Atopic dermatitis (AD) and psoriasis are common chronic inflammatory skin diseases associated with significant morbidity and occupational disability. Colonization and infection with Staphylococcus aureus and streptococci has been reported to exacerbate AD and psoriasis. The mechanisms by which bacteria participate in the pathogenesis of these skin diseases are unknown. Recent studies demonstrating that bacterial toxins can act as superantigens provide plausible mechanisms by which S. aureus and streptococci could mediate an inflammatory skin lesion which consists predominantly of activated T cells and monocytes. In particular, it has been shown that staphylococcal enterotoxins (SEs) can engage HLA-DR on macrophages to induce the release of cytokines and cause the selective stimulation of T cells expressing specific T cell receptor (TCR) Vbeta gene segments.
The specific aims will be: First, to determine whether AD and psoriasis is associated with the selective expansion of T cells, we will assess the TCR Vbeta usage of T cells from peripheral blood and skin infiltrates of these two skin diseases and contrast these findings to other inflammatory skin reactions. Second, to determine whether the selective stimulation of T cells is clonotypic or diverse, we will clone and sequence the individual TCR transcripts amplified by PCR from AD and psoriatic patients. Third, to investigate the role of bacterial toxins in AD and psoriasis, we will: a) determine whether S. aureus growing on the skin of patients with AD or psoriasis producer toxins known to act as bacterial superantigens, e.g., SEs; b) determine whether the TCR Vbeta gene usage of skin infiltrating T cells but not peripheral blood T cells from patients with AD and psoriasis reflect the superantigen growing on their skin; c) determine whether streptococcus-induced pharyngitis-associated exacerbation of guttate psoriasis is accompanied by preferential TCR Vbeta gene usage in blood and skin T cells which reflects the serologic change in IgG antistrep toxin responses. Fourth, to investigate the potential role of bacterial toxins in the pathogenesis of AD, we will analyze the profile of cytokines produced by peripheral blood and skin derived T cells stimulated with different SEs. We will also determine whether SEs induce IgE synthesis by B cells from AD patients and normal controls incubated in the presence or absence of IL-4. The role of bacterial toxins in the pathogenesis of human diseases are poorly understood. The skin is an important model to study the pathogenesis of immunologic reactions in tissues. Thus, the elucidation of immune mechanisms by which SEs exacerbate AD and psoriasis should have important consequences for the development of effective therapeutic modalities in the treatment of a variety of inflammatory diseases. In particular, identification of the T cells that react to S. aureus infection in AD or psoriasis, may allow us to more readily diagnose and treat those patients whose skin disease are flared by bacterial infection.
|Li, Jin; Zheng, Le; Uchiyama, Akihiko et al. (2018) A data mining paradigm for identifying key factors in biological processes using gene expression data. Sci Rep 8:9083|
|Dyjack, Nathan; Goleva, Elena; Rios, Cydney et al. (2018) Minimally invasive skin tape strip RNA sequencing identifies novel characteristics of the type 2-high atopic dermatitis disease endotype. J Allergy Clin Immunol 141:1298-1309|
|Berdyshev, Evgeny; Goleva, Elena; Bronova, Irina et al. (2018) Lipid abnormalities in atopic skin are driven by type 2 cytokines. JCI Insight 3:|
|Brauweiler, Anne M; Hall, Clifton F; Goleva, Elena et al. (2017) Staphylococcus aureus Lipoteichoic Acid Inhibits Keratinocyte Differentiation through a p63-Mediated Pathway. J Invest Dermatol 137:2030-2033|
|Huang, Amy; Cho, Christine; Leung, Donald Y M et al. (2017) Atopic Dermatitis: Early Treatment in Children. Curr Treat Options Allergy 4:355-369|
|Bin, Lianghua; Deng, Liehua; Yang, Hengwen et al. (2016) Forkhead Box C1 Regulates Human Primary Keratinocyte Terminal Differentiation. PLoS One 11:e0167392|
|Brar, Kanwaljit; Leung, Donald Y M (2016) Recent considerations in the use of recombinant interferon gamma for biological therapy of atopic dermatitis. Expert Opin Biol Ther 16:507-14|
|Bin, Lianghua; Leung, Donald Y M (2016) Genetic and epigenetic studies of atopic dermatitis. Allergy Asthma Clin Immunol 12:52|
|Brauweiler, Anne M; Goleva, Elena; Leung, Donald Y M (2016) Interferon-? Protects from Staphylococcal Alpha Toxin-Induced Keratinocyte Death through Apolipoprotein L1. J Invest Dermatol 136:658-664|
|Brauweiler, Anne M; Goleva, Elena; Hall, Clifton F et al. (2015) Th2 Cytokines Suppress Lipoteichoic Acid-Induced Matrix Metalloproteinase Expression and Keratinocyte Migration in Response to Wounding. J Invest Dermatol 135:2550-2553|
Showing the most recent 10 out of 179 publications