Allergic skin diseases : studies on mechanisms in experimental atopic dermatitis and allergic contact dermatitis
Year: 2012
Type: dissertation
Abstract: Atopic dermatitis (AD) is an allergic skin disease, characterized by relapsing eczema, dry skin and chronic skin inflammation. A large proportion of AD patients develop other allergies or asthma later in life. Allergic contact dermatitis (ACD) in turn, is one of the leading occupational diseases worldwide. Therefore, allergic skin diseases not only impair the quality of life of patients but also cause a great economical burden for the society. This thesis investigates some of the mechanisms behind allergic skin diseases. In an AD-model, an AD-like skin inflammation was induced by mechanical skin injury and epicutaneous sensitization. This induced a Th2 cytokine dominated inflammatory response at the site of allergen exposure, and elevation of allergy-related IgE antibody levels in the serum. The effects of skin colonizing bacteria Staphylococcus aureus derived enterotoxin B (SEB) were evaluated on the inflammatory response in AD-model. SEB application significantly exacerbated the allergen induced inflammatory response in the skin, increasing cellular infiltration, enhancing Th2 cytokine production and provoking Th1 cytokine production. Furthermore, SEB induced the production of SEB-specific IgE antibodies and enhanced the production of allergen-specific IgE antibodies. These results demonstrate that bacterial skin colonization may both augment the inflammatory response in AD patients and play a role in the chronification of the disease. Although regulatory T cells (Treg) are known to prevent allergic responses, their role in AD is still not clear. We utilized DEREG mice, in which the Foxp3+ Treg cells can be transiently depleted, to study the role of Foxp3+ Treg cells in the AD-like skin inflammation. The epidermal barrier in AD patients is often damaged by scratching or genetic defect. We observed that in the absence of Foxp3+ Treg cells, the skin injury alone induced a stronger inflammation compared with WT. The addition of allergen further enhanced the inflammatory response and especially increased the production of Th2 cytokines, suggesting that Foxp3+ cells are also essential in controlling the allergic responses in the skin. In addition, when allergen was administered into the lungs at a time point when the Treg compartment had been restored, augmented inflammatory response was observed in the lungs, indicating, that impaired Foxp3+ Treg function during skin sensitization may modulate the possible asthma responses developing later on. In the ACD-model, the skin inflammation was induced by epicutaneous application of oxazolone in two phases: sensitization, when memory cells against the hapten were generated and elicitation, when the same hapten was applied on the skin, resulting in a clinically observed inflammatory response. The role of Foxp3+ Treg cells was studied in these two phases and also in the clearance of the inflammation. The absence of Foxp3+ Treg cells in the sensitization phase dramatically exacerbated the skin inflammation, whereas the absence in the elicitation phase had no effect on the inflammatory response during the first 24 hours post challenge. Instead, both depletions severely impaired the resolution of the inflammation, most likely due to the impaired ability of restored Foxp3+ Treg cells to accumulate in the skin. These results reveal that Foxp3+ Treg cells are crucial during the sensitization phase in the LNs and during the resolution phase in the skin. CCR4 is a chemokine receptor which together with chemokine receptor CCR10 is involved in lymphocyte trafficking into the skin. Surprisingly, the ACD response in CCR4 knock-out mice was exacerbated as compared with WT. When the inflammatory response was followed at different time points after sensitization and challenge, increased proliferation of CD4+ cells was observed in CCR4-/- mice, indicating that CCR4 is somehow involved in the regulation of CD4+ cells during ACD responses.
Source: Työväentutkimus Vuosikirja
Author: Sari Lehtimäki
Language: English
Subfield: Dermatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1593977489