Staphylococcal Toxins and Protein A Differentially Induce Cytotoxicity and Release of Tumor Necrosis Factor–α From Human Keratinocytes

It has been proposed that toxins and other bacterial protein products of Staphylococcus aureus can act as triggers or persistence factors in several inflammatory skin diseases. In this study, we examined the S. aureus isolates from the skin of patients with atopic dermatitis and psoriasis. We found that the bacterial isolates from these patients exihibited either characteristics superantigenic toxins or thermolabile toxins believed to be staphylococal α-toxin. All of these staphylococcal strains also secreted extracellular staphylococcal protein A. We found significant differences in the action of these toxins on human keratinocytes and keratinocyte cell lines. The superantigenic toxins toxic shock syndrome toxin–1, staphylococcal enterotoxins A and B, and exfoliative toxin–A. as well as staphylococcal protein A, did not induce significant cytotoxic damage in the keratinocyte cell line HaCaT, whereas the staphylococcal α-toxin produced profound cytotoxicity. Keratinocyte cytotoxity induced by staphylococcal α-toxin was time and concentration dependent and demonstrated the morphologic and functional characteristics of necrosis, not apoptosis. Addition of α-toxin to keratinocytes simultaneously induced cell lysis and tumor necrosis factor–α release into the medium within 30 min; apparently, it was constitutive tumor necrosis factor–α. On the other hand, superantigenic toxins and, in particular, protein A showed stimulation of tumor necrosis factor-α secretion in keratinocytes and release of this cytokine after 6–12h of incubation. Thus, staphylococcal protein A, α-toxin, and superantigenic toxins found in S. aureus isolates from patients with psoriasis and atopic dermatitis can produce direct pro-inflammatory effects on kerationcytes through the release of tumor necrosis factor–α. We propose that these effects may be relevant to the induction and persistence of lesions in these two disease

Augmentation of Staphylococcal α-Toxin Signaling by the Epidermal Platelet-Activating Factor Receptor

Staphylococcal α-toxin is a cytolytic toxin secreted by many strains of Staphylococcus aureus that has proinflammatory and cytotoxic effects on human keratinocytes. α-toxin exerts its effects by forming a transmembrane pore that behaves like an ionophore for ions such as calcium. Because cellular membrane disruption with resultant intracellular calcium mobilization is a potent stimulus for the synthesis for the lipid mediator platelet-activating factor, the ability of α-toxin to induce platelet-activating factor production was assessed, and whether the epidermal platelet-activating factor receptor could augment toxin-induced signaling in epithelial cells examined. Treatment of the human keratinocyte-derived cell line HaCaT with α-toxin resulted in significant levels of platelet-activating factor, which were approximately 50% of the levels induced by calcium ionophore A23187. α-toxin also stimulated arachidonic acid release in HaCaT keratinocytes. Pretreatment of HaCaT cells with platelet-activating factor receptor antagonists, or overexpression of the platelet-activating factor metabolizing enzyme acetylhydrolase II blunted α-toxin-induced arachidonic acid release by approximately one-third, suggesting a role for toxin-produced platelet-activating factor in this process. Finally, retroviral-mediated expression of the platelet-activating factor receptor into the platelet-activating factor receptor-negative epithelial cell line KB resulted in an augmentation of α-toxin-mediated intracellular calcium mobilization and arachidonic acid release. These studies suggest that α-toxin-mediated signaling can be augmented via the epidermal platelet-activating factor receptor

Modulation of Contact Sensitivity Responses by Bacterial Superantigen

Superantigens are potent modulators of the immune system, especially T cells. Therefore, we determined the influence of superantigens on the T-cell-mediated immune response, contact sensitivity. We chose the combination of staphylococcal enterotoxin B (SEB) as superantigen and 2,4-dinitrofluorbenzene (DNFB) as the contact sensitizer, because in BALB/c mice SEB reacts almost exclusively with Vβ8+ T cells, and these cells are capable of transferring contact sensitivity to DNFB from sensitized donors to naive syngeneic recipients. Pretreatment with a single intradermal injection of 50 ng SEB 24 h before DNFB exposure at the same site on the lower abdomen enhanced the induction of contact sensitivity: its intradermal injection permitted sensitization with non-sensitizing concentrations of DNFB as assessed by ear swelling responses after challenge with DNFR. In contrast, pretreatment with repeated intradermal injections of 50 ng SEB every other day over at least 1 week inhibited the induction of contact sensitivity following sensitization. The enhancing effect of SEB may be explained by the creation of a proinflammatory milieu in the skin after a single intradermal injection of the bacterial toxin, whereas the inhibitory effect may be due to tolerization of Vβ8+ T cells. The data indicate that products of skin-colonizing bacteria that can serve as superantigens are able to augment or inhibit the development of contact sensitivity

Early-life gut microbiome composition and milk allergy resolution

Gut microbiota may play a role in the natural history of cow’s milk allerg

Impact of Allergic Reactions on Food-Specific IgE Concentrations and Skin Test Results

Although there is concern that food allergic reactions may negatively affect the natural history of food allergy, the impact of reactions on food-specific IgE (sIgE) or skin prick tests is unknown

Long-term treatment with egg oral immunotherapy enhances sustained unresponsiveness that persists after cessation of therapy

We previously reported results of a randomized, placebo-controlled study of egg oral immunotherapy (eOIT), in which 27.5% of subjects achieved sustained unresponsiveness (SU) after 2 years. Here we report results of treatment through 4 years and long-term follow-up