Atopic dermatitis (AD) and psoriasis are common chronic inflammatory skin diseases associated with significant morbidity and occupational disability. Colonization and infection with S. 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 Staphylococcus 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 different forms of psoriasis are associated with a selective expansion of T cells, we will assess the TCR Vbeta gene usage of T cells from peripheral blood and skin infiltrates of these two skin diseases and contrast these findings to irritant skin reactions in controls. Second, to determine whether the selective stimulation of T cells in AD vs psoriasis are clonotypic or diverse, we will clone and sequence the TCR transcripts amplified by PCR from AD and psoriatic skin lesions. Third, to investigate the role of bacterial toxins in AD and psoriasis, we will: a) correlate toxin secretion on the skin of patients with AD or psoriasis vulgaris with the TCR Vbeta gene usage in their skin infiltrate; b) determine whether strep pharyngitis-associated exacerbation of guttate psoriasis is associated with selective expansion of TCR Vbeta2 gene usage in peripheral blood and skin infiltrates, and correlate these with serologic changes in IgG anti-strep toxin responses and toxins secreted by streptococcal throat isolates; c) analyze the histologic and immunologic effects of staphylococcal and streptococcal toxins applied, by patch tests, to the skin of normal controls versus patients with psoriasis and AD. Fourth, to investigate the role of bacterial toxins in the allergic response of AD, we will determine the immunologic requirements for staphylococcal toxin- induced IgE synthesis by B cells from AD patients and normal controls. We will also determine whether there is any correlation between colonization with toxin-secreting S. aureus and the presence of IgE responses to particular allergens. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR041256-06
Application #
2429579
Study Section
Special Emphasis Panel (ZRG4-GMA-2 (01))
Project Start
1992-07-17
Project End
2000-05-31
Budget Start
1997-06-01
Budget End
1998-05-31
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206
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; 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
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
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