Bacterial superantigen facilitates epithelial presentation of allergen to T helper 2 cells

Abstract

Although clinical and laboratory evidence support roles for both staphylococcal infection and environmental allergens in the pathogenesis of atopic dermatitis, human studies have largely considered these variables independently. We sought to test the hypothesis that staphylococcal superantigen influences the allergen-specific T cell response. We first mapped a Der p 1 epitope and used HLA DRB1*1501 class II tetramer-based cell sorted populations to show that specific CD4 ؉ T cells were able to recognize the peptide presented by HLA DR-matched keratinocytes. We observed that staphylococcal enterotoxin B (SEB) enhanced the IL-4 Der p 1-specific T cell response. This response was mediated by two synergistic mechanisms: first, SEB-induced IFN-␥ promoted class II and intercellular adhesion molecule-1 expression by presenting keratinocytes; and second, SEB-induced IL-4 directly amplified allergen-specific CD4 ؉ T cell production of many cytokines. We propose that handling of staphylococcal infection is a critical step in the amplification of the allergen-specific T cell response, linking two common disease associations and with implications for the prevention and treatment of atopic disease.T here is convincing evidence that allergic reactivity to environmental challenge has a role in the pathogenesis of atopic dermatitis (AD). For example, the histology of AD shares many features with classic allergic contact delayed-type hypersensitivity, including spongiosis and a dominant T cell inflammatory infiltrate that is distributed predominantly in a dermal, and to a lesser extent epidermal pattern. Approximately 80% of individuals with AD have circulating specific IgE recognizing one or more of house dust mite, cat, dog, grass, and other ubiquitous environmental allergens (1). In many studies, allergen-specific CD4 ϩ and CD8 ϩ T cells have been documented to be present in the peripheral blood and lesional skin of affected individuals and to produce diverse cytokines but with a frequent T helper 2 (Th2) dominance (2, 3). House dust mite extract application to the skin of individuals with AD can reproduce eczematous changes (4, 5), and allergen avoidance has been shown by some to be partially effective (6, 7). Keratinocytes have been shown to up-regulate HLA class II and intercellular adhesion molecule-1 (ICAM-1) in AD and other inflammatory dermatoses (8, 9) and also in response to injection of IFN-␥ into normal skin (10). However, in isolation, allergic reactivity to an environmental challenge does not explain all of the features of AD. Twenty percent of affected individuals do not generate IgE responses to such ubiquitous proteins, and it is unclear why disease incidence changes during age and between different geographical regions. The risk of disease is clearly influenced by genetic susceptibility factors, some of which affect the immune response, e.g., polymorphisms of the Fc R1 and IL-4R genes (11-13). However, it is becoming increasingly clear from the genetic studies that skin-specific genes, determining variables s...

Current understanding in pathogenesis of atopic dermatitis

“…There are synergistic processes to drive AD, for example, S. aureus produces enterotoxin which has been shown to induce the production of enterotoxin-specific IgE resulting in proliferation and recruitment of more T-cells and aggravation of dermatitis. [39]…”

Mechanisms of Contact Sensitization Offer Insights into the Role of Barrier Defects vs. Intrinsic Immune Abnormalities as Drivers of Atopic Dermatitis

“…Th2 signaling has been demonstrated to produce many of the molecular findings seen in AD skin, with the exception of the characteristic epidermal hyperplasia. Allergen-specific Th2 T-cells can be found in AD but not in non-atopic controls (Ardern-Jones et al , 2007). More recently, Th22 T-cells and their cytokine, IL-22, have been shown to play a key role in the pathogenesis of AD, potentially accounting for the increased epidermal thickness.…”

Common Filaggrin Null Alleles Are Not Associated with Hymenoptera Venom Allergy in Europeans

“…The prevailing disease model is that filaggrin insufficiency results in barrier dysfunction of the skin, which predisposes to allergen penetration, sensitisation and cutaneous inflammation. This results in further barrier dysfunction [3,6]. However, whilst this is a plausible model, most forms of barrier dysfunction do not lead to sensitisation to common allergens.…”