells were predominately CD3+ and CD4+. T cells from IL-10-deficient mice were constitutively autoreactive, and SEB priming enhanced this further. The autoreactive, proliferative response of T cells from wild-type mice was suppressed by IL-10 in the primary or secondary culture, and this effect was inhibited by neutralizing Abs to the IL-10R. To confirm that an autoreactive repertoire was expanded after SEB priming, we used CBA/J mice (Mls-1a) in which autoreactive T cells recognizing the endogenous viral superantigen are depleted (Vβ6, 7, 8.1 TCR-bearing cells). However, SEB rescued these autoreactive T cell repertoires. Adding anti-MHC class II Ab blocked the autoreactive response. SEB-primed splenic or colonic T cells also induced apoptosis in syngeneic intestinal epithelial cells that was blocked significantly by IL-10. Thus, microbial Ags have the potential to abrogate self tolerance by stimulating autoreactive T cells that become cytolytic to target cells. IL-10 plays a protective role in maintaining self tolerance after microbial stimulation by preventing the activation of T cells that contribute to epithelial cell damage.

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Transcytosis of Staphylococcal Superantigen Toxins

Cited by 124 publications

References 46 publications

Neonatal exposure to staphylococcal superantigen improves induction of oral tolerance in a mouse model of airway allergy

Neonatal exposure to staphylococcal superantigen improves induction of oral tolerance in a mouse model of airway allergy

Monocyte Chemoattractant Protein-1 Production by Intestinal Myofibroblasts in Response to Staphylococcal Enterotoxin A: Relevance to Staphylococcal Enterotoxigenic Disease

Staphylococcal Enterotoxin B Stimulates Expansion of Autoreactive T Cells That Induce Apoptosis in Intestinal Epithelial Cells: Regulation of Autoreactive Responses by IL-10

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