Aspects of Microbial Influence on Skin Disease

Sammanfattning: The skin constitutes an effective barrier mediating protection against environmental danger and foreign substances. At the surface of the skin, the residential microorganisms grow as small colonies and consist of various non-pathogenic bacteria, fungi and viruses. However, the cutis is also exposed to pathogenic microorganisms, and to combat this threat the residential cells of the epidermis have evolved several mechanisms to prevent infection. One of the primary strategies used by epidermal cells is secretion of antimicrobial peptides (AMPs). AMPs are small cationic peptides, 20 to 60 amino acids in length, with the capacity to kill microorganisms. Individuals with atopic dermatitis (AD), a chronic inflammatory skin disease characterized by a defective epidermal barrier and abnormalities in the innate and adaptive immune systems, are highly predisposed to colonization and penetration of the skin by pathogenic microorganisms and their allergens. The results presented in this thesis indicate that IgE sensitization to skin-associated microbial antigens in patients with AD has an impact on disease severity. Furthermore, we showed that glycosaminoglycans (GAGs), inhibit the antibacterial activity of LL-37 in biological fluids. In paper III, the fungus Candida was found to induce complement degradation, leading to the generation of C3a. In addition, C3a and C3a-derived peptides demonstrated antifungal activities. By modifications of the net charge, hydrophobicity, as well as helical propensity of C3a-derived peptides, it was possible to enhance the antifungal activities of peptides. Thymic stromal lymphopoietin (TSLP) is a cytokine expressed by epithelial cells and of importance in AD. Novel antimicrobial activity, preferentially against Gram-negative bacteria, was discovered for TSLP. TSLP was degraded into low-molecular weight fragments by proteases derived from skin-associated pathogens, as well as human neutrophil elastase. Microbial pathogens and their products play an influential role and are potential triggers for the maintenance of the inflammatory processes in skin diseases such as AD. Knowledge of interactions between components of host defense and microbial pathogens can potentially facilitate development of strategies to control the microbial impact in skin infection and inflammation.