Adequate immune responses control infections, eliminate pathogens and ensure the integrity of the host. In contrast, inadequate immune responses against foreign antigens may lead to the development of allergy while inadequate immune responses against self-antigens may result in the onset of autoimmunity. Accumulating evidence suggests that infections and dysbiosis critically modulate the development of allergy as well as autoimmunity. Although the concepts are intriguing, the underlying mechanisms remain largely elusive.
The skin provides a first line of defence against microbial pathogens and represents a frequent site for the development of allergy and autoimmunity. Its easy accessibility makes the skin an ideal organ system for studies aiming to unravel pathogen-host interactions in the establishment and persistence of allergic and autoimmune disorders.
The clinical phenotype and natural history of skin-related allergic diseases, such as atopic dermatitis (AD)(1), or skin-related autoimmunity, such as psoriasis (PSO)(2), are extremely well characterized and significant advances with regard to the identification of genetic susceptibility foci have been achieved. This unique situation offers for the first time the opportunity to directly link susceptibility genes with altered hosts’ response against pathogens during the establishment and persistence of skin-related allergy and autoimmunity.
Our overall goal is to unravel the inflammatory pathways during the host-pathogen interactions which may trigger allergic or autoimmune inflammation using AD (surrogate for allergic diseases) and PSO (surrogate for autoimmune diseases) as disease models. We will identify key microbes and molecular targets to develop novel intervention strategies with the expected impact of delaying the onset of these diseases and improving quality of life.
Specific objectives of the present project are following:
• In clinical studies we will generate highly standardized and genetically stratified clinical sample material to unravel the role of microbiomes in the pathogenesis of AD and PSO. Samples from three European countries will be studied to reduce the possibility of population-based systematic errors in results. (WP1)
• We will characterize the skin microbiome from patients and healthy subjects using state-of-the-art high-throughput sequencing techniques. We will also sequence virus enriched serum samples from the same individuals to identify potentially relevant viruses. (WP2)
• We will perform gene expression profiling using DNA microarrays and high-throughput DNA sequencing to investigate microbe-regulated pathways in AD and PSO in genetically susceptible versus non-susceptible backgrounds. We will investigate expression profiles both from skin biopsies as well as from microbe stimulated skin explants from patients and from controls. Finally, we will explore kinetics of microbial-induced transcriptional network in primary keratinocytes by
• We will use advanced bioinformatics tools and systems biology methods to connect the different datasets from different WPs to identify key disease associated microbe as well as key gene targets. Reverse engineering methods will be also used in order to infer pathogenic stimuli from transcriptional profiles generated from lesional skin samples. (WP4)
• Identified molecular and microbial targets will be validated in vitro in cellular models relevant for AD and PSO. We will investigate the activation and regulation of antimicrobial defence molecules and cytokine networks in AD and PSO. Moreover, cellular interactions in the pathophysiology of AD and PSO will be investigated. (WP5)
• We will utilize established animal models of AD and PSO to unravel and validate molecular mechanisms and to test therapeutic targets to interfere with diseases processes of AD and PSO. Gene-targeted as well as transgenic mice, xenotransplant models and neutralizing antibodies will be used. (WP6)